Healthcare analytics, AI solutions for biological big data, providing an AI platform for the biotech, life sciences, medical and pharmaceutical industries, as well as for related technological approaches, i.e., curation and text analysis with machine learning and other activities related to AI applications to these industries.
Immunomodulatory Therapeutic Antibodies for Cancer
Scientific Strategies for Discovering and Developing Novel Immunotherapies and Agents to Improve the Efficacy and Toxicology Profiles of T Cell-Targeted Biotherapeutics August 28-29, 2017 Sheraton Boston Hotel | Boston, MA
Checkpoint inhibitors and other immune-oncology agents have shown significant promise in the treatment of a variety of cancers. However, many of these agents are only effective when an existing host immune response has already been induced by other therapeutic approaches. I will discuss strategies that may be used to effectively set the stage for immune-oncology treatments including Eleven BioTherapeutics’ Targeted Protein Therapeutics.
9:00 Immunomodulatory Antibodies – Potentiation by Fc Receptor Engagement
Rony Dahan, Ph.D., Principal Investigator, Immunology, Weizmann Institute of Science, Israel
Immunomodulatory mAbs are revolutionizing cancer treatment due to their clinical effective stimulation of therapeutic anti-cancer immunity. Recent studies demonstrated the importance of the Fc domain of these types of mAbs. Their optimal activity can be critically depended on their ability to engage defined FcgR pathways. I will discuss our recent characterization of these FcgR-dependent mechanisms, and how they can be exploited for introducing second generation Fc-optimized immunomodulatory mAbs.
9:30 Coffee Break
MECHANISMS OF ACTION
10:00 The Role of Metabolism in Immune Response in Tumors: Merging the Past and the Present of Tumor Microenvironment
Allison S. Betof, M.D., Ph.D., Medical Oncology Fellow, Memorial Sloan Kettering Cancer Center
Tumors are not simply collections of cancer cells that arise in a vacuum; they are instead complex structures composed of blood vessels, immune cells, and other supporting structures that interact, consume oxygen and other nutrients, and produce waste. Tumor metabolism has long been viewed as a therapeutic target. I will discuss recent data on how metabolism influences immunobiology and our group’s approach to harness these interactions to improve therapeutic outcomes.
10:30 PI3Kgamma Is a Molecular Switch that Controls Immune Suppression
Megan M. Kaneda, Ph.D., Assistant Project Scientist, University of California, San Diego
Macrophages play critical but opposite roles in inflammation and cancer. We have found that the predominant isoform of PI3K in myeloid cells, PI3Kgamma, controls the switch between immune stimulation and immune suppression. Inhibition of macrophage PI3Kgamma activity promotes an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity and synergizes with checkpoint inhibitor therapy to promote tumor regression and extend survival in mouse models of cancer.
11:00 Avelumab (hIgG1 Anti-human PD-L1) Mediates the anti-Tumor Efficacy via Multiple Pathways in Preclinical Models
Yan Qu, Ph.D., Senior Principal Scientist, Pfizer
Analysis of PD-L1 expression on various immune subpopulations in human patient samples showed that PD-L1 is enriched on non-T cells. In tumor-bearing mice, the percentage of splenic NK cells was increased with WT avelumab treatment but not with the Fc isotype variant. Avelumab-induced tumor shrinkage, tumor-infiltrating CD8+ T cell increase, and tumor PD-L1+ immature myeloid cell decrease appear to require NK cells, as such changes were abolished upon NK depletion.
11:30 Epitope Identification and Clinical Immune Monitoring in Immune Oncology Programs
TARGET DISCOVERY FOR NEXT GENERATION IMMUNOTHERAPIES
1:25 Chairperson’s Remarks
Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom
1:30 Functional Characterization of Macaque Fcr and IgG Subtypes
Margie Ackerman, Ph.D., Assistant Professor, Engineering, Dartmouth College
A number of antibody therapies rely on Fc receptor (FcR)-mediated effector functions for optimal activity, prompting the need to understand how native and IgG domains engineered to differentially bind to the human receptors translate in non-human primate (NHP) models. We report characterization of the affinity between an IgG Fc variant panel (including subclass, Fc mutants and glycosylation) and major human and rhesus FcR allotypic variants.
2:00 Utilizing Patient-Derived Organoids and High-Content Imaging for Screening and Characterization of Bispecific Antibodies
Mark Throsby, Ph.D., EVP & CSO, Merus N.V., The Netherlands
This presentation will provide a case study on how panels of patient-derived organoids grown ex-vivo in 3D culture combined with high-content imaging can be applied to bispecific antibody screening. Lead candidate bispecifics were selected targeting the wnt pathway with novel modes of action including immunomodulation.
2:30 Discovery and Development Strategies for New Small Molecule Immunotherapies
Small molecules are of interest as immunotherapies as both single agent and combinations, offering the possibility of modulating different aspects of the immune system to biologics. We are exploring targeting a number of different immunomodulatory mechanisms with small molecules derived using fragment-based drug design and will describe examples in this presentation.
3:30 STING Adjuvants for Immune System Priming for Antibody Therapy
Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom
Successful tumor-targeting antibody approaches appear to rely predominantly on the effector function of Fcγ receptor (FcγR) expressing macrophages. Unfortunately, tumor-associated macrophages (TAM) are frequently poorly cytotoxic, contribute to immune suppression and have suboptimal FcγR expression making treatment less effective. Here we show that STING agonists are able to overcome immunosuppression in the tumour microenvironment effectively reversing the TAM inhibitory FcγR profile and provided strong adjuvant effects to antibody therapy.
4:00 Next-Generation Cancer Vaccines
Daniel L. Levey, Ph.D., Senior Director, Vaccine Research, Agenus
Agenus is advancing two fully synthetic cancer vaccine platforms. The first is based on identification of mutations encoded in the tumor genome while the second relates to a novel class of tumor specific neo-epitopes arising from inappropriate phosphorylation of various proteins in malignant cells. The platforms support the manufacture of both individualized and off-the-shelf cancer vaccines against a range of tumor antigens, increasing the likelihood of immune recognition of tumors.
4:30 Oral T Cell Vaccines Targeting Immune Organs of the Gut for Generating Systemic Antigen Specific T Cells
Marc Mansour, Ph.D., Chief Business Officer, Vaximm AG
We use attenuated Salmonella typhi Ty21 as a vector to deliver a plasmid encoding antigens of interest via the oral route to Peyer’s patches. The bacteria have built in adjuvant properties and induce cross presentation to produce a systemic T cell response. Monotherapy with a candidate targeting VEGFR2 produced clinical responses in GBM, highlighting the unique properties of this T cell vaccine approach.
7:25 am Breakout Discussion Groups with Continental Breakfast
Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are below.
New Understandings of the Mechanisms of Action for Immunomodulatory Antibodies
Moderator: Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom
What are we learning about MOA from clinical trial data?
Optimizing MOA in next generation immunomodulators
The role of effector and receptor engagement
MOA and bispecific antibody design
Overcoming resistance mechanisms
Target Discovery for Next Generation Immunotherapies
Marc Mansour, Ph.D., Chief Business Officer, Vaximm AG
Tumor antigen identification: strengths and weaknesses of different methodologies
Drugable IO targets- using macromolecules versus small molecule
Novel targets in the tumor microenvironment
NON-RESPONDERS, SIDE EFFECTS AND TOXICOLOGY
8:25 Chairperson’s Opening Remarks
Adam J. Adler, Ph.D., Professor, Immunology, University of Connecticut
8:30 Cancer Immunotherapy with Live-attenuated, Double Deleted Listeria Monocytogenes (LADD) Combination Strategies for the Treatment of Malignant Pleural Mesothelioma
Chan C. Whiting, Ph.D., Director, Immune Monitoring and Biomarker Development, Aduro Biotech
We are advancing CRS-207, a clinical LADD strain engineered to express mesothelin, in combinations with various modalities for the treatment of malignant pleural mesothelioma. Data from a Phase 1b study combining CRS-207 with standard chemotherapy demonstrating encouraging clinical and immune responses will be discussed. An overview of the Phase 2 study design and progress of the CRS-207/Pembrolizumab combination study will also be highlighted.
9:00 Tumor and Class-Specific Patterns of Immune-Related Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review
Aaron Hansen, M.D., Ph.D., Assistant Professor, Department of Medicine, University of Toronto; Medical Oncologist, Princess Margaret Cancer Center
Through a systematic review, we identified distinct immune related adverse event (irAE) profiles based on tumor type and immune checkpoint inhibitor class (CTLA-4 and PD-1). CTLA-4 inhibitors have a higher frequency of grade 3/4 irAEs. Furthermore, for patients treated with PD-1 inhibitors, those with melanoma had a higher frequency of gastrointestinal and skin irAEs, and lower rate of pneumonitis compared with patients with NSCLC and RCC. Different immune microenvironments may drive histology-specific irAE patterns.
PROTEIN ENGINEERING
9:30 Combination Therapy with PD-1 Blockade Enhances the Antitumor Potency of T Cells Redirected by Novel Bispecific Antibodies
Ken Chang, Ph.D., Vice President, Research and Development, Immunomedics
Novel bispecific antibodies that bind bivalently to tumor antigens and monovalently to CD3 can redirect T cells to kill Trop-2- or CEACAM5-expressing solid cancer cells grown in monolayer cultures at low picomolar concentrations. The antitumor efficacy was demonstrated also in a humanized mouse model and in 3D spheroids generated with cells from TNBC and colonic cancers. Combining anti-PD-1 increased cell death in 3D spheroids and prolonged survival of tumor-bearing animals.
10:00 Accelerated Production of Immunomodulatory Therapeutic Antibodies & Bispecific Molecules Using Scalable Cell Engineering
Antibodies and antibody-like molecules are a proven means of modulating effective anti-tumor immune responses. MaxCyte’s delivery platform facilitates rapid, fully scalable, high quality transient protein production in the cell line-of-choice, as well as streamlined stable pool and cell line generation enabling accelerated development of relevant immunomodulatory candidates. Case studies will illustrate the identification and development of antibodies, tribodies & bi-specific T cell engaging molecules (BiTEs) using the MaxCyte platform.
10:30 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
11:15 A Novel, Dual-Specific Antibody Conjugate Targeting CD134 and CD137 Costimulates T Cells and Elicits Antitumor Immunity
Adam J. Adler, Ph.D., Professor, Immunology, University of Connecticut
Combining agonists to different costimulatory receptors can be more effective in controlling tumors compared to individual agonists, but presents logistical challenges and increases the potential for adverse events. We developed a novel immunotherapeutic agent by fusing agonists to CD134 and CD137 into a single biologic, OrthomAb, that potentiates cytokine secretion from TCR-stimulated T cells more potently than non-conjugated CD134 + CD137 agonists in vitro, and reduces tumor growth in vivo.
11:45 Targeted Tissue Delivery Using Caveolae Technology Improves Drug Efficacy
Ruchi Gupta, Ph.D., Team Lead Scientist, MedImmune
Current biotherapeutics focus on the molecular targets expressed on cells/tumors. However, less than 10% of the IV administrated biologics can reach the diseased tissues. Tissue targeting using caveolae proteins can allow for specific delivery to organs of interest. This talk will focus on caveolae technology that shows specific delivery to lungs and kidneys and improves drug efficacy. This targeting holds potential for several diseases including fibrosis, COPD, Infections as well as tumors.
12:15 pm Close of Immunomodulatory Therapeutic Antibodies for Cancer
LIVE 9/21 3:20PM to 6:40PM KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS & KINASE INHIBITORS FOR AUTOIMMUNE AND INFLAMMATORY DISEASES at CHI’s 14thDiscovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston
KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS
3:20 Chairperson’s Opening Remarks
Guido J.R. Zaman, Ph.D., Managing Director & Head of Biology, Netherlands Translational Research Center B.V. (NTRC)
3:25 FEATURED PRESENTATION: Inhibition of PI3K and Tubulin
Doriano Fabbro, Ph.D., CSO, PIQUR Therapeutics
The PI3K signaling pathway is frequently activated in tumors. PQR309 is a selective dual inhibitor of PI3K and mTOR (currently in Phase I) in cancer patients. The preclinical pharmacology and toxicology of PQR309 is presented, including its activity in lymphoma preclinical models. In addition, we elucidate structural factors defining the PI3K inhibitory activity and tubulin-binding of PQR309 derivatives.
PQR309 & GDC0941 arrest cells i G1/S (typical for PI3K/mTOR Inhibitor)
What drives Antiproliferative Activity of BKM120: PI3K or MT or both?
BKM120 Binds to beta-Tubulin/alpha -Tubulin Interfere
T2R-TTL complex
Orientation of BKM120 in PI3K
PQR309 – is a brain penetrating, PK and BAV by PO, good metabolic stability
PQR309 ANti-proliferative in Lymphoma
Clinical efficacy – Now in Phase II
4:05 Design and Development of a Novel PI3K-p110β/δ Inhibitor, KA2237 with Combined Tumor Immunotherapeutic, Growth Inhibition and Anti-Metastatic Activity
Stephen Shuttleworth, Ph.D., FRSC, CChem, CSO, Karus Therapeutics Ltd.
The design and development of KA2237, a novel and selective inhibitor of PI3K-p110β/δ, will be described. This molecule has clinical potential in the treatment of solid and hematological malignancies, through its direct inhibition of tumor growth and metastatic spread, and through immunotherapeutic mechanisms. Phase I studies for KA2237 are scheduled to commence in Q2 2016 at the MD Anderson Cancer Center.
Design & Development of Novel, Oral, selective PI3K enzyme family: CLass I,II, III, IV based upon:
phase I clinical study commenced in pathients with B cell Lymphoma
Potential for treatment of solid and hematological malignancies
4:35 InCELL Pulse: A Novel Cellular Target Engagement Assay Platform for Drug Discovery
Daniel Treiber, Ph.D., Vice President, KINOMEscan, DiscoverX Corporation
InCELL Pulse is a quantitative and rapid method for measuring cellular target engagement potencies for small molecule inhibitors. InCELL Pulse capitalizes on two novel DiscoverX technologies, Enzyme Fragment Complementation (EFC) and Pulse Denaturation, which overcome the limitations of related target engagement methods. Examples across multiple target classes will be described.
InCELL Pulse – cellular Target ENgagement Assays
cellular thermal stabilization-based approach
simple, rapid and generig cellular alternative to CETSa
Thermal melting Curves vs Isothermal Inhibitor EC50 curves
Pulse Denaturation compound binding, or not binding
MTH1 Hydrolase: InCELL Pulseassay validated for multiple substrate-competitive inhibitors
Validated InCELL Pulse Assays for Diverse Kinases
Kinase targets; BRAF, MEC1
Summary
validation across proteins
4:50 Potential Application of Fluorescence Lifetime Assays to Enable Robust, Rapid Protein Binding Assays
Paul Wylie, Ph.D., Head, Applications, TTP Labtech
Current methods to screen protein binding interactions often have limitations due to the reliance on antibodies, but also interference from fluorescent molecules. Fluorescence lifetime has the potential to overcome these problems through directly labelled proteins and lifetime measurements that are independent of total fluorescence intensity.
Protein binding as a target class
protein-protein interactions (PPIs)
FRET/HTRF
FP
AlphaScreen
What new in FLT?
long lifetime fluorophores, economical reagent platform
directly labelled reagents – no antibodies
independent of total intensity – reduced interference
robustness screen vs nuisance screen – caspase-3
productive; reduction false positives: FRET
protein-binding assays & FLT formats:
protein – small molecule binding – CECR2
protein – peptide binding: long and sholt lifetime
Site-specific labelling vs Non-selective labelling
Toolbox for PoC
Detection reagents
Further develop technology
5:05 Refreshment Break in the Exhibit Hall with Poster Viewing
Pioneers of Cancer Cell Therapy: Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors
Curator: Aviva Lev-Ari, PhD, RN
Article ID #209: Pioneers of Cancer Cell Therapy: Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors. Published on 8/19/2016
WordCloud Image Produced by Adam Tubman
Chimeric Antigen Receptor T-Cell Therapy: Players in Basic & Translational Research and Biotech/Pharma
The companies are teamed with academic pioneers:
Novartis with University of Pennsylvania;
Kite Pharma with the National Cancer Institute;
Juno Therapeutics with Sloan Kettering,
the Fred Hutchinson Cancer Research Center in Seattle and Seattle Children’s Hospital.
IMAGE SOURCE: National Cancer Institute
“CAR-T cell immunotherapy” – genetically modified T cells that are engineered to target specific tumor antigens and/or genes that are involved in survival, proliferation, and the enhancement of effector functions have been under intense research.
CAR technology was originally reported by Zelig Eshhar in 1993.
Prof. Zelig Eshhar, Ph.D., served as Chairman of the Department of Immunology at the Weizmann Institute. Prof. Eshhar has been Chair of Scientific Advisory Board at TxCell S.A. since April 2016. Prof. Eshhar has been a Member of Scientific Advisory Board at Kite Pharma, Inc. since August 8, 2013. Prof. Eshhar served as a Member of Scientific Advisory Board at Intellect Neurosciences, Inc. since April 2006.
Prof. Eshhar pioneered the CAR approach (or T-Body as he termed it) to redirect T cells to recognize, engage and kill patient’s tumor cells by engineering them with a construct that combines the anti-target specificity of an antibody with T cell activation domains. Prof. Eshhar serves on several editorial boards, including Cancer Gene Therapy, Human Gene Therapy, Gene Therapy, Expert Opinion on Therapeutics, European Journal of Immunology and the Journal of Gene Medicine. He was a Research Fellow in the Department of Pathology at Harvard Medical School and in the Department of Chemical Immunology at the Weizmann Institute in Israel. His achievements were recognized by several international awards, most recently the CAR Pioneering award by the ATTACK European Consortium. Prof. Eshhar obtained his B.Sc. in Biochemistry and Microbiology and his M.Sc. in Biochemistry from the Hebrew University, and his Ph.D. in the Department of Immunology from the Weizmann Institute of Science.
Zelig Eshhar and Carl H. June honored for research on T cell engineering for cancer immunotherapy
New Rochelle, NY, November 11, 2014–Zelig Eshhar, PhD, The Weizmann Institute of Science and Sourasky Medical Center, and Carl H. June, MD, PhD, Perelman School of Medicine, University of Pennsylvania, are co-recipients of the Pioneer Award, recognized for lentiviral gene therapy clinical trials and for their leadership and contributions in engineering T-cells capable of targeting tumors with antibody-like specificity through the development of chimeric antigen receptors (CARs). Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers, is commemorating its 25th anniversary by bestowing this honor on the leading Pioneers in the field of cell and gene therapy selected by a blue ribbon panel* and publishing a Pioneer Perspective by the award recipients. The Perspectives by Dr. Eshhar and Dr. June are available free on the Human Gene Therapy website at http://www.liebertpub.com/hgt until December 11, 2014.
In his Pioneer Perspective entitled “From the Mouse Cage to Human Therapy: A Personal Perspective of the Emergence of T-bodies/Chimeric Antigen Receptor T Cells” Professor Eshhar chronicles his team’s groundbreaking contributions to the development of the CAR T-cell immunotherapeutic approach to treating cancer. He describes the method’s conceptual development including initial proof-of-concept, and the years of experimentation in mouse models of cancer. They first tested the CAR T-cells on tumors transplanted into mice then progressed to spontaneously developing cancers in immune-competent mice, which Dr. Eshhar describes as “a more suitable model that faithfully mimics cancer patients.” He recounts successful antitumor effects in mice with CAR modified T-cells injected directly into tumors, with effects seen at the injection site and at sites of metastasis, and even the potential of the CAR T-cells to prevent tumor development.
Dr. Carl H. June has led one of the clinical groups that has taken the CAR therapeutic strategy from the laboratory to the patients’ bedside, pioneering the use of CD19-specific CAR T-cells to treat patients with leukemia. In his Pioneer Perspective, “Toward Synthetic Biology with Engineered T Cells: A Long Journey Just Begun” Dr. June looks back on his long, multi-faceted career and describes how he combined his knowledge and research on immunology, cancer, and HIV to develop successful T-cell based immunotherapies. Among the lessons Dr. June has embraced throughout his career are to follow one’s passions. He also says that “accidents can be good: embrace the unexpected results and follow up on these as they are often times more scientifically interesting than predictable responses from less imaginative experiments.”
“These two extraordinary scientists made seminal contributions at key steps of the journey from bench to bedside for CAR T-cells,” says James M. Wilson, MD, PhD, Editor-in-Chief of Human Gene Therapy, and Director of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
First publication on Adoptive transfer of genetically modified T cells is an attractive approach for generating antitumor immune responses
Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19
James N.Kochenderfer, Wyndham H.Wilson, John E.Janik, Mark E.Dudley, MaryaliceStetler-Stevenson, Steven A.Feldman, IrinaMaric, MarkRaffeld, Debbie-Ann N.Nathan, Brock J.Lanier, Richard A.Morgan, Steven A.Rosenberg
Adoptive transfer of genetically modified T cells is an attractive approach for generating antitumor immune responses. We treated a patient with advanced follicular lymphoma by administering a preparative chemotherapy regimen followed by autologous T cells genetically engineered to express a chimeric antigen receptor (CAR) that recognized the B-cell antigen CD19. The patient’s lymphoma underwent a dramatic regression, and B-cell precursors were selectively eliminated from the patient’s bone marrow after infusion of anti–CD19-CAR-transduced T cells. Blood B cells were absent for at least 39 weeks after anti–CD19-CAR-transduced T-cell infusion despite prompt recovery of other blood cell counts. Consistent with eradication of B-lineage cells, serum immunoglobulins decreased to very low levels after treatment. The prolonged and selective elimination of B-lineage cells could not be attributed to the chemotherapy that the patient received and indicated antigen-specific eradication of B-lineage cells. Adoptive transfer of anti–CD19-CAR-expressing T cells is a promising new approach for treating B-cell malignancies. This study is registered at www.clinicaltrials.gov as #NCT00924326.
According to Setting the Body’s ‘Serial Killers’ Loose on Cancer
After a long, intense pursuit, researchers are close to bringing to market a daring new treatment: cell therapy that turbocharges the immune system to fight cancer.
Dr. June’s 2011 publications did not cite Dr. Rosenberg’s paper [Blood, 2010] from the previous year, prompting Dr. Rosenberg to write a letter to The New England Journal of Medicine. Dr. June’s publications also did not acknowledge that the genetic construct he had used was the one he had obtained from Dr. Campana of St. Jude.
St. Jude sued the University of Pennsylvania. Novartis sided with Penn, and Juno Therapeutics with St. Jude.
The suit was settled last year, with Novartis agreeing to pay $12.25 million plus possible future payments and royalties. Within days, Dr. June sent a correction and letter of regret to The New England Journal of Medicine, acknowledging that the CAR used in his groundbreaking 2011 study, and in treating Emily Whitehead, was “designed, developed and provided” by St. Jude.
Dr. Sadelain was not alone in this work. Zelig Eshhar, an Israeli scientist, is credited with developing one of the first crude CARs around 1989. Dr. Rosenberg, always on the lookout for new types of immunotherapy, invited Dr. Eshhar to be a visiting scientist in his laboratory at the National Cancer Institute.
Another early developer was Dr. Dario Campana of St. Jude Children’s Research Hospital.
Douglas Green, who was one of Dr. Sadelain’s doctoral thesis advisers and is now chairman of immunology at St. Jude Children’s Research Hospital.
But Dr. Sadelain, he continued, “believed in his approach and he pursued it relentlessly.”
After earning his Ph.D., Dr. Sadelain headed for the Whitehead Institute for Biomedical Research in Cambridge, Mass., to learn how to do gene therapy, using disabled viruses that could not cause disease to deliver genes into cells. By 1992, he had demonstrated that he could genetically engineer mouse T-cells.
He then moved to Sloan Kettering. In 2003, he and his colleagues — including his partner and now wife, Isabelle Rivière — showed that genetically engineered T-cells could eradicate certain cancers in mice.
From the Lab to the bedside to the Out Patient Clinic
Natural killer (NK) cells have been known to have advantages over T cells, yet their therapeutic potential in the clinic has been largely unexplored.
Cambridge Healthtech Institute’s NK Cell-Based Cancer Immunotherapy Symposium, September 19 in Boston, is dedicated to the exploration of utilizing NK cells for new adoptive cell therapies, including updates from ongoing clinical studies.
NK CELL IMMUNO-ONCOLOGY AND CLINICAL STUDIES
Harnessing Adaptive NK Cells in Cancer Therapy
Karl-Johan Malmberg, M.D., Ph.D., Professor, Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital
We have recently completed a Phase I/II clinical trial with transfer of haploidentical NK cells to patients with high-risk myelodysplastic syndrome. Six of the 16 treated patients achieved morphological complete remission and five of these underwent allogeneic stem cell transplantation resulting in long-term survival in four patients. The quality and number of infused NK cells as well as their transient engraftment in the recipient correlated with decrease in mutational burden and clinical outcomes. These results suggest that adoptive transfer of allogeneic NK cells may hold utility as a bridge to transplant in patients who are refractory to induction therapy. Current efforts to selectively expand metabolically optimized adaptive NK cells for the next generation NK cell cancer immunotherapy will be discussed.
Update on Systemic and Locoregional Cancer Immunotherapy with IL-21-Expanded NK Cells
Dean Anthony Lee, M.D., Ph.D., Professor, Pediatrics; Director, Cellular Therapy and Cancer Immunotherapy Program, Nationwide Childrens Hospital; James Comprehensive Cancer Center/Solove Research Institute, The Ohio State University
The ability to generate clinical-grade NK cell products of sufficient purity, number, and function has enabled broader application of adoptive NK cell therapy in clinical trials. We translated our IL-21-based NK cell expansion platform to clinical grade and scale and initiated 7 clinical trials that administer NK cell immunotherapy with high cell doses or repeated dosing in transplant, adjuvant, or stand-alone settings. These trials have collectively delivered approximately 150 infusions to over 60 patients at doses of up to 10e8/kg. We will discuss the importance of STAT3 signaling in this setting, describe early outcome and correlative data from these studies, and present preclinical data supporting future clinical trials that build on this platform.
The exhibit hall was sold out in 2015, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2016, contact:
4:00 A New Era of Personalized Therapy: Using Tumor Neoantigens to Unlock the Immune System
Matthew J. Goldstein, M.D., Ph.D., Director, Translational Medicine, Neon Therapeutics, Inc.
Neon Therapeutics, Inc. launched in 2015 to focus on advancing neoantigen biology to improve cancer patient care. A neoantigen-based product engine will allow Neon to develop further treatment modalities including next-generation vaccines and T cell therapies targeting both personalized as well as shared neoantigens. The company’s first trial will launch later this year investigating the combination of a personalized, vaccine with nivolumab in advanced Melanoma, NSCLC, and Bladder Cancer.
4:30 Emerging Innate Immune Targets for Enhancing Adaptive Anti-Tumor Responses
Michael Rosenzweig, Ph.D., Executive Director, Biology-Discovery, IMR Early Discovery, Merck Research Laboratories
Novel cancer immunotherapies targeting T cell checkpoint proteins have emerged as powerful tools to induce profound, durable regression and remission of many types of cancer. Despite these advances, multiple studies have demonstrated that not all patients respond to these therapies, and the ability to predict which patients may respond is limited. Harnessing the innate immune system to augment the adaptive anti-tumor response represents an attractive target for therapy, which has the potential to enhance both the percentage and rate of response to checkpoint blockade.
5:00 Reading Tea Leaves:
The Dilemma of Prediction and Prognosis in Immunotherapy
Morganna Freeman, D.O., Associate Director, Melanoma & Cutaneous Oncology Program, The Angeles Clinic and Research Institute
With the rapid expansion of immunotherapeutics in oncology, scientifically significant advances have been made with both the depth and duration of antitumor responses. However, not all patients benefit, or quickly relapse, thus much scientific inquiry has been devoted to appropriate patient selection and how such obstacles might be overcome. While more is known about potential biomarkers, accurate prognostication persists as a knowledge gap, and efforts to bridge it will be discussed here.
Personalized Immunotherapy | The Immuno-Oncology Summit
August 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA
Fueled with advances in genomic technologies, personalized oncology promises to innovate cancer therapy and target the previously undruggable space. Developments in immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies, as well as biomarker-driven immuno-oncology clinical trials, are enabling the next generation of cancer therapy. Cambridge Healthtech Institute’s Inaugural Personalized Immunotherapy meeting brings together clinical immuno-oncologists and thought leaders from pharmaceutical and biotech companies, and leading academic teams to share research and case studies in implementing patient-centric approaches to using the immune system to beat cancer.
TUMOR NEOANTIGENS FOR PERSONALIZED IMMUNOTHERAPY
Basics of Personalized Immunotherapy: What Is a Good Antigen?
Pramod K. Srivastava, M.D., Ph.D., Professor, Immunology and Medicine, Director, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine
Novel Antibodies against Immunogenic Neoantigens
Philip M. Arlen, M.D., President & CEO, Precision Biologics, Inc.
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Luis Alberto Diaz, M.D., Associate Professor, Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
PERSONALIZED IMMUNOTHERAPY WITH CANCER VACCINES
Cancer Vaccines in the Era of Checkpoint Inhibitors
Keith L. Knutson, Ph.D., Professor, Immunology, Mayo Clinic
Developing Therapeutic Cancer Vaccine Strategies for Prostate Cancer
Ravi Madan, M.D., Clinical Director, Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health
Getting Very Personal: Fully Individualized Tumor Neoantigen-Based Vaccine Approaches to Cancer Therapy
Karin Jooss, Ph.D., CSO, Gritstone Oncology
Approaches to Assess Tumor Mutation Load for Selecting Patients for Cancer Immunotherapy
John Simmons, Ph.D., Manager, Research Services, Personal Genome Diagnostics
In situ Vaccination for Lymphoma
Joshua Brody, M.D., Director, Lymphoma Immunotherapy Program, Icahn School of Medicine at Mount Sinai
Immunotherapy Using Ad5 [E1-, E2b-] Vector Vaccines in the Cancer MoonShot 2020 Program
Frank R. Jones, Ph.D., Chairman & CEO, Etubics Corporation
PERSONALIZED CELL THERAPY
Integration of Natural Killer-Based Therapy into the Treatment of Lymphoma
Andrew M. Evens, D.O., Professor and Chief, Hematology/Oncology, Tufts University School of Medicine; Director, Tufts Cancer Center
Dendritic Cells: Personalized Cancer Vaccines and Inducers of Multi-Epitope-Specific T Cells for Adoptive Cell Therapy
Pawel Kalinski, M.D., Ph.D., Professor, Surgery, Immunology, and Bioengineering, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute
Mesothelin-Targeted CAR T-Cell Therapy for Solid Tumors
Prasad S. Adusumilli, M.D., FACS, Deputy Chief of Translational & Clinical Research, Thoracic Surgery, Memorial Sloan-Kettering Cancer Center
Synthetic Regulation of T Cell Therapies Adds Safety and Enhanced Efficacy to Previously Unpredicted Therapies
David M. Spencer, Ph.D., CSO, Bellicum Pharmaceuticals
Long-Term Relapse-Free Survival of Patients with Acute Myeloid Leukemia (AML) Receiving a Telomerase- Engineered Dendritic Cell Immunotherapy
Jane Lebkowski, Ph.D., President & CSO, Research and Development, Asterias Biotherapeutics
Activated and Exhausted Tumor Infiltrating B Cells in Non-Small Cell Lung Cancer Patients Present Antigen and Influence the Phenotype of CD4 Tumor Infiltrating T Cells
Tullia Bruno, Ph.D., Research Assistant Professor, Immunology, University of Pittsburgh
About the Immuno-Oncology Summit
CHI’s 4th Annual Immuno-Oncology Summit has been designed to support a coordinated effort by industry players to bring commercial immunotherapies and immunotherapy combinations through clinical development and into the market. This weeklong, nine-meeting set will include topics ranging from early discovery through clinical development as well as emerging areas such as oncolytic virotherapy. Overall, this event will provide a focused look at how researchers are applying new science and technology in the development of the next generation of effective and safe immunotherapies.
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Outsource a part of the T cell’s immune value chain, propose cancer immunotherapy researchers, from patient T cells to donor T cells. The novel allogeneic approach could rely on T-cell receptor gene transfer to generate broad and tumor-specific T-cell immune responses. [NIAID]
A new cancer immunotherapy approach could essentially outsource a crucial T-cell function. This function, T-cell reactivity to specific cancer antigens, is sometimes lacking in cancer patients. Yet, according to a new proof-of-principle study, these patients could benefit from T cells provided by healthy donors. Specifically, the healthy donors’ T cells could be used to broaden the T-cell receptor repertoires of the cancer patients’ T cells.
Ultimately, this approach relies on a cancer immunotherapy technique called T-cell receptor (TCR) transfer, or the genetic transfer of TCR chains. TCR transfer can be used to outsource the T cell’s learning function, the process by which a T cell acquires the ability to recognize foreign antigens—in this case, the sort of proteins that can be expressed on the surface of cancer cells. Because cancer cells harbor faulty proteins, they can also display foreign protein fragments, also known as neoantigens, on their surface, much in the way virus-infected cells express fragments of viral proteins.
The approach was detailed in a paper that appeared May 19 in the journal Science, in an article entitled, “Targeting of Cancer Neoantigens with Donor-Derived T Cell Receptor Repertoires.” This article, by scientists based at the Netherlands Cancer Institute and the University of Oslo, describes a novel strategy to broaden neoantigen-specific T-cell responses. Such a strategy would be useful in overcoming a common limitation seen in the immune response to cancer: Neoantigen-specific T-cell reactivity is generally limited to just a few mutant epitopes, even though the number of predicted epitopes is large.
“We demonstrate that T cell repertoires from healthy donors provide a rich source of T cells that specifically recognize neoantigens present on human tumors,” the study’s authors wrote. “Responses to 11 epitopes were observed, and for the majority of evaluated epitopes, potent and specific recognition of tumor cells endogenously presenting the neoantigens was detected.”
First, the researchers mapped all possible neoantigens on the surface of melanoma cells from three different patients. In all three patients, the cancer cells seemed to display a large number of different neoantigens. But when the researchers tried to match these to the T cells derived from within the patient’s tumors, most of these aberrant protein fragments on the tumor cells went unnoticed.
Next, the researchers tested whether the same neoantigens could be seen by T cells derived from healthy volunteers. Strikingly, these donor-derived T cells could detect a significant number of neoantigens that had not been seen by the patients’ T cells.
“Many of the T cell reactivities [among donor T cells] involved epitopes that in vivo were neglected by patient autologous tumor-infiltrating lymphocytes,” the authors of the Science article continued. “T cells re-directed with T cell receptors identified from donor-derived T cells efficiently recognized patient-derived melanoma cells harboring the relevant mutations, providing a rationale for the use of such ‘outsourced’ immune responses in cancer immunotherapy.”
“In a way, our findings show that the immune response in cancer patients can be strengthened; there is more on the cancer cells that makes them foreign that we can exploit. One way we consider doing this is finding the right donor T cells to match these neoantigens,” said Ton Schumacher, Ph.D., a principal investigator at the Netherlands Cancer Institute. “The receptor that is used by these donor T cells can then be used to genetically modify the patient’s own T cells so these will be able to detect the cancer cells.”
“Our study shows that the principle of outsourcing cancer immunity to a donor is sound,” added Johanna Olweus, M.D., Ph.D., who heads a research group at the University of Oslo. “However, more work needs to be done before patients can benefit from this discovery. Thus, we need to find ways to enhance the throughput.”
“We are currently exploring high-throughput methods to identify the neoantigens that the T cells can ‘see’ on the cancer and isolate the responding cells. But the results showing that we can obtain cancer-specific immunity from the blood of healthy individuals are already very promising.”
Targeting of cancer neoantigens with donor-derived T cell receptor repertoires
Accumulating evidence suggests that clinically efficacious cancer immunotherapies are driven by T cell reactivity against DNA mutation-derived neoantigens. However, among the large number of predicted neoantigens, only a minority is recognized by autologous patient T cells, and strategies to broaden neoantigen specific T cell responses are therefore attractive. Here, we demonstrate that naïve T cell repertoires of healthy blood donors provide a source of neoantigen-specific T cells, responding to 11/57 predicted HLA-A2-binding epitopes from three patients. Many of the T cell reactivities involved epitopes that in vivo were neglected by patient autologous tumor-infiltrating lymphocytes. Finally, T cells re-directed with T cell receptors identified from donor-derived T cells efficiently recognized patient-derived melanoma cells harboring the relevant mutations, providing a rationale for the use of such “outsourced” immune responses in cancer immunotherapy.
Metabolic maintenance of cell asymmetry following division in activated T lymphocytes.
Asymmetric cell division, the partitioning of cellular components in response to polarizing cues during mitosis, has roles in differentiation and development. It is important for the self-renewal of fertilized zygotes in Caenorhabditis elegans and neuroblasts in Drosophila, and in the development of mammalian nervous and digestive systems. T lymphocytes, upon activation by antigen-presenting cells (APCs), can undergo asymmetric cell division, wherein the daughter cell proximal to the APC is more likely to differentiate into an effector-like T cell and the distal daughter is more likely to differentiate into a memory-like T cell. Upon activation and before cell division, expression of the transcription factor c-Myc drives metabolic reprogramming, necessary for the subsequent proliferative burst. Here we find that during the first division of an activated T cell in mice, c-Myc can sort asymmetrically. Asymmetric distribution of amino acid transporters, amino acid content, and activity of mammalian target of rapamycin complex 1 (mTORC1) is correlated with c-Myc expression, and both amino acids and mTORC1 activity sustain the differences in c-Myc expression in one daughter cell compared to the other. Asymmetric c-Myc levels in daughter T cells affect proliferation, metabolism, and differentiation, and these effects are altered by experimental manipulation of mTORC1 activity or c-Myc expression. Therefore, metabolic signalling pathways cooperate with transcription programs to maintain differential cell fates following asymmetric T-cell division.
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy associated with Notch pathway mutations. While both normal activated and leukemic T cells can utilize aerobic glycolysis to support proliferation, it is unclear to what extent these cell populations are metabolically similar and if differences reveal T-ALL vulnerabilities. Here we show that aerobic glycolysis is surprisingly less active in T-ALL cells than proliferating normal T cells and that T-ALL cells are metabolically distinct. Oncogenic Notch promoted glycolysis but also induced metabolic stress that activated 5′ AMP-activated kinase (AMPK). Unlike stimulated T cells, AMPK actively restrained aerobic glycolysis in T-ALL cells through inhibition of mTORC1 while promoting oxidative metabolism and mitochondrial Complex I activity. Importantly, AMPK deficiency or inhibition of Complex I led to T-ALL cell death and reduced disease burden. Thus, AMPK simultaneously inhibits anabolic growth signaling and is essential to promote mitochondrial pathways that mitigate metabolic stress and apoptosis in T-ALL.
Obesity and diabetes are associated with excessive inflammation and impaired wound healing. Increasing evidence suggests that macrophage dysfunction is responsible for these inflammatory defects. In the setting of excess nutrients, particularly dietary saturated fatty acids (SFAs), activated macrophages develop lysosome dysfunction, which triggers activation of the NLRP3 inflammasome and cell death. The molecular pathways that connect lipid stress to lysosome pathology are not well understood, but may represent a viable target for therapy. Glutamine uptake is increased in activated macrophages leading us to hypothesize that in the context of excess lipids glutamine metabolism could overwhelm the mitochondria and promote the accumulation of toxic metabolites. To investigate this question we assessed macrophage lipotoxicity in the absence of glutamine using LPS-activated peritoneal macrophages exposed to the SFA palmitate. We found that glutamine deficiency reduced lipid induced lysosome dysfunction, inflammasome activation, and cell death. Under glutamine deficient conditions mTOR activation was decreased and autophagy was enhanced; however, autophagy was dispensable for the rescue phenotype. Rather, glutamine deficiency prevented the suppressive effect of the SFA palmitate on mitochondrial respiration and this phenotype was associated with protection from macrophage cell death. Together, these findings reveal that crosstalk between activation-induced metabolic reprogramming and the nutrient microenvironment can dramatically alter macrophage responses to inflammatory stimuli.
Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α
CD8(+) T cells can respond to unrelated infections in an Ag-independent manner. This rapid innate-like immune response allows Ag-experienced T cells to alert other immune cell types to pathogenic intruders. In this study, we show that murine CD8(+) T cells can sense TLR2 and TLR7 ligands, resulting in rapid production of IFN-γ but not of TNF-α and IL-2. Importantly, Ag-experienced T cells activated by TLR ligands produce sufficient IFN-γ to augment the activation of macrophages. In contrast to Ag-specific reactivation, TLR-dependent production of IFN-γ by CD8(+) T cells relies exclusively on newly synthesized transcripts without inducing mRNA stability. Furthermore, transcription of IFN-γ upon TLR triggering depends on the activation of PI3K and serine-threonine kinase Akt, and protein synthesis relies on the activation of the mechanistic target of rapamycin. We next investigated which energy source drives the TLR-induced production of IFN-γ. Although Ag-specific cytokine production requires a glycolytic switch for optimal cytokine release, glucose availability does not alter the rate of IFN-γ production upon TLR-mediated activation. Rather, mitochondrial respiration provides sufficient energy for TLR-induced IFN-γ production. To our knowledge, this is the first report describing that TLR-mediated bystander activation elicits a helper phenotype of CD8(+) T cells. It induces a short boost of IFN-γ production that leads to a significant but limited activation of Ag-experienced CD8(+) T cells. This activation suffices to prime macrophages but keeps T cell responses limited to unrelated infections.
The bidirectional interaction between the immune system and whole-body metabolism has been well recognized for many years. Via effects on adipocytes and hepatocytes, immune cells can modulate whole-body metabolism (in metabolic syndromes such as type 2 diabetes and obesity) and, reciprocally, host nutrition and commensal-microbiota-derived metabolites modulate immunological homeostasis. Studies demonstrating the metabolic similarities of proliferating immune cells and cancer cells have helped give birth to the new field of immunometabolism, which focuses on how the cell-intrinsic metabolic properties of lymphocytes and macrophages can themselves dictate the fate and function of the cells and eventually shape an immune response. We focus on this aspect here, particularly as it relates to regulatory T cells.
Figure 1: Proposed model for the metabolic signatures of various Treg cell subsets.
(a) Activated CD4+ T cells that differentiate into the Teff cell lineage (green) (TH1 or TH17 cells) are dependent mainly on carbon substrates such as glucose and glutamine for their anabolic metabolism. In contrast to that, pTreg cells…
T-bet is a key modulator of IL-23-driven pathogenic CD4+ T cell responses in the intestine
IL-23 is a key driver of pathogenic Th17 cell responses. It has been suggested that the transcription factor T-bet is required to facilitate IL-23-driven pathogenic effector functions; however, the precise role of T-bet in intestinal T cell responses remains elusive. Here, we show that T-bet expression by T cells is not required for the induction of colitis or the differentiation of pathogenic Th17 cells but modifies qualitative features of the IL-23-driven colitogenic response by negatively regulating IL-23R expression. Consequently, absence of T-bet leads to unrestrained Th17 cell differentiation and activation characterized by high amounts of IL-17A and IL-22. The combined increase in IL-17A/IL-22 results in enhanced epithelial cell activation and inhibition of either IL-17A or IL-22 leads to disease amelioration. Our study identifies T-bet as a key modulator of IL-23-driven colitogenic responses in the intestine and has important implications for understanding of heterogeneity among inflammatory bowel disease patients.
Th17 cells are enriched at mucosal sites, produce high amounts of IL-17A, IL-17F and IL-22, and have an essential role in mediating host protective immunity against a variety of extracellular pathogens1. However, on the dark side, Th17 cells have also been implicated in a variety of autoimmune and chronic inflammatory conditions, including inflammatory bowel disease (IBD)2. Despite intense interest, the cellular and molecular cues that drive Th17 cells into a pathogenic state in distinct tissue settings remain poorly defined.
The Th17 cell programme is driven by the transcription factor retinoid-related orphan receptor gamma-t (RORγt) (ref. 3), which is also required for the induction and maintenance of the receptor for IL-23 (refs 4, 5). The pro-inflammatory cytokine IL-23, composed of IL-23p19 and IL-12p40 (ref. 6), has been shown to be a key driver of pathology in various murine models of autoimmune and chronic inflammatory disease such as experimental autoimmune encephalomyelitis (EAE)7, collagen induced arthritis8 and intestinal inflammation9, 10, 11, 12. Several lines of evidence, predominantly derived from EAE, suggest that IL-23 promotes the transition of Th17 cells to pathogenic effector cells9, 10, 11, 12. Elegant fate mapping experiments of IL-17A-producing cells during EAE have shown that the majority of IL-17A+IFN-γ+ and IL-17A−IFN-γ+ effector cells arise from Th17 cell progeny13. This transition of Th17 cells into IFN-γ-producing ‘ex’ Th17 cells required IL-23 and correlated with increased expression of T-bet. The T-box transcription factor T-bet drives the Th1 cell differentiation programme14 and directly transactivates the Ifng gene by binding to its promoter as well as multiple enhancer elements15. Indeed, epigenetic analyses have revealed that the loci for T-bet and IFN-γ are associated with permissive histone modifications in Th17 cells suggesting that Th17 cells are poised to express T-bet which could subsequently drive IFN-γ production16, 17.
A similar picture is emerging in the intestine where IL-23 drives T-cell-mediated intestinal pathology which is thought to be dependent on expression of T-bet18 and RORγt (ref. 19) by T cells. In support of this we have recently shown that IL-23 signalling in T cells drives the emergence of IFN-γ producing Th17 cells in the intestine during chronic inflammation20. Collectively these studies suggest a model whereby RORγt drives differentiation of Th17 cells expressing high amounts of IL-23R, and subsequently, induction of T-bet downstream of IL-23 signalling generates IL-17A+IFN-γ+ T cells that are highly pathogenic. Indeed, acquisition of IFN-γ production by Th17 cells has been linked to their pathogenicity in several models of chronic disease13, 21, 22, 23, 24 and a population of T cells capable of producing both IL-17A and IFN-γ has also been described in intestinal biopsies of IBD patients25, 26.
However, in the context of intestinal inflammation, it remains poorly defined whether the requirement for RORγt and T-bet reflects a contribution of Th17 and Th1 cells to disease progression or whether Th17 cells require T-bet co-expression to exert their pathogenic effector functions. Here, we use two distinct models of chronic intestinal inflammation and make the unexpected finding that T-bet is dispensable for IL-23-driven colitis. Rather the presence of T-bet serves to modify the colitogenic response restraining IL-17 and IL-22 driven pathology. These data identify T-bet as a key modulator of IL–23-driven colitogenic effector responses in the intestine and have important implications for understanding of heterogeneous immune pathogenic mechanisms in IBD patients.
Figure 1: IL-23 signalling is required for bacteria-driven T-cell-dependent colitis and the emergence of IL-17A+IFN-γ+ T cells.
C57BL/6 WT and Il23r−/− mice were infected orally with Hh and received weekly i.p. injections of IL-10R blocking antibody. Mice were killed at 4 weeks post infection and assessed for intestinal inflammation. (a) Colitis scores. (b) Typhlitis sores. (c) Representative photomicrographs of colon and caecum (× 10 magnification; scale bars, 200μM). (d) Representative flow cytometry plots of colonic lamina propria gated on viable CD4+ T cells. (e) Frequencies of IL-17A+ and/or IFN-γ+ CD4+ T cells present in the colon. Data represent pooled results from two independent experiments (n=12 for WT, n=10 for Il23r−/−). Bars are the mean and each symbol represents an individual mouse. *P<0.05, ***P<0.001 as calculated by Mann–Whitney U test.
C57BL/6 Rag1−/− mice were injected i.p. with 4 × 105 CD4+CD25−CD45RBhi T cells from C57BL/6 WT,Rorc−/− or Tbx21−/− donors. Mice were killed when recipients of Tbx21−/− T cells developed clinical signs of disease (4–6 weeks) and assessed for intestinal inflammation. (a) Colitis scores. (b) Representative photomicrographs of proximal colon sections (× 10 magnification; scale bars, 200μM). (c) Concentration of cytokines released from colon explants into the medium after overnight culture. Data represent pooled results from two independent experiments (n=14 for WT, n=11 for Rorc−/−, n=14 forTbx21−/−). Bars are the mean and each symbol represents an individual mouse. Bars are the mean and error bars represent s.e.m. *P<0.05, **P<0.01, ***P<0.001 as calculated by Kruskal–Wallis one-way ANOVA with Dunn’s post-test.
C57BL/6 Rag1−/− mice were injected i.p. with 4×105 CD4+CD25−CD45RBhi T cells from C57BL/6 WT,Rorc−/− or Tbx21−/− donors. Mice were killed when recipients of Tbx21−/−T cells developed clinical signs of disease (4–6 weeks). (a) Representative plots of IL-17A and IFN-γ expression in colonic CD4+ T cells. (b) Frequencies of IL-17A+ and/or IFN-γ+ cells among colonic CD4+ T cells. (c) Total numbers of IL-17A+and/or IFN-γ+ CD4+ T cells present in the colon. Data represent pooled results from three independent experiments (n=20 for WT, n=18 for Tbx21−/−, n=12 for Rorc−/−). Bars are the mean and each symbol represents an individual mouse. *P<0.05, **P<0.01, ***P<0.001 as calculated by Kruskal–Wallis one-way ANOVA with Dunn’s post-test.
T-bet deficiency promotes an exacerbated Th17-type response
Our transfer of Tbx21−/− T cells revealed a striking increase in the frequency of IL-17A+IFN-γ−cells (Fig. 3) and we reasoned that T-bet-deficiency could impact on Th17 cell cytokine production. Therefore, we transferred WT or Tbx21−/− CD4+ T cells into Rag1−/− recipients and measured the expression of RORγt, IL-17A, IL-17F and IL-22 by CD4+ T cells isolated from the colon. In agreement with our earlier findings, Tbx21−/− T cells gave rise to significantly increased frequencies of RORγt-expressing T cells capable of producing IL-17A (Fig. 4a). Furthermore, T-bet deficiency also led to a dramatic expansion of IL-17F and IL-22-expressing cells, which constituted only a minor fraction in WT T cells (Fig. 4a,b). By contrast, the frequency of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-γ producing cells was significantly reduced in T-bet-deficient T cells as compared with WT T cells. When analysed in more detail we noted that the production of IL-17A, IL-17F and IL-22 increased specifically in T-bet-deficient IL-17A+IFN-γ+ T cells as compared with WT T cells whereas IFN-γ production decreased overall in the absence of T-bet as expected (Supplementary Fig. 4A). Similarly, GM-CSF production was also generally reduced in Tbx21−/− CD4+ T cells further suggesting a shift in the qualitative nature of the T cell response.
Figure 4: T-bet-deficient CD4+ T cells promote an exacerbated Th17-type inflammatory response.
C57BL/6 Rag1−/− mice were injected i.p. with 4×105 CD4+CD25−CD45RBhi T cells from C57BL/6 WT orTbx21−/− donors. Mice were killed when recipients of Tbx21−/−T cells developed clinical signs of disease (4–6 weeks). (a) Representative plots of cytokines and transcription factors in WT or Tbx21−/− colonic CD4+ T cells. (b) Frequency of IL-17A+, IL-17F+, IL-22+, GM-CSF+ or IFN-γ+ colonic T cells in WT orTbx21−/−. (c) quantitative reverse transcription PCR (qRT-PCR) analysis of mRNA levels of indicated genes in colon tissue homogenates. (d) Total number of neutrophils (CD11b+ Gr1high) in the colon. (e) Primary epithelial cells were isolated from the colon of steady state C57BL/6 Rag1−/− mice and stimulated with 10ngml−1 cytokines for 4h after which cells were harvested and analysed by qRT-PCR for the indicated genes. Data in b–d represent pooled results from two independent experiments (n=14 for WT, n=11 for Tbx21−/−). Bars are the mean and error bars represent s.e.m. Data in e are pooled results from four independent experiments, bars are the mean and error bars represent s.e.m. *P<0.05, **P<0.01,***P<0.001 as calculated by Mann–Whitney U test.
T-bet-deficient colitis depends on IL-23, IL-17A and IL-22
In the present study we show that bacteria-driven colitis is associated with the IL-23-dependent emergence of IFN-γ-producing Th17 cells co-expressing RORγt and T-bet. Strikingly, while RORγt is required for the differentiation of IFN-γ-producing Th17 cells and induction of colitis, T-bet is dispensable for the emergence of IL-17A+IFN-γ+ T cells and intestinal pathology. Our results show that instead of a mandatory role in the colitogenic response, the presence of T-bet modulates the qualitative nature of the IL-23-driven intestinal inflammatory response. In the presence of T-bet, IL-23-driven colitis is multifunctional in nature and not functionally dependent on either IL-17A or IL-22. By contrast, in the absence of T-bet a highly polarized colitogenic Th17 cell response ensues which is functionally dependent on both IL-17A and IL-22. T-bet-deficient T cells are hyper-responsive to IL-23 resulting in enhanced STAT3 activation and downstream cytokine secretion providing a mechanistic basis for the functional changes. These data newly identify T-bet as a key modulator of IL-23-driven colitogenic CD4+ T cell responses.
Contrary to our expectations T-bet expression by CD4 T cells was not required for their pathogenicity. In keeping with the negative effect of T-bet on Th17 differentiation40, 41, 42, we observed highly polarized Th17 responses in T-bet-deficient intestinal T cells. Early studies demonstrated that IFN-γ could suppress the differentiation of Th17 cells40 and thus the reduced IFN-γ production by Tbx21−/−T cells could facilitate Th17 cell generation. However, our co-transfer studies revealed unrestrained Th17 differentiation of Tbx21−/− T cells even in the presence of WT T cells, suggesting a cell autonomous role for T-bet-mediated suppression of the Th17 programme. Indeed, the role of T-bet as a transcriptional repressor of the Th17 cell fate has been described recently. For example, T-bet physically interacts with and sequesters Runx1, thereby preventing Runx1-mediated induction of RORγt and Th17 cell differentiation43. In addition, T-bet binds directly to and negatively regulates expression of many Th17-related genes15, 34 and we identified IL23r to be repressed in a T-bet-dependent manner. In line with this we show here that T-bet-deficient intestinal T cells express higher amounts of Il23r as well as Rorc. This resulted in enhanced IL-23-mediated STAT3 activation and increased production of IL-17A and IL-22. It has also been suggested that T-bet activation downstream of IL-23R signalling is required for pathogenic IL-23-driven T cell responses43, 44. However, we did not find a role for IL-23 in the induction and/or maintenance of T-bet expression and colitis induced by T-bet-deficient T cells was IL-23 dependent. Collectively, these findings demonstrate that T-bet deficiency leads to unrestrained expansion of colitogenic Th17 cells, which is likely mediated through enhanced activation of the IL-23R-STAT3 pathway.
The observation that T-bet-deficient T cells retain their colitogenic potential is in stark contrast to earlier studies. Neurath et al.18 convincingly showed that adoptive transfer of Tbx21−/− CD4+ T cells into severe combined immunodeficiency (SCID) recipients failed to induce colitis and this correlated with reduced IFN-γ and increased IL-4 production. Another study revealed that IL-4 plays a functional role in inhibiting the colitogenic potential of Tbx21−/− T cells, as recipients ofStat6−/−Tbx21−/− T cells developed severe colitis37. Importantly, the intestinal inflammation that developed in recipients of Stat6−/−Tbx21−/− T cells could be blocked by administration of IL-17A neutralizing antibody, suggesting that the potent inhibitory effect of IL-4/STAT6 signals on Th17 differentiation normally prevent colitis induced by Tbx21−/− T cells37. Various explanations could account for the discrepancy between our study and those earlier findings. First, in contrast to the published reports, we used naïve Tbx21−/− CD4+ T cells from C57BL/6 mice instead of BALB/c mice. An important difference between Tbx21−/− CD4+ T cells from these genetic backgrounds appears to be their differential susceptibility to suppression by IL-4/STAT6 signals. We found that transfer of Tbx21−/− T cells induced IL-17A-dependent colitis despite increased frequencies of IL-4-expressing cells in the intestine. This discrepancy may be due to higher amounts of IL-4 produced by activated CD4+ T cells from BALB/c versus C57BL/6 mice45, leading to the well-described Th2-bias of the BALB/c strain45. Second, differences in the composition of the intestinal microbiota between animal facilities can have a substantial effect on skewing CD4+ T cells responses. In particular, the Clostridium-related segmented filamentous bacteria (SFB) have been shown to drive the emergence of IL-17 and IL-22 producing CD4+ T cells in the intestine46. Importantly, the ability of naïve CD4+ T cells to induce colitis is dependent on the presence of intestinal bacteria, as germ-free mice do not develop pathology upon T cell transfer47. In line with this, we previously described that colonization of germ-free mice with intestinal microbiota containing SFB was necessary to restore the development of colitis47. Since our Rag1−/− colony is SFB+ and the presence of SFB was not reported in the previous studies, it is possible that differences in SFB colonization status contributed to the observed differences in pathogenicity ofTbx21−/− T cells.
It is important to note that T-bet-deficient T cells did not induce more severe colitis than WT T cells but rather promoted a distinct mucosal inflammatory response. Colitis induced by WT T cells is characterized by a multifunctional response with high amounts of IFN-γ and GM-CSF and a lower IL-17A and IL-22 response. Consistent with this, we have shown that blockade of GM-CSF abrogates T cell transfer colitis48 as well as bacteria-driven intestinal inflammation49 in T-bet sufficiency whereas blockade of IL-17A or IL-22 fails to do so. By contrast T-bet deficiency leads to production of high amounts of IL-17A and IL-22 in the colon and neutralization of either was sufficient to reduce intestinal pathology. Our in vitro experiments suggest that IL-17A and IL-22 synergise to promote intestinal epithelial cell responses, which may in part explain the efficacy of blocking IL-17A or IL-22 in colitis induced by T-bet-deficient T cells. A similar synergistic interplay has been described in the lung where IL-22 served a tissue protective function in homeostasis but induced airway inflammation in the presence of IL-17A (ref. 50). This highlights the complexity of the system in health and disease, and the need for a controlled production of both cytokines. We describe here only one mechanism of how IL-17A/IL-22 induce a context-specific epithelial cell response that potentially impacts on the order or composition of immune cell infiltration. Overall, these results provide a new perspective on T-bet, revealing its role in shaping the qualitative nature of the IL-23-driven colitogenic T cell response.
We also describe here the unexpected finding that a substantial proportion of T-bet-deficient intestinal T cells retain the ability to express IFN-γ. To investigate the potential mechanisms responsible for T-bet-independent IFN-γ production by intestinal CD4+ T cells we focused on two transcription factors, Runx3 and Eomes. Runx3 has been shown to promote IFN-γ expression directly through binding to the Ifng promoter38 and Eomes is known to compensate for IFN-γproduction in T-bet-deficient Th1 cells37. We found IL-23-mediated induction of Runx3 protein in WT and Tbx21−/− T cells isolated from the intestine, thus identifying Runx3 downstream of IL-23R signalling. By contrast, we could only detect Eomes protein and its induction by IL-23 in T-bet-deficient but not WT T cells. Thus, Runx3 and Eomes are activated in response to IL-23 in T-bet-deficient cells and are likely to be drivers of T-bet-independent IFN-γ production. In support of this we found that the majority of T-bet-deficient IL-17A−IFN-γ+ T cells expressed Eomes. However, only a minor population of IL-17A+IFN-γ+ T cells stained positive for Eomes, suggesting the existence of alternative pathways for IFN-γ production by Th17 cells. Intriguingly, a recent study identified Runx3 and Runx1 as the transcriptional regulators critical for the differentiation of IFN-γ-producing Th17 cells51. The author’s demonstrated that ectopic expression of Runx transcription factors was sufficient to induce IFN-γ production by Th17 cells even in the absence of T-bet. These findings, combined with our data on Runx3 activation downstream of IL-23R signalling strongly suggest that Runx3 rather than Eomes is driving IFN-γ expression by intestinal Th17 cells.
We have not formally addressed the role of IFN-γ in colitis driven by T-bet-deficient T cells. A recent report by Zimmermann et al.52 found that antibody-mediated blockade of IFN-γ ameliorates colitis induced by WT or T-bet-deficient T cells suggesting IFN-γ also contributes to the colitogneic response mediated by T-bet-deficient T cells as originally described for WT T cells53, 54. By contrast with our results the Zimmerman study found that IL-17A blockade exacerbated colitis following transfer of Tbx21−/− T cells. The reason for the differential role of IL-17A in the two studies is not clear but it is notable that the Zimmerman study was performed in the presence of co-infection with SFB and Hh, and this strong inflammatory drive may alter the pathophysiological role of particular cytokines. Together the data indicate that T-bet deficiency in T cells does not impede their colitogenic activity but that the downstream effector cytokines of the response are context dependent.
In conclusion, our data further underline the essential role for IL-23 in intestinal inflammation and demonstrate that T-bet is an important modulator of the IL–23-driven effector T cell response. The colitogenic T cell response in a T-bet sufficient environment is multifunctional with a dominant GM-CSF and IFN-γ response. By contrast T-bet-deficient colitogenic responses are dominated by IL-17A and IL-22-mediated immune pathology. These results may have significant bearing on human IBD where it is now recognized that differential responsiveness to treatment may reflect considerable disease heterogeneity. As such, identification of suitable biomarkers such as immunological parameters, that allow stratification of patient groups, is becoming increasingly important55. Genome-wide association studies have identified polymorphisms in loci related to innate and adaptive immune arms that confer increased susceptibility to IBD. Among these are Th1 (STAT4, IFNG and STAT1) as well as Th17-related genes (RORC, IL23R and STAT3) (refs56, 57). Thus, detailed profiling of the T cell response in IBD patients may help identify appropriate patient groups that are most likely to benefit from therapeutic blockade of certain effector cytokines. Finally, our studies highlight the importance of IL-23 in the intestinal inflammatory hierarchy and suggest that IL-23 could be an effective therapeutic target across a variety of patient groups.
Yale study: How antibodies access neurons to fight infection
Yale scientists have solved a puzzle of the immune system: how antibodies enter the nervous system to control viral infections. Their finding may have implications for the prevention and treatment of a range of conditions, including herpes and Guillain-Barre syndrome, which has been linked to the Zika virus.
Many viruses — such as West Nile, Zika, and the herpes simplex virus — enter the nervous system, where they were thought to be beyond the reach of antibodies. Yale immunobiologists Akiko Iwasaki and Norifumi Iijima used mice models to investigate how antibodies could gain access to nerve tissue in order to control infection.
In mice infected with herpes, they observed a previously under-recognized role of CD4 T cells, a type of white blood cell that guards against infection by sending signals to activate the immune system. In response to herpes infection, CD4 T cells entered the nerve tissue, secreted signaling proteins, and allowed antibody access to infected sites. Combined, CD4 T cells and antibodies limited viral spread.
“This is a very elegant design of the immune system to allow antibodies to go to the sites of infection,” said Iwasaki. “The CD4 T cells will only go to the site where there is a virus. It’s a targeted delivery system for antibodies.”
Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help
Circulating antibodies can access most tissues to mediate surveillance and elimination of invading pathogens. Immunoprivileged tissues such as the brain and the peripheral nervous system are shielded from plasma proteins by the blood–brain barrier1 and blood–nerve barrier2, respectively. Yet, circulating antibodies must somehow gain access to these tissues to mediate their antimicrobial functions. Here we examine the mechanism by which antibodies gain access to neuronal tissues to control infection. Using a mouse model of genital herpes infection, we demonstrate that both antibodies and CD4 T cells are required to protect the host after immunization at a distal site. We show that memory CD4 T cells migrate to the dorsal root ganglia and spinal cord in response to infection with herpes simplex virus type 2. Once inside these neuronal tissues, CD4 T cells secrete interferon-γ and mediate local increase in vascular permeability, enabling antibody access for viral control. A similar requirement for CD4 T cells for antibody access to the brain is observed after intranasal challenge with vesicular stomatitis virus. Our results reveal a previously unappreciated role of CD4 T cells in mobilizing antibodies to the peripheral sites of infection where they help to limit viral spread.
T Cells Help Reverse Ovarian Cancer Drug Resistance
T cells (red) attack ovarian cancer cells (green). [University of Michigan Health System]
Researchers at the University of Michigan have recently published the results from a new study that they believe underscores why so many ovarian tumors develop resistance to chemotherapy. The tumor microenvironment is made up of an array of cell types, yet effector T cells and fibroblasts constitute the bulk of the tissue. The investigators believe that understanding the interplay between these two cell types holds the key to how ovarian cancer cells develop resistance.
The new study suggests that the fibroblasts surrounding the tumor work to block chemotherapy, which is why nearly every woman with ovarian cancer becomes resistant to treatment. Conversely, the scientists published evidence that T cells in the microenvironment can reverse the resistance phenotype—suggesting a whole different way of thinking about chemotherapy resistance and the potential to harness immunotherapy drugs to treat ovarian cancer.
“Ovarian cancer is often diagnosed at late stages, so chemotherapy is a key part of treatment,” explained co-senior study author J. Rebecca Liu, M.D., associate professor of obstetrics and gynecology at the University of Michigan. “Most patients will respond to it at first, but everybody develops chemoresistance. And that’s when ovarian cancer becomes deadly.”
Dr. Liu continued, stating that “in the past, we’ve thought the resistance was caused by genetic changes in tumor cells. But we found that’s not the whole story.”
The University of Michigan team looked at tissue samples from ovarian cancer patients and separated the cells by type to study the tumor microenvironment in vitro and in mice. More importantly, the scientists linked their findings back to actual patient outcomes.
The results of this study were published recently in Cell through an article entitled “Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer.”
Ovarian cancer is typically treated with cisplatin, a platinum-based chemotherapy. The researchers found that fibroblasts blocked platinum. These cells prevented platinum from accumulating in the tumor and protected tumor cells from being killed off by cisplatin.
Diagram depicting how T cells can reverse chemotherapeutic resistance. [Cell, Volume 165, Issue 5, May 19, 2016]
“We show that fibroblasts diminish the nuclear accumulation of platinum in ovarian cancer cells, resulting in resistance to platinum-based chemotherapy,” the authors wrote. “We demonstrate that glutathione and cysteine released by fibroblasts contribute to this resistance.”
T cells, on the other hand, overruled the protection of the fibroblasts. When researchers added the T cells to the fibroblast population, the tumor cells began to die off.
“CD8+ T cells abolish the resistance by altering glutathione and cystine metabolism in fibroblasts,” the authors explained. “CD8+ T-cell-derived interferon (IFN)γ controls fibroblast glutathione and cysteine through upregulation of gamma-glutamyltransferases and transcriptional repression of system xc−cystine and glutamate antiporter via the JAK/STAT1 pathway.”
By boosting the effector T cell numbers, the researchers were able to overcome the chemotherapy resistance in mouse models. Moreover, the team used interferon, an immune cell-secreted cytokine, to manipulate the pathways involved in cisplatin.
“T cells are the soldiers of the immune system,” noted co-senior study author Weiping Zou, M.D., Ph.D., professor of surgery, immunology, and biology at the University of Michigan. “We already know that if you have a lot of T cells in a tumor, you have better outcomes. Now we see that the immune system can also impact chemotherapy resistance.”
The researchers suggest that combining chemotherapy with immunotherapy may be effective against ovarian cancer. Programmed death ligand 1 (PD-L1) and PD-1 pathway blockers are currently FDA-approved treatments for some cancers, although not ovarian cancer.
“We can imagine re-educating the fibroblasts and tumor cells with immune T cells after chemoresistance develops,” Dr. Zou remarked.
“Then we could potentially go back to the same chemotherapy drug that we thought the patient was resistant to. Only now we have reversed that, and it’s effective again,” Dr. Liu concluded.
Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer
•Fibroblasts diminish platinum content in cancer cells, resulting in drug resistance
•GSH and cysteine released by fibroblasts contribute to platinum resistance
•T cells alter fibroblast GSH and cystine metabolism and abolish the resistance
•Fibroblasts and CD8+ T cells associate with patient chemotherapy response
Summary
Effector T cells and fibroblasts are major components in the tumor microenvironment. The means through which these cellular interactions affect chemoresistance is unclear. Here, we show that fibroblasts diminish nuclear accumulation of platinum in ovarian cancer cells, resulting in resistance to platinum-based chemotherapy. We demonstrate that glutathione and cysteine released by fibroblasts contribute to this resistance. CD8+ T cells abolish the resistance by altering glutathione and cystine metabolism in fibroblasts. CD8+ T-cell-derived interferon (IFN)γ controls fibroblast glutathione and cysteine through upregulation of gamma-glutamyltransferases and transcriptional repression of system xc− cystine and glutamate antiporter via the JAK/STAT1 pathway. The presence of stromal fibroblasts and CD8+ T cells is negatively and positively associated with ovarian cancer patient survival, respectively. Thus, our work uncovers a mode of action for effector T cells: they abrogate stromal-mediated chemoresistance. Capitalizing upon the interplay between chemotherapy and immunotherapy holds high potential for cancer treatment.
Activation of effect or T cells leads to increased glucose uptake, glycolysis, and lipid synthesis to support growth and proliferation. Activated T cells were identified with CD7, CD5, CD3, CD2, CD4, CD8 and CD45RO. Simultaneously, the expression of CD95 and its ligand causes apoptotic cells death by paracrine or autocrine mechanism, and during inflammation, IL1-β and interferon-1α.. The receptor glucose, Glut 1, is expressed at a low level in naive T cells, and rapidly induced by Myc following T cell receptor (TCR) activation. Glut1 trafficking is also highly regulated, with Glut1 protein remaining in intracellular vesicles until T cell activation. CD28 co-stimulation further activates the PI3K/Akt/mTOR pathway in particular, and provides a signal for Glut1 expression and cell surface localization. Mechanisms that control T cell metabolic reprogramming are now coming to light, and many of the same oncogenes importance in cancer metabolism are also crucial to drive T cell metabolic transformations, most notably Myc, hypoxia inducible factor (HIF)1a, estrogen-related receptor (ERR) a, and the mTOR pathway. The proto-oncogenic transcription factor, Myc, is known to promote transcription of genes for the cell cycle, as well as aerobic glycolysis and glutamine metabolism. Recently, Myc has been shown to play an essential role in inducing the expression of glycolytic and glutamine metabolism genes in the initial hours of T cell activation. In a similar fashion, the transcription factor (HIF)1a can up-regulate glycolytic genes to allow cancer cells to survive under hypoxic conditions
UPDATE 6/11/2021
Bispecific Antibodies Emerging as Effective Cancer Therapeutics
Science 28 May 2021: Vol. 372, Issue 6545, pp. 916-917 DOI: 10.1126/science.abg1209
Bispecific antibodies (bsAbs) bind two different epitopes on the same or different antigens. Through this dual specificity for soluble or cell-surface antigens, bsAbs exert activities beyond those of natural antibodies, offering numerous opportunities for therapeutic applications. Although initially developed for retargeting T cells to tumors, with a first bsAb approved in 2009 (catumaxomab, withdrawn in 2017), exploring new modes of action opened the door to many additional applications beyond those of simply combining the activity of two different antibodies within one molecule. Examples include agonistic “assembly activities” that mimic the activity of natural ligands and cofactors (for example, factor VIII replacement in hemophilia A), inactivation of receptors or ligands, and delivery of payloads to cells or tissues or across biological barriers. Over the past years, the bsAb field transformed from early research to clinical applications and drugs. New developments offer a glimpse into the future promise of this exciting and rapidly progressing field.
Monoclonal antibodies (mAbs) comprise antigen-binding sites formed by the variable domains of the heavy and light chain and an Fc region that mediates immune responses. BsAbs, produced through genetic engineering, combine the antigen-binding sites of two different antibodies within one molecule, with a plethora of formats available (1). Conceptually, one can discriminate between bsAbs with combinatorial modes of action where the antigen-binding sites act independently from each other, and bsAbs with obligate modes of action where activity needs binding of both, either in a sequential (temporal) way or dependent on the physical (spatial) linkage of both (see the figure) (2). BsAbs approved as drugs are so far in the obligate dual-binding category: A T cell recruiter (blinatumomab) against cancer and a factor VIIIa mimetic to treat hemophilia A (emicizumab). Most but not all of the more than 100 bsAbs in clinical development address cancers. Some are in late stage (such as amivantamab, epcoritamab, faricimab, and KNO46), but most are still in early stages (2). Most of these entities enable effector cell retargeting to induce target cell destruction.
An increasing number of programs also explore alternative modes of action. This includes bsAbs that target pathways involved in tumor proliferation (such as amivantamab), invasion, ocular angiogenesis (such as faricimab), or immune regulation by blocking receptors and/or ligands, mainly in a combinatorial manner. Challenges for all of these entities are potential adverse effects, toxicity in normal tissues, and overshooting and systemic immune responses, especially with T cell retargeting or immune-modulating or activating entities. Such issues need to be carefully addressed.
Most of the bispecific T cell engagers comprise a binding site for a tumor-associated antigen and CD3 [a component of the T cell receptor (TCR) activation complex] as trigger molecule on T cells. To prevent or ameliorate “on-target, off-tumor” effects of T cell recruiters, approaches currently investigated include the modulation of target affinities and mechanisms to allow conditional activation upon target cell binding. Thus, a reduced affinity for CD3 increased tolerability by reducing peripheral cytokine concentrations that are associated with nonspecific or overshooting immune reactions (3). Similarly, reduced affinity for the target antigen was shown to ameliorate cytokine release and damage of target-expressing tissues (4). Tumor selectivity can be further increased by implementing avidity effects—for example, by using 2+1 bsAb formats with two low-affinity binding sites for target antigens and monovalent binding to CD3 (4).
In further approaches, binders to CD3 were identified that efficiently trigger target cell destruction without inducing undesired release of cytokines, demonstrating the importance of epitope specificity to potentially uncouple efficacy from cytokine release (5). Complementing these T cell–recruiting principles, the nonclassical T cell subset of γ9d2 T cells with strong cytotoxic activity emerged as potent effectors, which can be retargeted with bsAbs binding to the γ9d2 TCR. Thereby, global activation of all T cells, including inhibitory regulatory T cells (Treg cells), through CD3 binding, may be avoided (6). However, even these approaches might result in a narrow therapeutic window to treat solid tumors because of T cell activation in normal tissues.
Consequently, there are several approaches to conditionally activate T cells within tumors, including a local liberation of the CD3-binding sites or triggering local assembly of CD3-binding sites from two half-molecules. For example, CD3-binding sites have been masked by fusing antigen binding or blocking moieties—such as peptides, aptamers, or anti-idiotypic antibody fragments—to one or both variable domains. These moieties are released within the tumor by tumor-associated proteases, or through biochemical responses to hypoxia or low pH (7). This approach can also be applied to confer specific binding of antibody therapeutics, including bsAbs, to antigens on tumor cells (8).
An on-target restoration of CD3-binding sites requires application of two target-binding entities, each comprising parts of the CD3-binding site, which assemble into functional binding sites upon close binding of both half-antibodies. The feasibility of this approach was recently shown, for example, for a split T cell–engaging antibody derivative (Hemibody) that targets a cell surface antigen (9). Such approaches can also be applied to half-antibodies that recognize two different targets expressed on the same cell, further increasing tumor selectivity.
Regarding T cell engagers, increasing efforts are made to target not only cell-surface antigens expressed on tumor cells but also human leukocyte antigen (HLA)–presented tumor-specific peptides. This expands the target space of bsAbs toward tumor-specific intracellular antigens and can be achieved by using either recombinant TCRs or antibodies with TCR-like specificities combined with, for example, CD3-binding arms to engage T cell responses. A first TCR–anti-CD3 bispecific molecule is in phase I and II trials to treat metastatic melanoma (10). A challenge of this approach is the identification of TCRs or TCR-like antibodies that bind the peptide in the context of HLA with high affinity and specificity, without cross-reacting with related peptides to reduce or avoid off-target activities. Comprehensive screening tools and implementation of computational approaches are being developed to achieve this task.
A rapidly growing area of bsAbs in cancer therapy is their use to foster antitumor immune responses. Here, they are especially applied for dual inhibition of checkpoints that prevent immune responses—for example, programmed cell death protein 1 (PD-1) and its ligand (PD-L1), cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), or lymphocyte activation gene 3 (LAG-3; for example, KNO46). Tumor-targeted bsAbs can also target costimulatory factors such as CD28 or 4-1BB ligand (4-1BBL) to enhance T cell responses when combined with PD-1 blockade or to provide an activity-enhancing costimulatory signal in combination with CD3-based bsAbs (11). Furthermore, bsAbs are being developed for local effects by targeting one arm to antigens that are expressed by tumor cells or cells of the tumor microenvironment (2).
Clinical application of bsAbs now expands to other therapeutic areas, including chronic inflammatory, autoimmune, and neurodegenerative diseases; vascular, ocular, and hematologic disorders; and infections. In contrast to mAbs, bsAbs can inactivate the signaling of different cytokines with one molecule to treat inflammatory diseases (12). Simultaneous dual-target binding is not essential to elicit activity for bsAbs against combinations of proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1α (IL-1α), IL-1β, IL-4, IL-13, IL-17, inducible T cell costimulator ligand (ICOSL), or B cell–activating factor (BAFF). This presumably also applies to blockade of immune cell receptors, although dual targeting might confer increased efficacy due to avidity effects and increased selectivity through simultaneous binding of two different receptors.
A further application of combinatorial dual targeting is in ophthalmology. Loss of vision in wet age-related macular degeneration (AMD) results from abnormal proliferation and leakiness of blood vessels in the macula. This can be treated with antibodies that bind and inactivate factors that stimulate their proliferation (13). In contrast to mAbs or fragments that recognize individual factors, bsAbs bind two such factors. For example, faricimab that binds vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (ANG2), demonstrated dual efficacy in preclinical studies, and is currently in phase 3 trials.
BsAbs with obligate modes of action that mandate simultaneous dual-target binding are “assemblers” that replace the function of factors necessary to form functional protein complexes. One of these bsAbs with an assembly role (emicizumab, approved in 2018) replaces factor VIIIa in the clotting cascade. Deficiency of factor VIII causes hemophilia A, which can be overcome by substitution with recombinant factor VIII. However, a proportion of patients develop factor VIII–neutralizing immune responses and no longer respond to therapy. To overcome this, a bsAb was developed with binding sites that recognize and physically connect factors IXa and X, a process normally mediated by factor VIIIa. Extensive screening of a large set of bsAbs was required to identify those that combine suitable epitopes with optimized affinities and geometry to serve as functional factor VIIIa mimetics (14). This exemplifies the complexity of identifying the best bsAb for therapeutic applications.
A mode of action requiring sequential binding of two targets is the transport of bsAbs across the blood-brain barrier (BBB). This is a tight barrier of brain capillary endothelial cells that controls the transport of substances between the blood and the cerebrospinal fluid—the brain parenchyma. Passage of large molecules, including antibodies, across the BBB is thereby restricted. Some proteins, such as transferrin or insulin, pass through the BBB by way of transporters on endothelial cells. Antibodies that bind these shuttle molecules, such as the transferrin receptor (TfR), can hitchhike across the BBB. BsAbs that recognize brain targets (such as β-amyloid for Alzheimer’s disease) and TfR with optimized affinities, epitopes, and formats can thereby enter the brain. Such bsAbs are currently in clinical evaluation to treat neurodegenerative diseases (15).
In the past years, there has been a transition from a technology-driven phase, solving hurdles to generate bsAbs with defined composition, toward exploring and extending the modes of action for new therapeutic options. The challenge of generating bsAbs is not only to identify suitable antigen pairs to be targeted in a combined manner. It is now recognized that the molecular composition has a profound impact on bsAb functionality (13). That more than 30 different bsAb formats are in clinical trials proves that development is now driven by a “fit for purpose” or “format defines function” rationale. Many candidates differ in their composition, affecting valency, geometry, flexibility, size, and half-life (1). Not all members of this “zoo of bsAb formats” qualify to become drugs. Strong emphasis is therefore on identifying candidates that exhibit drug-like properties and fulfill safety, developability, and manufacturability criteria. There is likely to be an exciting new wave of bsAb therapeutics available in the coming years.
IMMUNOTHERAPIES HAVE REVOLUTIONIZEDthe treatment of many cancer types over the past two decades. But researchers have long suspected that steroids—which are known to suppress immune responses—could blunt their effectiveness. Evaluating whether that is true and to what extent is important: Steroids are often given to cancer patients experiencing symptoms like decreased appetite, respiratory distress, and fatigue.
A new study published July 7, 2025, in the journal Cancer Research Communications provides evidence that steroids taken at the start of treatment can indeed lower the effectiveness of immunotherapy. By studying 277 patients with non-small cell lung cancer at two California hospitals, researchers found a “profound” disparity between the 21 patients who were receiving steroids at the start of treatment with immune checkpoint inhibitors (ICIs) and the patients who didn’t receive steroids.
Most significantly, median overall survival time for patients at one hospital was 21 months for those who did not receive steroids, compared with about eight months for those who did. At the second hospital, the median survival was about 16 months compared with four months for those receiving steroids.
Fumito Ito, a surgeon-scientist at Keck Medicine of USC in Los Angeles and lead author of the study, says the results help affirm a growing body of research on using steroids at the start of ICI treatment. By adjusting for important variables such as smoking and treatment history, cancer stage, and personal characteristics, Ito says the study offers additional evidence of steroids’ effects on ICI treatment.
“Whether or not [a patient] was on steroids at the beginning of treatment was the only independent factor” that impacted outcomes in both cohorts, Ito says.
However, researchers note that steroids are an important treatment for certain symptoms. The patients receiving steroids in Ito’s study all either had brain metastases or underlying lung conditions; steroids are used to reduce inflammation from both. Ito’s research also suggests the timing of steroid administration, as well as dosage level, can significantly impact outcomes.
For example, Ito’s study found that patients who received moderate doses of steroids “did not show a significant difference” in survival times compared with the group who received none. And a 2021 study, led by hematologist-oncologist Diana Maslov, found that cancer patients who received steroids two months or more after starting immunotherapy lived an average of 25 months. Those who received steroids earlier in treatment lived about six months.
“We were looking for ways that we can use steroids as needed to keep patients safe, while still getting the best of the immunotherapy.” says Maslov, a hematologist-oncologist at Sharp Rees-Stealy Medical Group in San Diego.
Maslov notes that despite steroids’ known effect of suppressing immune responses, at the time of her 2021 research, many studies had actually found no detriments to their use alongside immune checkpoint inhibitors. It is only as researchers began to apply more refined techniques and tease out variables that potential problems arose. Now, scientists still have important questions to answer about the role of timing and dosage.
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For their research, Ito’s team also studied the effect in mice. They found mice that stopped receiving steroids just prior to the start of ICI therapy did not appear to have a worse outcome, an important finding in the controlled environment. Ito and colleagues say they hope the work can serve to advance a more thorough understanding of the interactions between the two treatments.
As scientists continue their hunt for answers, Maslov says that immunotherapy patients should not develop a view that all steroid use is detrimental, even if a doctor recommends it early during ICI treatment. She offers as an example people who experience lung inflammation, which if left untreated by steroids, could progress to a severe and potentially fatal stage. Cases diagnosed at a more progressed stage would then be treated with an even larger dose of steroids. Maslov urges patients not to conceal any symptoms, such as cough or trouble breathing from their doctors and instead stay in close contact about any adverse symptoms.
“Of course we want to minimize steroid use, but at the same time, they can be what patients need,” Maslov says. “And the only way for doctors to know is for that patient to communicate with them. You don’t want to wait until you can’t breathe.”
KNOWLEDGE-BASED APPROACHES FOR CANCER IMMUNOTHERAPY TARGETS
The field of cancer immunotherapy is in its infancy but has already led to a major shift in the treatment of cancer – and this is only the beginning
Cancer is the second leading cause of death in the US, accounting for almost a quarter of US deaths.1 The American Cancer Society estimates the total worldwide economic impact of cancer at $900 billion annually.2 Until recently, treatments largely relied on nonspecific toxic compounds that showed limited success. But treatment paradigms are beginning to change and an old observation about tumors and the immune system may be responsible for a new wave of cancer treatments.
Using the immune system to regulate cancer progression traces its roots back to the 1890s when William B. Coley observed that bacterial infection often coincided with cancer regression. Coley developed the theory that post-surgical infections had helped patients to recover better from their cancer by provoking an immune response. He later reported the successfully creation of a filtered mixture of bacteria and bacterial lysates to treat tumors.3 The field progressed little over the following century until the comparatively recent explosion of research which has identified the mechanisms by which cancer cells evade detection by the immune system. Armed with this knowledge, researchers have identified several protein targets, most notably Programmed Cell Death-1 (PD-1)4 and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)5, and more importantly, antibodies that act on these targets resulting in the activation of the immune system towards the targeting of cancer cells.
These findings have yielded unprecedented success in the treatment of certain cancers and ushered in the era of cancer immunotherapy.6 However, several cancers have proven refractory to PD-1 and CTLA-4 targeted therapies. For these diseases new classes of targets and new mechanisms must be identified. 7
FIGURE 2: Components of the Immune System with targets for Cancer Immunotherapy
Identifying these new targets is arguably the most important step in the multimillion dollar drug discovery process. Fewer than 1 in 10 compounds that enter clinical trials becomes a medicine.8 Most fail because they are not effective against the disease they are designed to combat.9 Often these failures can be traced back to not selecting the right target to drug.10
To address this challenge Thomson Reuters analysts are applying knowledge based approaches and scouting biological pathways for potential new targets for immune based therapies for cancer. Our knowledge comes from a combination of retrospective analysis of ongoing development programs coupled with information extracted from the literature. We use this evidence to better understand the role of the immune system in fighting cancer.
Scouting known targets for cancer immunotherapy and interrogating the regulators of these targets is one method to identify new potential targets. As an example we researched PD-1, the well-known checkpoint protein mentioned above. Analysis of the known transcriptional regulators of PD-1 highlighted that the majority of PD-1 expression is centered on activation of the JAK/STAT pathway and that targeting these proteins may represent a novel way to modulate the activity of PD-1. In addition, we uncovered interesting biomarkers for patient stratification or combination drug targets such as IFN-, NOTCH1, and the STATs.
FIGURE 4: Signaling Pathways leading to the expression of PD-1
Novel Targets for New Approaches
For novel targets we performed analysis of publically available gene sets of cancer patients to identify differentially regulated genes. Interrogating the differentially expressed genes and superimposing these onto proprietary canonical pathway maps for immune response we are able to identify several targets that can serve as starting points for immunotherapy drug discovery, biomarkers for disease progression, and for stratifying patients for clinical trials.
The field of cancer immunotherapy is in its infancy but has already led to a shift in the treatment of cancer. Instead of treating the cancer, researchers are treating the immune system which in turn specifically targets only the cancer. And that is just the beginning. The knowledge gained from this research can be applied to diseases other than cancer, ushering in a new era of immunotherapy. Not a bad outcome even if it took over 100 years to come about.
For more detail on this topic, download the slide presentation given by author Richard K. Harrison, Thomson Reuters Chief Scientific Officer, at the Molecular Med Tri-Con 2016: “Knowledge Based Approaches to New Targets in Cancer Immunotherapy.”
References:
1. Globacan, International Agency for Research on Cancer; “Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. (2012).
2. American Cancer Society Cancer Facts and Figures. (2013).
3. Coley WB, The Treatment of Malignant Tumors By Repeated Inoculations of Erysipelas: With A Report of Ten Original Cases.
The American Journal of Medical Sciences 10, 487-511 (1893).
4. H. Nishimura, M. Nose, H. Hiai, N. Minato, T. Honjo, Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying
immunoreceptor. Immunity 11, 141-151 (1999).
5. K. M. Lee et al., Molecular basis of T cell inactivation by CTLA-4. Science 282, 2263-2266 (1998).
6. A. Swaika, W. A. Hammond, R. W. Joseph, Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Mol. Immunol. 67, 4-17 (2015).
7. A. C. Anderson, Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol. Res 2, 393-398 (2014).
8. J. Arrowsmith, A decade of change. Nat. Rev. Drug. Discov. 11, 17-18 (2012).
9. J. Arrowsmith, P. Miller, Trial watch: phase II and phase III attrition rates 2011-2012. Nat. Rev. Drug. Discov. 12, 569 (2013).
10. P. Morgan et al., Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival.
Drug Discov.Today 17, 419-424 (2012).
Within immuno-oncology, checkpoint inhibitors and therapeutic cancer vaccines exhibit unique trends and challenges
Immunotherapy trials comprise more than one third of the current clinical oncology space. As innovators race to market, challenges inherent in immuno-oncology (I/O) are being met. Predictive and prognostic biomarkers have become notoriously difficult to pinpoint and regulatory bodies are struggling to maintain pace with the burgeoning field.
In taking a closer look at the 2,500 active I/O clinical trials in Cortellis Clinical Trials Intelligence, there are two classes experiencing interesting trends, each with their unique challenges. Therapeutic cancer vaccine trials have seen a shift in sponsors while steadily decreasing in number. Checkpoint inhibitors, meanwhile, have been rapidly gaining momentum.
Therapeutic Cancer Vaccines
Specialized biotech companies and research institutions have taken on the challenge of therapeutic cancer vaccine development. Following Dendreon’s success in 2010 with Provenge (sipuleucel-T), the only therapeutic cancer vaccine approved by the FDA thus far, drug developers are employing diverse strategies to effectively introduce cancer vaccines to immuno-compromised patients while mitigating adverse or unintended effects. Although the majority of therapeutic cancer vaccine studies are in the early stages, approximately 10 percent are those that have progressed to late-stage trials. These numbers indicate both an interest in the class as well as modest success with trial candidates.
On the opposite end of the spectrum, checkpoint inhibitor trials are exhibiting a rapid-fire growth pattern and tremendous success. Since 2010, they have experienced a twenty-fold increase in the number of commercially relevant trials as compared to those started in 2015. Anti-CTLA-4 trials comprise a quarter of the current space, while target newcomers, PD-1 and PD-L1, make up the remainder, with PD-1 being studied in more than half of current trials.
PD-1 is a receptor on T-cells and binds ligands PD-L1 and PD-L2 to prevent T-cell activation. Upregulation of these proteins causes cancer cells to go unnoticed by the immune system. Inhibiting this checkpoint, however, lifts the veil, allowing the immune system to launch an attack. Both big pharma and biotech companies are active in the space and are taking on trials at almost double the rate of therapeutic vaccines.
BMS, following up on their success with Yervoy (CTLA-4) and Opdivo (PD-1), are at the top of the space, followed by Merck (Keytruda, PD-1) and Roche. Early and late phase trials are split down the middle indicating both interest in the space and successful progression to phase III trials. Until recently, melanoma has been the top indication in the space; however it has since been surpassed by lung cancer.
Advanced metastatic cancers, those where other treatments have failed, remain the top patient segments in checkpoint inhibitor trials. Challenges in this space lie in identifying predictive and prognostic biomarkers. Correlating response rate to the PD-L1 biomarker, which is currently seen in 39 percent of checkpoint inhibitor trials measuring biomarkers, is not always possible.
Conclusion
Immuno-oncology is a highly marketable and dynamic space currently led by checkpoint inhibitors. However, as niches become saturated, developers must look to identify novel approaches. Immunotherapy and cross-class combinations are proving to be successful, and the recent approval of Amgen’s oncolytic virus (T-vec) for inoperable melanoma is giving hope that there are opportunities beyond T-cells. Our immune system is a complex defense structure full of cells ready to take on the fight against cancer – they just need the right orders.
Collaboration With Bristol Myers Squib Led to Successful Launch of Ono Pharmaceutical’s Cancer Immune Therapy (Opdivio®)
Reporter: Stephen J. Williams, Ph.D.
Updated 7/25/2019
Below are excerpts and a great story on the origins on Opdivo and its early marketing troubles and eventual success when Bristol Myers partnered with a small Japanese pharma, Ono Pharmaceuticals.
Ten years ago, representatives from Japan’s Ono Pharmaceutical Co. went from hospital to hospital, attempting to convince doctors to test a new product under development: drugs that helped the body’s immune system fight cancer. Nobody would listen.
Immuno-therapy was another fad, they were told. The treatment probably offered no bigger benefit than eating mushrooms to fight cancer, one critic opined. Another said he’d shave his head if it worked.
Ten years ago, representatives from Japan’s Ono Pharmaceutical Co. went from hospital to hospital, attempting to convince doctors to test a new product under development: drugs that helped the body’s immune system fight cancer. Nobody would listen.
Immuno-therapy was another fad, they were told. The treatment probably offered no bigger benefit than eating mushrooms to fight cancer, one critic opined. Another said he’d shave his head if it worked.
Ono’s Chief Executive Officer Gyo Sagara says he received plenty of apologies when Opdivo, the drug the Japanese company worked on with Bristol-Myers Squibb Co., got the green light from regulators. The drug’s approval in Japan 20 months ago was the first worldwide in a new class of cancer treatments called PD-1 inhibitors.
It is among a string of therapies coming to market in the immuno-oncology category – medicines that help the body combat cancer rather than directly attacking the cancer cells themselves. The influential Science journal called cancer immunotherapy the “breakthrough of the year” in 2013, and the biggest global pharmaceutical companies are rushing into the field.
“They found the treasure of the century,” said Fumiyoshi Sakai, a health-care analyst with Credit Suisse, who boosted his target price for the stock to 25,000 yen in mid February. Ono’s shares closed at an all-time high of 22,605 yen on Thursday after climbing more than 70 percent over the past year.
The drug is pumping fresh life into Ono, which for years has battled slumping sales, patent expirations and rising competition from cheaper generics. Analysts now forecast that the Japanese company — among the biggest makers of specialty pharmaceuticals in Asia with a market cap of about $23 billion — will more than double annual revenue to about $3 billion by fiscal year end March 2018.
For the average U.S. patient, Opdivo costs about $12,500 a month, or $150,000 for a year of therapy. Bloomberg Intelligence says that consensus analyst estimates suggest that by 2020, Bristol-Myers and Ono’s Opdivo could have global sales of $9.5 billion and Merck & Co.’s Keytruda $5.1 billion.
Bristol-Myers releases mixed Opdivo lung cancer results
Bristol-Myers released mixed results on Wednesday from trials testing the survival benefit of its immunotherapy Opdivo in combination with either chemotherapy or its other immuno-oncology drug, Yervoy, as an initial treatment for advanced lung cancer.
The U.S. drugmaker said that Opdivo combined with chemotherapy failed to extend overall survival more than chemotherapy alone in patients with advanced non-squamous non-small cell lung cancer (NSCLC).
The result sent Bristol-Myers shares 3% lower in extended trading, as it is likely to further solidify the domination of rival drug Keytruda from Merck as an initial treatment for advanced lung cancer, by far the most lucrative oncology market.
Both multibillion-dollar sellers are already approved for lung and several other types of cancer.
Opdivo did demonstrate an improvement in overall survival in combination with Yervoy in lung cancer patients whose tumors expressed at least 1% of the PD-L1 protein that the drug is designed to target. That accounts for about 70% of NSCLC patients, the company said.
PRINCETON, N.J.–(BUSINESS WIRE)–Bristol-Myers Squibb Company (NYSE: BMY) today announced that Part 2 of the Phase 3 CheckMate -227 trial did not meet the primary endpoint of overall survival (OS) with Opdivo®(nivolumab) plus chemotherapy versus chemotherapy in patients with first-line non-squamous non-small cell lung cancer (NSCLC), regardless of PD-L1 status (HR 0.86; 95% CI 0.69-1.08). The median OS for patients treated with Opdivo plus chemotherapy was 18.83 months vs. 15.57 months for chemotherapy, and the landmark one-year OS was 67.3 percent vs. 59.2 percent, respectively. In an exploratory analysis of patients with first-line squamous NSCLC, the median OS was 18.27 months for Opdivo plus chemotherapy vs. 11.96 months for chemotherapy (HR 0.69; 95% CI 0.50-0.97). No new safety signals were observed. The company will share complete findings from this trial at an upcoming medical meeting.
“While this is not the outcome we had hoped for, the Opdivo plus chemotherapy one-year landmark overall survival in the non-squamous population was consistent with the experimental arms in previously-reported trials of IO/chemotherapy combination regimens,” said Fouad Namouni, M.D., head, Oncology Development, Bristol-Myers Squibb. “We thank the patients and investigators who participated in this trial.”
Bristol-Myers Squibb also announced that Part 1a of the CheckMate -227 trial met the co-primary endpoint of OS, demonstrating a statistically significant benefit for Opdivo plus low-dose Yervoy®(ipilimumab) versus chemotherapy in patients whose tumors express PD-L1 ≥1%. Additional information can be found at www.bms.com.
Other related articles in this Open Access Journal include:
Since the first immune checkpoint–blocking monoclonal antibody was approved in the United States in 2011 for the treatment of advanced cancer, the rate of progress in the field of cancer immunotherapy has only accelerated. This mode of cancer treatment has yielded durable complete responses in a subset of patients with metastatic cancer for whom no other treatment was effective. It is a class of therapy that is not inherently cancer type–specific, and investigators are only beginning to understand why some cancers, such as melanoma, are more sensitive to immunotherapy than others. Although immunotherapy is not yet approved for the treatment of gastrointestinal cancers, it is already clear that many gastrointestinal cancers can be sensitive to it. We will review recent clinical trial results demonstrating this, and offer our perspective on the role that immunotherapy might play in the treatment of advanced gastrointestinal malignancies in the years ahead.
Introduction Immunotherapy can be defined as a therapeutic intervention that is focused on the immune system, as opposed to the cancer itself. Thus, it becomes the patient’s own immune response, rather than an exogenous drug, that acts directly against the disease. This approach to the treatment of cancer is viewed by many as a modern paradigm shift in oncology, in part because of recent successes of immune checkpoint blockade in diverse cancers.[1-3] It is important to keep in mind, however, that attempts to recruit the immune system in the effort against cancer are not new, and there is much to learn from early experiences in the field.
Immunotherapy has long been part of the standard treatment for early-stage cancers. For example, the intravesical Bacillus Calmette-Guérin vaccine and topical imiquimod are used to treat non–muscle-invasive bladder cancer and superficial basal cell carcinoma, respectively. Both of these agents are immunostimulants that function by activating immune cells in an antigen-nonspecific manner.[4,5] Their efficacy suggests that directing the immune response to a specific target is unnecessary in some cases, presaging disappointing efforts in therapeutic cancer vaccination designed to direct the immune system to targets associated with malignant cells.[6,7]
The experience with systemic immunotherapy for cancer in prior decades has been more controversial. High-dose interleukin (IL)-2 treatment for renal cell carcinoma and melanoma has led to extremely durable responses for a minority of patients, but has also led to excessive toxicity for others.[8] Without evidence of improved overall survival (OS) in a large randomized clinical trial, the precise setting for this therapy in patient care has been disputed. Nevertheless, IL-2 allowed the oncology community to glimpse both the potential efficacy and the potential harms of using the immune system to treat metastatic cancer.
Immune Checkpoint Blockade
Immune checkpoint blockade represents a class of anticancer agents that function by blocking inhibitory immune cell receptors. Among the most important members of this category are monoclonal antibodies (mAbs) that block cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) or its ligand PD-L1. After an antigen-presenting cell (APC) captures a tumor-associated antigen, it presents a portion of the antigen as a peptide to naive T cells in the context of a so-called immunologic synapse. Both stimulatory and inhibitory signaling between the T cell and the APC occur at this synapse. One inhibitory T-cell receptor that functions in this context is CTLA-4; therapeutically blocking CTLA-4 strengthens the immunogenic signal that the APC transmits to the T cell. Once the T cell is activated by the APC, it can then encounter a malignant cell presenting a cognate peptide and mediate its lysis. It is at this phase that the T cell encounters another set of inhibitory signals, including PD-L1 and PD-L2, which are both recognized by PD-1 on T cells. Anti–PD-1 mAbs block this interaction and thus enhance the ability of the activated T cell to lyse its target cell.
Immune checkpoint blockade as a means of treating cancer rose to prominence in 2010 when the anti–CTLA-4 mAb ipilimumab was found to improve median OS for patients with metastatic melanoma from 6.4 to 10 months.[7] This result was important for a number of reasons. First, ipilimumab was the first therapy to improve OS in this patient population in a phase III clinical trial. Second, since an independent study arm incorporated a therapeutic vaccine, it showed that such antigen-directed therapy did not add benefit in this context. Finally, it demonstrated that anti–CTLA-4 therapy can result in durable remissions.[9]
Following the unprecedented activity of CTLA-4 blockade, PD-1 blockade quickly rose to prominence. In fact, anti–PD-1 axis (ie, anti–PD-1 or anti–PD-L1) therapy showed response rates of over 40% in some melanoma studies,[1,10] and it has shown activity in a host of other malignancies, including non–small-cell lung cancer (NSCLC; response rate of 20%),[11,12] bladder cancer (response rate of over 40% in select patients),[3] and gastrointestinal malignancies, as discussed below.
The marked, but non-uniform, responses to checkpoint blockade triggered an international effort to identify biomarkers of response. PD-L1 expression in the tumor, whether on malignant cells or tumor-associated cells, was found to correlate with response to PD-1 axis blockade across a range of malignancies.[3,13,14] It should be noted, however, that a subset of tumors found to be PD-L1–negative did benefit from anti–PD-1 axis therapy, highlighting the fact that PD-L1 should not necessarily be used as a binary biomarker to predict response to therapy.
Although baseline PD-L1 expression correlates with response to PD-1 axis blockade, there is now evidence that genomic alterations may predict for response to checkpoint blockade more broadly. Whole-exome sequencing has demonstrated that mutation burden correlates with response to CTLA-4 blockade in melanoma,[15] and similar work revealed that mutation burden also correlates with response to PD-1 blockade in NSCLC.[16] It is not yet clear, however, that specific mutated sequences (so-called neoepitopes) reliably predict for response to any form of immunotherapy.[17] Such a finding, if prospectively validated, would enable clinicians to administer immunotherapy in much the same way that modern targeted therapies are used—based on the presence of discreet and predefined genetic lesions.
In addition, tumors that were responsive to checkpoint blockade were found to be more inflamed at baseline. For example, tumors rich in infiltrating T cells, and T helper 1 (Th1)-associated cytokines, were found to be particularly responsive.[18,19]
These findings do not only further our understanding of why immunotherapy is effective for some patients, but they also impact how immunotherapy will be used in the future. Therefore, they are of major significance as the field of immunotherapy begins to expand into gastrointestinal malignancies.
Pancreatic Cancer
Despite its historic intransigence, there are multiple lines of evidence indicating that pancreatic cancer can be responsive to immunotherapy. Pancreatic tumors have been found to exclude T cells at baseline in a manner that can be reversed.[20] Combination regimens designed to stimulate T cells with PD-L1 blockade and overcome T-cell exclusion via inhibition of the chemokine C-X-C ligand 12 (CXCL12) mediated tumor regression in an autochthonous animal model of pancreatic ductal adenocarcinoma.[21]
Based on clinical data, considering the paucity of responses to date, it is unlikely that anti–CTLA-4 therapy alone will have a role in the care of pancreatic cancer patients in the future. Nevertheless, there is instructive anecdotal evidence that even single-agent ipilimumab has activity among patients with pancreatic cancer. ….
Gastric Cancer
As with pancreatic cancer, responses to anti–CTLA-4 monotherapy in gastric carcinoma are rare and can be quite delayed. For example, in a phase II study of the anti–CTLA-4 mAb tremelimumab, 1 of 18 gastric cancer patients achieved a PR after 25 months on treatment.[30]
Consistent with other cancers, responses to PD-1 axis blockade in gastric cancer appear to be more frequent than responses to CTLA-4 blockade. Such results were anticipated by preclinical data showing that PD-L1 expression on gastric carcinoma cells, but not healthy gastric tissue or gastric adenomas, could induce T-cell apoptosis in a manner that was reversible with PD-L1–blocking mAbs.[31]
The anti–PD-1 mAb pembrolizumab is currently being tested in an ongoing phase I study of patients with adenocarcinoma of the stomach or gastroesophageal junction.[32] Preliminary results were presented at the European Society for Medical Oncology 2014 Congress. ….
Colorectal Cancer
There is extensive circumstantial data suggesting that colorectal cancer can respond to immune modulation. For example, colorectal cancer is generally associated with a relatively high mutation burden similar to other immune-responsive cancers, such as gastric and head and neck cancers.[33] In addition, there are reports associating immune signatures (eg, increased lymphocytes, especially cytotoxic and Th1 T cells, within the tumor or at the invasive margin) with improved prognosis.[34-36]
It is now apparent that two distinct immunologic subtypes of colorectal cancer exist, according to their mismatch repair (MMR) status. MMR deficiency occurs in approximately 4% of patients with metastatic colorectal cancer.[37] Tumors with MMR deficiency are rich in mutations that may be recognized as neoepitopes when presented to the adaptive immune system.[38,39] As would therefore be expected, MMR-deficient colorectal cancers are enriched for tumor-infiltrating lymphocytes.[40] This immunologic subtype of colorectal cancer represents an inherently sensitive population for T-cell stimulatory therapy. In a recently published phase II study of pembrolizumab,[41] 4 of 10 MMR-deficient patients had an immune-related objective response[23] vs 0 of 18 MMR-proficient patients. In an update presented at the 2015 American Society of Clinical Oncology Annual Meeting, which reported on 13 MMR-deficient and 25 MMR-proficient patients,[42] objective response rates were 62% and 0%, respectively. It is against this background that patients with MMR-deficient colorectal cancer will be evaluated for their response to pembrolizumab in phase II (Clinicaltrials.gov identifier: NCT02460198) and phase III (Clinicaltrials.gov identifier: NCT02563002) clinical trials; as well as for their response to durvalumab in an ongoing phase II study (Clinicaltrials.gov identifier: NCT02227667) we are currently conducting.
The Future of Immunotherapy in Gastrointestinal Cancers
We are optimistic that immunotherapy will become standard of care in at least a subset of gastrointestinal malignancies. In the near term, we anticipate that PD-1 axis blockade will be incorporated into the care of patients with gastroesophageal cancer and MMR-deficient colorectal cancer, and perhaps others, as it has been for patients with NSCLC and melanoma.
CTLA-4 and PD-1 are only two receptors among over a dozen known inhibitory and stimulatory T-cell receptors that can be targeted to augment antitumor T-cell activity.[45] There are thus innumerable combination regimens that can be designed to boost the already notable activity of checkpoint blockade. Furthermore, receptors on other immune cell populations can be activated or blocked to synergize with T-cell stimulatory therapy.[46] For example, current clinical trials are coupling the blockade of an inhibitory killer-cell immunoglobulin-like receptor on natural killer (NK) cells with anti–CTLA-4 (Clinicaltrials.gov identifier: NCT01750580) and anti–PD-1 (Clinicaltrials.gov identifier: NCT01714739) mAbs.
Given that tumor antigen–targeting mAbs (eg, cetuximab, trastuzumab) are approved or in clinical development for several types of gastrointestinal cancers,[47-49] there is interest in enhancing their efficacy through stimulation of immune cells. NK cells represent an attractive target for such a strategy, as they can mediate antibody-dependent cell-mediated cytotoxicity of malignant cells bound by tumor-targeting mAbs. In one such study that includes colorectal cancer patients, cetuximab is being combined with the anti-CD137 agonist mAb urelumab, which is designed to stimulate NK cells, in addition to T cells (Clinicaltrials.gov identifier: NCT02110082). …..
Although adoptive T-cell therapy is not yet ready for widespread clinical application, it has immense potential significance. Tran et al have effectively treated a patient with metastatic cholangiocarcinoma using CD4 T cells selected to recognize the product of a mutation specific to the patient’s tumor.[54] This type of adoptive transfer of selected, but unmodified, T cells has the notable limitation of being restricted to cancer-specific epitopes presented within patient-specific major histocompatibility complex (MHC) molecules. ….
The need for ex vivo manipulation to direct T cells to malignant cells in an MHC-independent manner can be circumvented using so-called bispecific T-cell engager (BiTE) technology. With this approach a therapeutic protein is constructed using mAb fragments specific to CD3 (present on the surface of T cells) and a molecule on the surface of the malignant cell. As with CAR technology, BiTEs have been studied primarily for the treatment of hematologic malignancies.[57] However, BiTEs that recognize the colorectal cancer–associated carcinoembryonic antigen have been developed,[58] and they will soon undergo clinical testing.
Most modern cancer immunotherapy is not inherently disease-specific. Furthermore, such treatments offer patients a chance at durable remissions, something not typically associated with cytotoxic chemotherapy or so-called targeted therapies. For these two reasons it is clear that, despite the remarkable successes to date, we are only at the start of an era in which the patient’s own immune system—with its unique combination of potency, specificity, and memory—begins to take the place of therapies that are designed to be directly toxic to malignant cells.
Lack of microsatellite instability in colon cancer dooms a Combination MEK/PD-L1 Inhibitor Trial
IMblaze370 a ‘great disappointment’ following promise in preclinical models
by Ian Ingram, Deputy Managing Editor, MedPage Today April 24, 2019
An immunotherapy and targeted therapy combination failed to improve survival over standard third-line therapy for patients with chemorefractory metastatic colorectal cancer (CRC) and microsatellite-stable disease, a phase III trial found.
Median overall survival with the PD-L1 inhibitor atezolizumab (Tecentriq) plus MEK inhibitor cobimetinib (Cotellic) was no better than treatment with regorafenib (Stivarga) for these patients (8.9 vs 8.5 months; HR 1.00, 95% Cl 0.73-1.38, P=0.99), reported Fortunato Ciardiello, MD, PhD, of Università degli Studi della Campania Luigi Vanvitelli in Naples, Italy, and colleagues.
And with a median overall survival of 7.1 months, atezolizumab alone was numerically worse than regorafenib (HR 1.19, 95% Cl 0.83-1.71, P=0.34), the researchers wrote in Lancet Oncology.
Median progression-free survival was 1.9 months in each of the atezolizumab arms versus 2.0 months in the regorafenib arm, and objective responses occurred in 3% of patients treated with atezolizumab-cobimetinib and in 2% of patients treated with each of the single agents.
“Although many patients with metastatic colorectal cancer who have tumors with high microsatellite instability benefit from clinical improvement after immune checkpoint inhibitor therapy, patients with microsatellite-stable tumors do not,” Ciardiello’s group wrote.
Only about 3% to 5% of CRC patients have microsatellite instability, a genetic marker for immunotherapy response that led to the FDA approval of the anti-PD-1 agents pembrolizumab (Keytruda) and nivolumab (Opdivo) and the anti–CTLA-4/PD-1 combination of ipilimumab (Yervoy) plus nivolumab for all solid tumor patients who harbor this genetic abnormality and have previously been treated with chemotherapy.
Mouse models of cobimetinib showed anti-tumor activity “while promoting the effector phenotype and longevity of tumor-infiltrating CD8+ T cells,” and an anti-MEK/PD-L1 combination had a synergistic effect that led to durable treatment responses and complete regression in some cases. A phase Ib trial that reported objective responses in 8% of CRC patients with microsatellite stable disease led to development of the phase III IMblaze370 trial.
“Despite the rationale supported by preclinical data, our results suggest that dual inhibition of the PD-L1 immune checkpoint and MAPK-mediated immune suppression is insufficient to generate anti-tumor immune responses in immune-excluded tumors, such as microsatellite-stable metastatic colorectal cancer,” the authors wrote. “This failure to generate a response could be because of alternative mechanisms to bypass the inhibition of the MAPK pathway by a MEK inhibitor.”
In an editorial that accompanied the study, Francesco Sclafani, MD, of the Institut Jules in Brussels, said the findings appear to put an end to the suggestion that MEK inhibition can overcome immune resistance in CRC patients with microsatellite-stable disease.
“There is great disappointment for the negative results of the IMblaze370 trial because of the scientific interest and general enthusiasm for the underlying biological rationale and supportive preliminary clinical findings,” he wrote. “Dwelling on potential reasons for such an unexpected failure is therefore imperative.”
Sclafani noted that the immunomodulatory effects of MEK inhibition are not actually a settled matter, with some data reporting “suppression of T lymphocyte proliferative response and antigen-specific expansion and impairment of antigen processing by dendritic cells,” which could account for the trial’s negative findings.
He also questioned the trial’s lack of a biomarker strategy and said that heterogeneous tumor characteristics in microsatellite-stable CRC may require “distinct immunomodulatory strategies” to restore immunogenicity and generate anti-tumor immune responses.
The investigators noted that a limitation of the study was that it was not designed to examine patient subgroups that may have been more likely to respond to the combination therapy.
From 2016 to 2017, the IMblaze370 study randomized 363 adult CRC patients 2:1:1 to the combination of 840-mg atezolizumab (IV every 2 weeks) plus 60-mg oral cobimetinib daily (days 1-21 of 28-day cycles), 1200-mg atezolizumab monotherapy (IV every 3 weeks), or 160-mg regorafenib monotherapy (days 1-21 of 28-day cycles). Patients were eligible if they had an Eastern Cooperative Oncology Group performance status of 0-1 and had progressed or were intolerant of ≥2 prior lines of systemic therapy. Enrollment of patients with microsatellite instability–high CRC was allowed, but capped at 5%.
Grade 3/4 adverse events (AEs) in the combination arm were twice as frequent as in the atezolizumab monotherapy arm (61% vs 31%, respectively), but similar to the regorafenib arm (58%). Common grade 3/4 AEs (>5%) in the combination arm included diarrhea (11%), increased blood creatine phosphokinase (7%), and anemia (6%).
Serious AEs occurred in 40% of patients in the combination arm versus 23% with regorafenib and 17% with atezolizumab alone. There were two therapy-related deaths with the combination arm due to sepsis and one in the regorafenib arm due to intestinal perforation.
The study was funded by Roche/Genentech.
Ciardiello disclosed financial relationships with Roche/Genentech, Merck Serono, Pfizer, Amgen, Servier, Lilly, Bayer, Bristol-Myers Squibb, and Celgene. Co-authors reported relationships with Roche/Genentech and various other industry entities.
Other posts on the correlation of Microsatellite Instability with PDL1 efficacy on this Open Access Journal include:
Cancer Immunotherapy Conference & Biomarkers for Cancer Immunotherapy Symposium, March 6-11, 2016 | Moscone North Convention Center | San Francisco, CA
Reporter: Aviva Lev-Ari, PhD, RN
Molecular Med Tri-Con 2016 | March 6-11, 2016 | Moscone North Convention Center | San Francisco, CA
Immunotherapy Conference & Symposia at Tri-Con 2016. Attend both for best value!
Cancer immunotherapy, hailed as the biggest breakthrough in modern cancer treatment, has quickly permeated mainstream basic and clinical research. With vast excitement seen over the past few years stirred by remarkable clinical efficacy of immunotherapy agents, the emergence and rapid growth of biotechs and pharmaceutical partnering, and recent regulatory approvals of checkpoint inhibitors and T-cell engagers, it has become clear that immuno-oncology research and the development of immunotherapies and their combinations will continue to revolutionize cancer treatment.
Cambridge Healthtech Institute’s inaugural Cancer Immunotherapy meeting will convene immuno-oncology researchers, cancer immunotherapy developers, and technology providers to discuss current challenges and opportunities – from discovery immuno-oncology to clinical studies; share latest technologies and development approaches; discuss advances in adoptive T-cell therapies and combinations, as well as to provide updates on clinical findings.
Preliminary Agenda
HARNESSING NK CELLS FOR NEW ADOPTIVE CELL THERAPIES
Enhancing NK Cell Function for Transplantation and Cancer Therapy
Jeffrey Miller, M.D., Professor, Medicine; Deputy Director; Roger L. and Lynn C. Headrick Chair in Cancer Therapeutics, University of Minnesota Cancer Center
Immunosurveillance and Immunotherapy of Cancer Mediated by Natural Killer Cells
David H. Raulet, Ph.D., CH Li Professor of Immunology and Pathogenesis; Co-Chair, Department of Molecular and Cell Biology, University of California, Berkley
Utilizing Function-Enabled NK Cells for Cancer Immunotherapy
Todd A. Fehniger, M.D., Ph.D., Associate Professor, Department of Medicine, Oncology Division, Bone Marrow Transplantation & Leukemia Section, Washington University School of Medicine
NK Adoptive Transfer and mAb Combination for Colon Cancer
Nina D. Shah, M.D., Medical Director and Assistant Professor, Stem Cell Transplantation Center, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center
Enhancing Antibody-Directed Innate Immunity to Improve Cancer Outcome
Paul M. Sondel, M.D., Ph.D., Reed and Carolee Walker Professor of Pediatrics and Human Oncology; Head, Division of Pediatric Hematology, Oncology and BMT; University of Wisconsin
ADVANCES IN ADOPTIVE T-CELL THERAPY
CAR T-Cells as Immunotherapy: Where Are We Now?
Marcela Valderrama Maus, M.D., Ph.D., Director, Cellular Immunotherapy, Massachusetts General Hospital Cancer Center; Member of the Faculty, Harvard Medical School
The ImmTAC Technology: A Cutting Edge Immunotherapy for Cancer Treatment
Martina Canestraro, Ph.D., Scientist, Cell biology, Immunocore Limited
Panel Discussion: Current Challenges and Opportunities for CAR T-Cell Therapy This panel discussion will tackle current challenges and emerging opportunities within the rapidly emerging space of chimeric antigen receptor (CAR) T-cell therapy. Topics will include, but are not limited to:
– Novel and emerging antigens for targeting
– Challenges and opportunities in targeting solid tumors
– Approaches for avoiding or controlling cytokine syndrome
– Enhancing expansion and persistence of T-cells
– Combination strategies to combat tumor microenvironment
Moderator: James Smothers, Ph.D., Senior Director and Head, Discovery, Immuno-Oncology & Combinations DPU, Oncology R&D, GlaxoSmithKline
Panelists:
-Richard Morgan, Ph.D., Vice President, Immunotherapy, bluebird bio
-David M. Spencer, Ph.D., CSO, Bellicum Pharmaceuticals, Inc.
– Philippe Duchateau, Ph.D., CSO, Cellectis SA
– Marcela Valderrama Maus, M.D., Ph.D., Director, Cellular Immunotherapy, Massachusetts General Hospital Cancer Center; Member of the Faculty, Harvard Medical School
EMERGING STRATEGIES FOR CHECKPOINT COMBINATION THERAPY
Cyclic Dinucleotides and Cancer Vaccine Development
Thomas W. Dubensky, Jr., Ph.D., CSO, Aduro Biotech
OX40 Agonist Combined with PD-1 and TGFb Receptor Blockade
Andrew D. Weinberg, Ph.D., Chief, Laboratory of Basic Immunology, Providence Cancer Center
Pre-Clinical Evaluation of an Agonist Antibody Targeting ICOS
Robert Mabry, Ph.D., Director, Protein Sciences and Antibody Technology, Jounce Therapeutics
Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells
John C. Lin, Ph.D., Senior Vice President & CSO, Cancer Immunotherapy, Pfizer
Combination Immunotherapies – Opening the Gate: Increasing Tumor Infiltrating Activated T-Cells to Optimize and Expand the Benefits of Immune Checkpoint Therapies
Jeff T. Hutchins, Ph.D., Vice President, Preclinical Research, Peregrine Pharmaceuticals
Checkpoint Immunotherapy Combinations with Small Molecules
James Smothers, Ph.D., Senior Director and Head, Discovery, Immuno-Oncology & Combinations DPU, Oncology R&D, GlaxoSmithKline
NOVEL TARGETS FOR IMMUNOTHERAPY DEVELOPMENT AND SYNERGISTIC COMBINATIONS
4-1BB as an Immune Target
Holbrook Kohrt, M.D., Ph.D., Assistant Professor, Medicine (Oncology), Stanford University Medical Center
Emerging Targets in Cancer Immunotherapy: Beyond CTLA-4 and PD-1
Xingxing Zang, Ph.D., Associate Professor, Microbiology, Immunology and Medicine, Albert Einstein College of Medicine
oxMIF as a New Therapeutic Target in Cancer
Michael Thiele, Ph.D., Manager R&D, Research & Innovation, Baxalta Innovations GmbH
TECHNOLOGICAL INNOVATIONS ENABLING DISCOVERY
New Insight into Mode of Action of Checkpoint Inhibitors via QC Cell Based Assays
Cancer immunotherapy research continues to charge forward at a rapid pace. There have been advances in existing technologies, mounting research in target discovery, and better understanding of molecular mechanisms. Still, much work needs to be done before immunotherapies are ready for standard use and biomarkers will play a pivotal role.
Cambridge Healthtech Institute’s Inaugural Biomarkers for Cancer Immunotherapy will showcase research on both predictive and prognostic biomarkers while addressing the biggest questions around predictors of immune response. Focus will be given to clinical trial case studies, global vs. type-specific markers, and molecular mechanisms. Overall, this event will provide solutions to bridge the gap between biomarkers and therapy selection.
Preliminary Agenda
PREDICTIVE AND PROGNOSTIC BIOMARKERS FOR IMMUNO-ONCOLOGY
Cancer Immunotherapy Biomarkers: Lessons from Clinical Trials
Lisa H. Butterfield, Ph.D., Professor, Medicine, Surgery and Immunology; Director, UPCI Immunologic Monitoring and Cellular Products Laboratory, University of Pittsburgh
An Assay for Simultaneous Measurement of Subpopulations of Tumor Infiltrating Lymphocytes
Kurt Schalper, M.D., Ph.D., Associate Research Scientist, Pathology, Yale School of Medicine
The Role of Global Immunocompetence In Cancer Immunotherapy
Holden Maecker, Ph.D., Associate Professor, Microbiology and Immunology; Director, Human Immune Monitoring Center, Stanford University
Peritumoral vs. Intratumoral Cells in Outcome Coordination
Paul Tumeh, M.D., Assistant Professor, Department of Medicine, University of California Los Angeles
Tissue-Based Analyses to Guide Immunotherapy for Lymphoma
Scott Rodig, M.D., Ph.D., Hematopathologist, Department of Pathology, Brigham and Women’s Hospital
PREDICTORS FOR CHECKPOINT INHIBITORS
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Luis Diaz, M.D., Associate Professor, Oncology, John Hopkins Kimmel Cancer Center
PD-L1/PD-1 Tumor Biology
Kathleen Mahoney, M.D., Ph.D., Instructor, Medicine, Hematology Oncology, Beth Israel Deaconess Medical Center
THE ROLE OF THE TUMOR MICROENVIRONMENT
Imprime PGG and the Tumor Microenvironment
Jeremy R. Graff, Ph.D., Senior Vice President, Research, Pharmaceutical Group, Biothera, Inc.
Genomic Approaches to Deciphering Protective Immune Mechanisms in Cancer
Brad Nelson, Ph.D., Director, Deeley Research Centre, BC Cancer Agency
IMMUNOTHERAPY CLINICAL TRIALS
Immunotherapy at a Tipping Point: DPV-001 – A DC-Targeted Strategy with More than 100 Cancer Antigens, Multiple TLR Agonists and Damps Induces Broad-Spectrum Anti-Cancer Immunity in Patients with Cancer
Bernard A. Fox, Ph.D., Harder Family Chair for Cancer Research, Member & Chief, Laboratory of Molecular & Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Providence Portland Medical Center; CEO, UbiVac
Combinations with CRS-207, a Live-Attenuated Listeria Monocytogenes Expressing Mesothelin
Dirk G. Brockstedt, Ph.D., Senior Vice President, Research & Development, Aduro BioTech, Inc.
Product Characteristics and Pharmacodynamic Biomarker Profile of Patients Receiving Anti-CD19 CAR T Cell Therapy: Correlates of Clinical Response
Margo Roberts, Ph.D., CSO, Kite Pharma, Inc.
ESTABLISHING COMPANION DIAGNOSTICS ACROSS TARGETED IMMUNOTHERAPIES
Establishing a PD-L1 Diagnostic for Nivolumab, a Novel Immune PD-1 Checkpoint Inhibitor for the Treatment of Cancer
Steven D. Averbuch, M.D., Vice President, Development, Oncology & Pharmacodiagnostics, Bristol-Myers Squibb Company
A Critical Appraisal of Biomarkers for Immune Therapy: The Pathologist’s Perspective
Robert A. Anders, Ph.D., Associate Professor, Pathology, Johns Hopkins School of Medicine; Director, Liver Pathology, Division of Gastrointestinal and Liver Pathology, Johns Hopkins Hospital
Talk Title to be Announced
Abigail McElhinny, Ph.D., Vice President, Assay and Reagent Development, Ventana
Developing an Immunohistochemistry Test for “Programmed Cell Death 1 Ligand” (PD-L1) as a Companion Diagnostic for Pembrolizumab
Kenneth Emancipator, M.D., Executive Medical Director, Molecular Biomarkers and Diagnostics, Merck Research Laboratories
PANEL DISCUSSION Moderator to be Announced
Panelists:
-Robert A. Anders, Ph.D., Associate Professor, Pathology, Johns Hopkins School of Medicine; Director, Liver Pathology, Division of Gastrointestinal and Liver Pathology, Johns Hopkins Hospital
-Steven D. Averbuch, M.D., Vice President, Development, Oncology & Pharmacodiagnostics, Bristol-Myers Squibb Company
-Abigail McElhinny, Ph.D., Vice President, Assay and Reagent Development, Ventana
-Kenneth Emancipator, M.D., Executive Medical Director, Molecular Biomarkers and Diagnostics, Merck Research Laboratories
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SC21: Best Practices in Personalized and Translational Medicine | Learn More
Julio Fernandez, Ph.D., Principal Scientist, Pfizer
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Gregory Adams, Ph.D., CSO, Eleven Biotherapeutics
9:00 Immunomodulatory Antibodies – Potentiation by Fc Receptor Engagement
Rony Dahan, Ph.D., Principal Investigator, Immunology, Weizmann Institute of Science, Israel
9:30 Coffee Break
Allison S. Betof, M.D., Ph.D., Medical Oncology Fellow, Memorial Sloan Kettering Cancer Center
Megan M. Kaneda, Ph.D., Assistant Project Scientist, University of California, San Diego
Yan Qu, Ph.D., Senior Principal Scientist, Pfizer
11:30 Epitope Identification and Clinical Immune Monitoring in Immune Oncology Programs
Emilee Knowlton, Ph.D., Immunology Sales Specialist, ProImmune
Mark Throsby, Ph.D., EVP & CSO, Merus N.V., The Netherlands
Nicola Wallis, Ph.D., Senior Director, Biology, Astex Therapeutics, Ltd.
Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom
Daniel L. Levey, Ph.D., Senior Director, Vaccine Research, Agenus
Marc Mansour, Ph.D., Chief Business Officer, Vaximm AG
Chan C. Whiting, Ph.D., Director, Immune Monitoring and Biomarker Development, Aduro Biotech
Aaron Hansen, M.D., Ph.D., Assistant Professor, Department of Medicine, University of Toronto; Medical Oncologist, Princess Margaret Cancer Center
Ken Chang, Ph.D., Vice President, Research and Development, Immunomedics
10:00 Accelerated Production of Immunomodulatory Therapeutic Antibodies & Bispecific Molecules Using Scalable Cell Engineering
James Brady, Ph.D., Vice President, Technical Applications & Customer Support, MaxCyte
Adam J. Adler, Ph.D., Professor, Immunology, University of Connecticut
Ruchi Gupta, Ph.D., Team Lead Scientist, MedImmune
2012pharmaceutical
sjwilliamspa
