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Archive for the ‘Synergistic Innate and Adaptive Immunotherapy’ Category


2018 Nobel Prize in Physiology or Medicine for contributions to Cancer Immunotherapy to James P. Allison, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Dr. Allison shares the prize with Tasuku Honjo, M.D., Ph.D., of Kyoto University Institute, Japan

Reporter: Aviva Lev-Ari, PhD, RN

 

See

Immune System Stimulants: Articles of Note @pharmaceuticalintelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/05/01/immune-system-stimulants-articles-of-note-pharmaceuticalintelligence-com/

 

Immune-Oncology Molecules In Development & Articles on Topic in @pharmaceuticalintelligence.com

Curators: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/11/articles-on-immune-oncology-molecules-in-development-pharmaceuticalintelligence-com/

 

 

Monday, October 1, 2018

NIH grantees win 2018 Nobel Prize in Physiology or Medicine.

The 2018 Nobel Prize in Physiology or Medicine has been awarded to National Institutes of Health grantee James P. Allison, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Dr. Allison shares the prize with Tasuku Honjo, M.D., Ph.D., of Kyoto University Institute, Japan, for their discovery of cancer therapy by inhibition of negative immune regulation.

The Royal Swedish Academy of Sciences said, “by stimulating the inherent ability of our immune system to attack tumor cells this year’s Nobel Laureates have established an entirely new principle for cancer therapy.”

Dr. Allison discovered that a particular protein (CTLA-4) acts as a braking system, preventing full activation of the immune system when a cancer is emerging. By delivering an antibody that blocks that protein, Allison showed the brakes could be released. The discovery has led to important developments in cancer drugs called checkpoint inhibitors and dramatic responses to previously untreatable cancers. Dr. Honjo discovered a protein on immune cells and revealed that it also operates as a brake, but with a different mechanism of action.

“Jim’s work was pivotal for cancer therapy by enlisting our own immune systems to launch an attack on cancer and arrest its development,” said NIH Director Francis S. Collins, M.D., Ph.D. “NIH is proud to have supported this groundbreaking research.”

Dr. Allison has received continuous funding from NIH since 1979, receiving more than $13.7 million primarily from NIH’s National Cancer Institute (NCI) and National Institute of Allergy and Infectious Diseases (NIAID).

“This work has led to remarkably effective, sometime curative, therapy for patients with advanced cancer, who we were previously unable to help,” said NCI Director Ned Sharpless, M.D. “Their findings have ushered in the era of cancer immunotherapy, which along with surgery, radiation and cytotoxic chemotherapy, represents a ‘fourth modality’ for treating cancer. A further understanding of the biology underlying the immune system and cancer has the potential to help many more patients.”

“Dr. Allison’s elegant and groundbreaking work in basic immunology over four decades and its important applicability to cancer is a vivid demonstration of the critical nature of interdisciplinary biomedical research supported by NIH,” says NIAID Director Anthony S. Fauci, M.D.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

SOURCE

https://www.nih.gov/news-events/news-releases/nih-grantees-win-2018-nobel-prize-physiology-or-medicine

 

Dr. Lev-Ari covered in person the following curated articles about James Allison, PhD since his days at University of California, Berkeley, including the prizes awarded prior to the 2018 Nobel Prize in Physiology.

 

2018 Albany Medical Center Prize in Medicine and Biomedical Research goes to NIH’s Dr. Rosenberg and fellow immunotherapy researchers James P. Allison, Ph.D., and Carl H. June, M.D.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/08/15/2018-albany-medical-center-prize-in-medicine-and-biomedical-research-goes-to-nihs-dr-rosenberg-and-fellow-immunotherapy-researchers-james-p-allison-ph-d-and-carl-h-june-m-d/

 

Lectures by The 2017 Award Recipients of Warren Alpert Foundation Prize in Cancer Immunology, October 5, 2017, HMS, 77 Louis Paster, Boston

REAL TIME Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/09/08/lectures-by-the-2017-award-recipients-of-warren-alpert-foundation-prize-in-cancer-immunology-october-5-2017-hms-77-louis-paster-boston/

 

Cancer-free after immunotherapy treatment: Treating advanced colon cancer – targeting KRAS gene mutation by tumor-infiltrating lymphocytes (TILs) and Killer T-cells (NK)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/08/cancer-free-after-immunotherapy-treatment-treating-advanced-colon-cancer-targeting-kras-gene-mutation-by-tumor-infiltrating-lymphocytes-tils-and-killer-t-cells-nk/

 

New Class of Immune System Stimulants: Cyclic Di-Nucleotides (CDN): Shrink Tumors and bolster Vaccines, re-arm the Immune System’s Natural Killer Cells, which attack Cancer Cells and Virus-infected Cells

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/24/new-class-of-immune-system-stimulants-cyclic-di-nucleotides-cdn-shrink-tumors-and-bolster-vaccines-re-arm-the-immune-systems-natural-killer-cells-which-attack-cancer-cells-and-virus-inf/

 

UC Berkeley research led to Nobel Prize-winning immunotherapy

Immunologist James P. Allison today shared the 2018 Nobel Prize in Physiology or Medicine for groundbreaking work he conducted on cancer immunotherapy at UC Berkeley during his 20 years as director of the campus’s Cancer Research Laboratory.

James Allison

James Allison, who for 20 years was a UC Berkeley immunologist conducting fundamental research on cancer, is now at the M.D. Anderson Cancer Center in Houston, Texas.

Now at the University of Texas M.D. Anderson Cancer Center in Houston, Allison shared the award with Tasuku Honjo of Kyoto University in Japan “for their discovery of cancer therapy by inhibition of negative immune regulation.”

Allison, 70, conducted basic research on how the immune system – in particular, a cell called a T cell – fights infection. His discoveries led to a fundamentally new strategy for treating malignancies that unleashes the immune system to kill cancer cells. A monoclonal antibody therapy he pioneered was approved by the Food and Drug Administration in 2011 to treat malignant melanoma, and spawned several related therapies now being used against lung, prostate and other cancers.

“Because this approach targets immune cells rather than specific tumors, it holds great promise to thwart diverse cancers,” the Lasker Foundation wrote when it awarded Allison its 2015 Lasker-DeBakey Clinical Medical Research Award.

Allison’s work has already benefited thousands of people with advanced melanoma, a disease that used to be invariably fatal within a year or so of diagnosis. The therapy he conceived has resulted in elimination of cancer in a significant fraction of patients for a decade and counting, and it appears likely that many of these people are cured.

“Targeted therapies don’t cure cancer, but immunotherapy is curative, which is why many consider it the biggest advance in a generation,” Allison said in a 2015 interview. “Clearly, immunotherapy now has taken its place along with surgery, chemotherapy and radiation as a reliable and objective way to treat cancer.”

“We are thrilled to see Jim’s work recognized by the Nobel Committee,” said Russell Vance, the current director of the Cancer Research Laboratory and a UC Berkeley professor of molecular and cell biology. “We congratulate him on this highly deserved honor. This award is a testament to the incredible impact that the fundamental research Jim conducted at Berkeley has had on the lives of cancer patients”

“I don’t know if I could have accomplished this work anywhere else than Berkeley,” Allison said. “There were a lot of smart people to work with, and it felt like we could do almost anything. I always tell people that it was one of the happiest times of my life, with the academic environment, the enthusiasm, the students, the faculty.”

In this video about UC Berkeley’s new Immunotherapeutics and Vaccine Research Initiative (IVRI), Allison discusses his groundbreaking work on cancer immunotherapy.

In fact, Allison was instrumental in creating the research environment of the current Department of Molecular and Cell Biology at UC Berkeley as well as the department’s division of immunology, in which he served stints as chair and division head during his time at Berkeley, said David Raulet, director of Berkeley’s Immunotherapeutics and Vaccine Research Initiative (IVRI).

“His actions helped create the superb research environment here, which is so conducive to making the fundamental discoveries that will be the basis of the next generation of medical breakthroughs,” Raulet said.

Self vs. non-self

Allison joined the UC Berkeley faculty as a professor of molecular and cell biology and director of the Cancer Research Laboratory in 1985. An immunologist with a Ph.D. from the University of Texas, Austin, he focused on a type of immune system cell called the T cell or T lymphocyte, which plays a key role in fighting off bacterial and viral infections as well as cancer.

Supercharging the immune system to cure disease: immunotherapy research at UC Berkeley. (UC Berkeley video by Roxanne Makasdjian and Stephen McNally)

At the time, most doctors and scientists believed that the immune system could not be exploited to fight cancer, because cancer cells look too much like the body’s own cells, and any attack against cancer cells would risk killing normal cells and creating serious side effects.

“The community of cancer biologists was not convinced that you could even use the immune system to alter cancer’s outcome, because cancer was too much like self,” said Matthew “Max” Krummel, who was a graduate student and postdoctoral fellow with Allison in the 1990s and is now a professor of pathology and a member of the joint immunology group at UCSF. “The dogma at the time was, ‘Don’t even bother.’ ”

“What was heady about the moment was that we didn’t really listen to the dogma, we just did it,” Krummel added. Allison, in particular, was a bit “irreverent, but in a productive way. He didn’t suffer fools easily.” This attitude rubbed off on the team.

Trying everything they could in mice to tweak the immune system, Krummel and Allison soon found that a protein receptor called CTLA-4 seemed to be holding T cells back, like a brake in a car.

Postdoctoral fellow Dana Leach then stepped in to see if blocking the receptor would unleash the immune system to actually attack a cancerous tumor. In a landmark paper published in Science in 1996, Allison, Leach and Krummel showed not only that antibodies against CTLA-4 released the brake and allowed the immune system to attack the tumors, but that the technique was effective enough to result in long-term disappearance of the tumors.

“When Dana showed me the results, I was really surprised,” Allison said. “It wasn’t that the anti-CTLA-4 antibodies slowed the tumors down. The tumors went away.”

After Allison himself replicated the experiment, “that’s when I said, OK, we’ve got something here.”

Checkpoint blockade

The discovery led to a concept called “checkpoint blockade.” This holds that the immune system has many checkpoints designed to prevent it from attacking the body’s own cells, which can lead to autoimmune disease. As a result, while attempts to rev up the immune system are like stepping on the gas, they won’t be effective unless you also release the brakes.

Allison in 1993

James Allison in 1993, when he was conducting research at UC Berkeley on a promising immunotherapy now reaching fruition. (Jane Scherr photo)

“The temporary activation of the immune system though ‘checkpoint blockade’ provides a window of opportunity during which the immune system is mobilized to attack and eliminate tumors,” Vance said.

Allison spent the next few years amassing data in mice to show that anti-CTLA-4 antibodies work, and then, in collaboration with a biotech firm called Medarex, developed human antibodies that showed promise in early clinical trials against melanoma and other cancers. The therapy was acquired by Bristol-Myers Squibb in 2011 and approved by the FDA as ipilimumab (trade name Yervoy), which is now used to treat skin cancers that have metastasized or that cannot be removed surgically.

Meanwhile, Allison left UC Berkeley in 2004 for Memorial Sloan Kettering research center in New York to be closer to the drug companies shepherding his therapy through clinical trials, and to explore in more detail how checkpoint blockade works.

“Berkeley was my favorite place, and if I could have stayed there, I would have,” he said. “But my research got to the point where all the animal work showed that checkpoint blockade had a lot of potential in people, and working with patients at Berkeley wasn’t possible. There’s no hospital, no patients.”

Thanks to Allison’s doggedness, anti-CTLA-4 therapy is now an accepted therapy for cancer and it opened the floodgates for a slew of new immunotherapies, Krummel said. There now are several hundred ongoing clinical trials involving monoclonal antibodies to one or more receptors that inhibit T cell activity, sometimes combined with lower doses of standard chemotherapy.

Antibodies against one such receptor, PD-1, which Honjo discovered in 1992, have given especially impressive results. Allison’s initial findings can be credited for prompting researchers, including Allison himself, to carry out the studies that have demonstrated the potent anti-cancer effects of PD-1 antibodies. In 2015, the FDA approved anti-PD-1 therapy for malignant melanoma, and has since approved it for non-small-cell lung, gastric and several other cancers.

Science magazine named cancer immunotherapy its breakthrough of 2013 because that year, “clinical trials … cemented its potential in patients and swayed even the skeptics. The field hums with stories of lives extended: the woman with a grapefruit-size tumor in her lung from melanoma, alive and healthy 13 years later; the 6-year-old near death from leukemia, now in third grade and in remission; the man with metastatic kidney cancer whose disease continued fading away even after treatment stopped.”

Allison pursued more clinical trials for immunotherapy at Sloan-Kettering and then in 2012 returned to his native Texas.

Born in Alice, Texas, on Aug. 7, 1948, Allison earned a B.S. in microbiology in 1969 and a Ph.D. in biological science in 1973 from the University of Texas, Austin.

RELATED INFORMATION

SOURCE

http://news.berkeley.edu/2018/10/01/uc-berkeley-research-led-to-nobel-prize-winning-immunotherapy/

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Image Source:Koch Institute

LIVE – OCTOBER 17 – DAY 2- Koch Institute Immune Engineering Symposium 2017, MIT, Kresge Auditorium

Koch Institute Immune Engineering Symposium 2017

http://kochinstituteevents.cvent.com/events/koch-institute-immune-engineering-symposium-2017/agenda-64e5d3f55b964ff2a0643bd320b8e60d.aspx

Image Source: Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Aviva Lev-Ari, PhD, RN will be in attendance covering the event in REAL TIME

@pharma_BI

@AVIVA1950

#IESYMPOSIUM

@KOCHINSTITUTE

  • The Immune System, Stress Signaling, Infectious Diseases and Therapeutic Implications: VOLUME 2: Infectious Diseases and Therapeutics and VOLUME 3: The Immune System and Therapeutics (Series D: BioMedicine & Immunology) Kindle Edition – on Amazon.com since September 4, 2017

https://www.amazon.com/dp/B075CXHY1B

SYMPOSIUM SCHEDULE

OCTOBER 17 – DAY 2

8:30 – 9:45 Session V
Moderator: Stefani Spranger | MIT, Koch Institute

K. Christopher Garcia – Stanford University
Exploiting T Cell and Cytokine Receptor Structure and Mechanism to Develop New Immunotherapeutic Strategies

  • T Cell Receptor, peptide-MHC, 10 to the power of 10 is combinatorics – Library for selection to determine enrichment possibilities
  • Ligand identification for orphan TCRs
  1. Industrializing process
  2. use pMHC
  • IL-2 – Receptor Signaling Complex
  • Effector cells (NK, T)
  • Engineered  T Cell – Tunable expansion, ligand-Receptor interface
  • Randomize IL-2RBeta interface: Orthogonal receptor vs wild type
  • In Vivo adoptive transfer model: to quantify orthogonality ratio
  • CD4, CD8, Treg,C57BL/6J
  • Ligand discovery
  • Orthogonal IL-2

Stefani Spranger – MIT, Koch Institute
Batf3-DC as Mediators of the T Cell-Inflamed Tumor Microenvironment

  • Melanoma – solid cancer and other types, Immune inhibitory regulatory pathway patient with Immune response present
  • T cell-inflamed Tumor vs Non-T cell-inflamed Tumor
  • identify oncogenic pathways differentially activated between T cell-inflamed and non-Tcell-inflamed infiltration
  • If on Tumor:
  1. Braf/PTEN
  2. Braf/CAT
  3. Braf/PTEN/CAT
  • The role of T cell priming – lack of initial
  • Beta-catenin-expressing tumors fail to prime 2C TCR-transgenic T cells
  • Deficiency in number of CD8+ and CD103+ dendritic cells
  • CD103+ DC are essential for T cell Priming and T cell-inflammation #StefaniSpranger
  • Adoptive transfer of effector 2C T cells fails to control Beta-catenin+ tumors
  • Vaccination induced anti-gen specific T cell memory fails to control Beta-catenin+ tumors
  • What cell type in tumor microenvironment effect monilization of T cell
  • CD103+ Dendritic cellsare source chymokine
  • Recruitment of effector T cells: Reconstitution od Beta-catenin-expressing SIY+
  • Are Batf3-DC within the tumor required for the recruitment of effector T cells?
  • Tumor-residing Batf3-drive CD103+ DC are required for the recruitment of effector T cells
  • Gene spore for correlation with recturment of effector cells
  • T cell Priming – CD103+ DC are essential for effector T cells

George Georgiou – University of Texas at Austin
The Human Circulating Antibody Repertoire in Infection, Vaccination or Cancer

  • Serological Antibody Repertoire: in blood or in secretions
  • Antibody in serum – is difficult sequence identity
  • Serum IgG – 7-17 mg/ml if less immune deficient if more hyper globular
  • antibodies produced in long lived plasma cells in the bone marrow — experimentally inaccessible
  • Discovery of antibodies from the serological repertoire – not B cells
  • BM-PCs
  • Serum antibodies function via Fc effector mechanism – complement activation
  • Ig-SEQ – BCR-SEQ
  • Repertoire-wide computational modelling of antibody structures
  • En masse analysis & Mining of the Human Native Antibody Repertoire
  • hypervariable – High-Throughput Single B Cell VH:VL (or TCRalpha, beta) sequencing
  • EBOV Vaccinee Peak ASCs (day 8) mining: Neutralization
  • Features of the Serum Antibody Repertoire to Vaccine ANtigens:The Serum IgG Repertoire is Highly Polarized
  • Each bar represents a distinct antibody lineage
  • Serum IgG Repertoire becomes increasingly polarized with AGE >50 – may be predictive of tumor development process
  • Human Norovirus – explosive Diarreha, chromically infected – HuNoV BNAb Discovery – Takeda 214 bivalent Vaccine – Binding antibodies binding to avccine antigen VLP
  • HuNoV causes 800 death in the US per year of immune deficient
  • Influenza Trivalent Vaccine: Antibodies to hemaggiutinin: H1, H3, and B COmponenet
  • Abundant H1 +H3 Serum IgGs do not neutralize but confer Protection toInfluenza challenge with Live Virus #GeorgeGeorgiou
  • Non-Neutralizing Antibodies: The role of Complement in Protection

9:45 – 10:15 Break

10:15 – 11:30 Session VI
Moderator: K. Dane Wittrup | MIT, Koch Institute

Harvey Lodish – Whitehead Institute and Koch Institute
Engineered Erythrocytes Covalently Linked to Antigenic Peptides Can Protect Against Autoimmune Disease

  • Modified Red blood cells are microparticles for introducing therapeutics & diagnostics into the human body
  • Bool transfusion is widely used therapeutics
  • Covalently linking unique functional modalities to mouse or human red cells produced in cell culture:
  • PRODUCTION OF HUMAN RED BLOD CELLS EXPRESSING A FOREIN PROTEIN: CD34+ stem/progenitor cells that generates normal enucleated RBC.
  • PPAR-alpha and glucocorticoticoid receptor
  • Norman morphology: Sortase A is a bactrial transpeptidase that covalently links a “donor”
  • Engineering Normal Human RBC biotin-LPETG
  • Covelantely – Glycophorin A with camelid VHHs specific for Botulinum toxin A or B
  • Generation of immuno tolerance: SOruggable Mature RBCs: CRISPR mice expressing Kell-LPETG
  • Ovalbumin as Model Antigens:
  1. OBI B,
  2. OTI CD8 T cells
  3. OTII CD4 T cells
  4. OT-1
  5. OT-2
  • RBC induced peptides challenged and experiences apoptosis
  • Type I Diabetes in NOD mice
  • RBCs bearing InsB9-23 – prevented development of diabetes

Multiple sclerosis

  • MOG – Myelin Oligodend

Sai Reddy – ETH Zurich
Molecular Convergence Patterns in Antibody Responses Predict Antigen Exposure

  • Clonal diversity – estimating the size of antibody repertoire: 10 to power of 18 or 10 to 13
  • Clonal selection in antibody repertoire
  • Convergent selection in antibody repertoire
  • Convergent selection in TCR repertoire complex have restriction with MCH interactions
  • How molecular abundance of convergence predicts antigen exposure identify antigen-associated clusters #SaiReddy
  • molecular convergence 0 gene expression analysis, immunization scheme molecular bar coding to correct errors
  • Recoding antibody repertoire sequence space: Cross correlation reveals different clusters
  • Building a classifier model based on cluster frequency: Clones from immunized mice
  • epitope specificity is driving antibody repertoire response
  • deep learning,

K. Dane Wittrup – MIT, Koch Institute
Temporal Programming of Synergistic Innate and Adaptive Immunotherapy

  • Innate effector functions of anti-tumor antibodies
  • Innate & adaptive Immunotherapy
  • Innate mAb –>> tumor cell; adaptive CD8+ T cells
  • Chemokines Antigens
  • Cytokines Chemokines – back and forth innate Adaptive –> <— neutrophils impact
  • AIPV vaccine:
  • How anti-TAA mAbs helping T cell Immune response
  • Anti-TAA mAbs drive vaccinal T cell responses: NK cells
  • antibody drives T cells responses: alpha-TAA mAbs potentiate T cell therapies: ACT +MSA-IL-2 vs alphaPD-1 + vaccine
  • CD8+ T cells required for alpha TAA mAb efficacy- In absence of T cells Treatment does not work
  • Anti-TAA mAb +Fc/IL-2 induces intramural cytokine storm #KDaneWittrup
  • How to simplify and improve AIPV? Hypothesis: ALign dose schedule
  • Immune response to infection follwos a temporal progression: Innate … Adaptive
  • Antigenic material kill cells: Chemo, cell death Antigen presentation, T cell priming, T cell recirculation, Lymphocyte tumor infiltrate, TCR
  • IFN alpha 2 dys after mAb +Il-2: Curative: days post tumor injection
  • Necessary components: CD8+ T cells & DC, Macrophages,
  • Optimal IFNalpha coincides with max innate response vs Mature DCs after antigen loading #KDaneWittrup
  • Optimal timing od agent administration effect on Therapy Outcome: IL-2, IFNalpha, TAAmAb
  • Cytkine timing can be better than protein engineering #KDaneWittrup

11:30 – 1:00 Lunch Break

1:00 – 2:15 Session VII
Moderator: Michael Birnbaum | MIT, Koch Institute

Kai Wucherpfennig – Dana-Farber Cancer Institute
Discovery of Novel Targets for Cancer Immunotherapy

  • POSITIVE STRESS SIGNAL during malignant Transformation
  • NKG2G=D Receptor: MICA/B Results in Immune escape – Proteolytic cleavage  shedding of MICA/B present in serum, indication of tumor progression
  • Shed MICA vs Surface MICA/B – restore NK cell cytotoxicity and IFNgamma Production
  • Human NK cells express NKG2D and Fc Receptors
  • Synergistic NKG2D and CD16 signaling enhances NK cell cytootxicity: Control IgG vs Anti NKG2D
  • MICA Antibody induces Immunity Against Lung Metastases
  • NK cells are required to inhibit Growth of metastases: Anti-CD8beta,
  • Contribution to Therapeutic Efficacy: NKG2D and CD16 Receptors #KaiWucherpfennig
  • Strategy to analyze Pulmonary NK cells: Activation and expression
  • Single cell RNA-seq of lung NK cells Revealed higher infiltration of activated NK cells: Isotype vs 7C6-migG2a
  • Cytokines and Chemokines produce NK cells
  • MICA/B increaces NK
  •  Induction of Tumor cell Apoptosis
  • Xenotransplant Model with Human Melanoma Cel Line A2058
  • Lung metastasis, liver metastasis
  • Inhibition of human melanoma Metastases in NSG Mice Reconstitute with Human NK
  • Liver metastases are controlled by Myeloid Cells that include Kupffer cells

Michael Birnbaum – MIT, Koch Institute
An Unbiased Determination of pMHC Repertoires for Better Antigen Prediction

  • Vaccines TCR gene therapy adoptive T cel therapy
  • Tumor genone – Tumor pMHC repertoire = Tumor TCR repertoire T cell repertoire
  • Neoantigen vaccines as a personalized anti-cancer therapy
  • Tumor procurement – Target selection – personal vaccine production – vaccine administration
  • Prediction of neoantigen-MHC Binding due to polimorphism affecting recognition, rare in MHC Allells #Michael Birnbaum
  • Antigenicity – Chaperones HLA-DM sculp the peptide binding repertoire of MHC
  • Identification of loaded peptide ligands: pMHC mass spectroscopy of tissue
  • TCR recognition, pMHC yeast display: Cleave peptide-MHC linker, catalyze peptide exchange
  • HLA-DR4 library design and selection to enrich HLA-DM: Amino Acid vs Peptide position: Depleted vs Enriched – relative to expected for NNK codon
  •  6852 _ predicted to bind vs 220 Non-binding peptides
  • HLA polymorphism: repertoire differences caused by
  • Antigen – T cell-driven antigen discovery: engaging Innate and Adaptive Immune response
  • Sorting TIL and select: FOcus of T cell-driven antigen discovery
  • T cell-driven antigen discovery: TCR

Jennifer R. Cochran – Stanford University
Innate and Adaptive Integrin-targeted Combination Immunotherapy

  • alpa-TAA
  • Targeting Integrin = universal target involved in binding to several receptors: brest, lung, pancreatic, brain tumors arising by mutations – used as a handle for binding to agents
  • NOD201 Peptide-Fc Fusion: A Psudo Ab
  • Handle the therapeutics: NOD201 + alphaPD1
  • NOD201 effectively combines with alphaPD-L1, alphaCTLA-4, and alpha4-1BB/CD137
  • Corresponding monotherapies vs ComboTherapy invoking Innate and Adaptive Immune System
  • Microphages, CD8+ are critical vs CD4+ Neutrophils, NK cells, B cells #JenniferR. Cochran
  • Macrophages activation is critical – Day 4, 4 and 5
  • NOD201 + alphaPD1 combo increases M1 macrophages
  • Who are the best responders to PD1 – genes that are differentially expressed
  • NOD201 deives T cells reaponses through a “vaccinal” effect
  • CAncer Immune CYcle
  • Integrin – localization
  • Prelim NOD201 toxicity studies: no significant effects
  • Targeting multiple integrins vs antibodies RJ9 – minimal effect
  • NOD201 – manufacturability – NEW AGENT in Preclinical stage

2:15 – 2:45 Break

2:45 – 3:35 Session VIII
Moderator: Jianzhu Chen | MIT, Koch Institute

Jennifer Wargo – MD Anderson Cancer Center
Understanding Responses to Cancer Therapy: The Tissue is the Issue, but the Scoop is in the Poop

  • Optimize Targeted Treatment response
  • Translational research in patients on targeted therapy revealed molecular and immune mechanisms of response and resistance
  • Molecular mechanisms – T cell infiltrate after one week of therapy
  • Role of tumor stroma in mediating resistance to targeted therapy
  • Tumor microenvironment
  • Intra-tumoral bacteria identified in patients with Pancreatic Cancer
  • Translational research in patients on immune checkpoint blockade revealed molecualr and immune mechanism of response and resistance
  • Biomarkers not found
  • SYstemic Immunity and environment (temperature) on response to checkpoint blockade – what is the role?
  • Role of mIcrobiome in shaping response to checkpoint blockade in Melanoma
  • Microbime and GI Cancer
  • Diversity of the gut microbiome is associated with differential outcomes in the setting of stem cell transplant in AML
  • Oral and gut fecal microbiome in large cohort patient with metastatic melanoma undergoing systemic therapy
  • Repeat oral & gut AFTER chemo
  • WGSeq – Diversity of microbiome and response (responders vs non-responders to anti PD-1 – High diversity of microbiome have prolonged survival to PD-1 blockade
  • Anti tumor Immunity and composition of gut microbiome in patient on anti-PD-1 favorable AND higher survival #JenniferWargo
  • Enhance therapeutic responses in lang and renal carcinoma: If on antibiotic – poorer survival
  • sharing data important across institutions

Jianzhu Chen – MIT, Koch Institute
Modulating Macrophages in Cancer Immunotherapy

  • Humanized mouth vs de novo human cancer
  • B cell hyperplasia
  • double hit lymphoma
  • AML
  • Overexpression of Bcl-2 & Myc in B cells leads to double-hit lymphoma
  • antiCD52 – CLL
  • Spleen, Bone marrow, Brain
  • Microphages are required to kill Ab-bound lymphoma cells in vivo #JianzhuChen
  • COmbinatorial chemo-Immunotherapy works for solid tumors: treating breast cancer in humanized mice
  • Infiltration of monocytic cells in the bone marrow
  • Cyclophosphophamide-antibody synergy extending to solid tumor and different antibodies #JianzhuChen
  • Polarization of macrophages it is dosage-dependent M1 and M2
  • Antibiotic induces expression of M1 polarizing supresses development and function of tumor-associated macrophages (TAM)
  • Antibiotic inhibits melanoma growth by activating macrophages in vivo #JianzhuChen

 

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