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Archive for the ‘Monoclonal Immunotherapy’ Category


An Intelligent DNA Nanorobot to Fight Cancer by Targeting HER2 Expression

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

HER2 is an important prognostic biomarker for 20–30% of breast cancers, which is the most common cancer in women. Overexpression of the HER2 receptor stimulates breast cells to proliferate and differentiate uncontrollably, thereby enhancing the malignancy of breast cancer and resulting in a poor prognosis for affected individuals. Current therapies to suppress the overexpression of HER2 in breast cancer mainly involve treatment with HER2-specific monoclonal antibodies. However, these monoclonal anti-HER2 antibodies have severe side effects in clinical trials, such as diarrhea, abnormal liver function, and drug resistance. Removing HER2 from the plasma membrane or inhibiting the gene expression of HER2 is a promising alternative that could limit the malignancy of HER2-positive cancer cells.

 

DNA origami is an emerging field of DNA-based nanotechnology and intelligent DNA nanorobots show great promise in working as a drug delivery system in healthcare. Different DNA-based nanorobots have been developed as affordable and facile therapeutic drugs. In particular, many studies reported that a tetrahedral framework nucleic acid (tFNA) could serve as a promising DNA nanocarrier for many antitumor drugs, owing to its high biocompatibility and biosecurity. For example, tFNA was reported to effectively deliver paclitaxel or doxorubicin to cancer cells for reversing drug resistance, small interfering RNAs (siRNAs) have been modified into tFNA for targeted drug delivery. Moreover, the production and storage of tFNA are not complicated, and they can be quickly degraded in lysosomes by cells. Since both free HApt and tFNA can be diverted into lysosomes, so,  combining the HApt and tFNA as a novel DNA nanorobot (namely, HApt-tFNA) can be an effective strategy to improve its delivery and therapeutic efficacy in treating HER2-positive breast cancer.

 

Researchers reported that a DNA framework-based intelligent DNA nanorobot for selective lysosomal degradation of tumor-specific proteins on cancer cells. An anti-HER2 aptamer (HApt) was site-specifically anchored on a tetrahedral framework nucleic acid (tFNA). This DNA nanorobot (HApt-tFNA) could target HER2-positive breast cancer cells and specifically induce the lysosomal degradation of the membrane protein HER2. An injection of the DNA nanorobot into a mouse model revealed that the presence of tFNA enhanced the stability and prolonged the blood circulation time of HApt, and HApt-tFNA could therefore drive HER2 into lysosomal degradation with a higher efficiency. The formation of the HER2-HApt-tFNA complexes resulted in the HER2-mediated endocytosis and digestion in lysosomes, which effectively reduced the amount of HER2 on the cell surfaces. An increased HER2 digestion through HApt-tFNA further induced cell apoptosis and arrested cell growth. Hence, this novel DNA nanorobot sheds new light on targeted protein degradation for precision breast cancer therapy.

 

It was previously reported that tFNA was degraded by lysosomes and could enhance cell autophagy. Results indicated that free Cy5-HApt and Cy5-HApt-tFNA could enter the lysosomes; thus, tFNA can be regarded as an efficient nanocarrier to transmit HApt into the target organelle. The DNA nanorobot composed of HApt and tFNA showed a higher stability and a more effective performance than free HApt against HER2-positive breast cancer cells. The PI3K/AKT pathway was inhibited when membrane-bound HER2 decreased in SK-BR-3 cells under the action of HApt-tFNA. The research findings suggest that tFNA can enhance the anticancer effects of HApt on SK-BR-3 cells; while HApt-tFNA can bind to HER2 specifically, the compounded HER2-HApt-tFNA complexes can then be transferred and degraded in lysosomes. After these processes, the accumulation of HER2 in the plasma membrane would decrease, which could also influence the downstream PI3K/AKT signaling pathway that is associated with cell growth and death.

 

However, some limitations need to be noted when interpreting the findings: (i) the cytotoxicity of the nanorobot on HER2-positive cancer cells was weak, and the anticancer effects between conventional monoclonal antibodies and HApt-tFNA was not compared; (ii) the differences in delivery efficiency between tFNA and other nanocarriers need to be confirmed; and (iii) the confirmation of anticancer effects of HApt-tFNA on tumors within animals remains challenging. Despite these limitations, the present study provided novel evidence of the biological effects of tFNA when combined with HApt. Although the stability and the anticancer effects of HApt-tFNA may require further improvement before clinical application, this study initiates a promising step toward the development of nanomedicines with novel and intelligent DNA nanorobots for tumor treatment.

 

References:

 

https://pubs.acs.org/doi/10.1021/acs.nanolett.9b01320

 

https://www.ncbi.nlm.nih.gov/pubmed/27939064

 

https://www.ncbi.nlm.nih.gov/pubmed/11694782

 

https://www.ncbi.nlm.nih.gov/pubmed/27082923

 

https://www.ncbi.nlm.nih.gov/pubmed/25365825

 

https://www.ncbi.nlm.nih.gov/pubmed/26840503

 

https://www.ncbi.nlm.nih.gov/pubmed/29802035

 

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Real Time Coverage @BIOConvention #BIO2019: What’s Next: The Landscape of Innovation in 2019 and Beyond. 3-4 PM June 3 Philadelphia PA

Reporter: Stephen J. Williams, PhD @StephenJWillia2

 

Results from Clarivate
In 2018 most of deals were in CART area but now we are seeing more series A rounds that are on novel mechanisms as well as rare diseases.  US is still highest in venture capital series A but next is China. 10 of top ex US VC are from China, a whole lot of money.
Preclinical is very strong for US VC but China VC is focused on clinical.  First time this year we see US series A break above 100.  But ex US the series A is going down.  Although preclinical deals in US is coming back not like as good as in 2006.  But alot of > 1 billion $ deals.  Most of money into mAbs and protein therapy;  antisense is big and cell therapy is big too; small molecule not as much
ClearView Healthcare
Which innovation classes attracted VC in 2018?
  • Oncology drives a disproportionate focus could be driven by pharma focus on oncology; however there is some focus on neuro and infectious disease
  • therapeutic classes: shift to differentiated technology…. companies want technologic platforms not just drugs.  Nucleic Acid tech and antibody tech is high need platforms.  Startups can win by developing a strong platform not just a drug
There are pros and cons of developing a platform company versus a focused company.  Many VCs have a portfolio and want something to fit in so look for a focused company and may not want a platform company.  Pfizer feels that when alot of money is available (like now) platform investing is fine but when money becomes limited they will focus on those are what will be needed to fill therapy gaps.  They believe buy the therapy and only rent the platform.
Merck does feel the way Pfizer does but they have separate ventures so they can look and license platforms.  they are active in looking at companies with new modalities but they are focused on the money so they feel best kept in hands of biotech not pharma.
At Celgene they were solely focused on approvals not platforms.  Alot of money is required to get these platforms to market.  Concentration for platform companies should be the VCs not partnering or getting bought out by pharma.  it seems from panel speakers from pharma that they are waiting for science to prove itself and waiting for favorable monetary environments (easy money).  However it seems they (big pharma) are indicating that money is drying up or at least expect it too.
At Axial and with VCs they feel it is important to paint a picture or a vision at the early stage.
At Ontogeny, they focus on evaluating assets especially and most important, ThE MANAGEMENT TEAM.  There are not that many great talented drug development management teams he feels out there even though great science out there.

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Newly Found Functions of B Cell

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The importance of B cells to human health is more than what is already known. Vaccines capable of eradicating disease activate B cells, cancer checkpoint blockade therapies are produced using B cells, and B cell deficiencies have devastating impacts. B cells have been a subject of fascination since at least the 1800s. The notion of a humoral branch to immunity emerged from the work of and contemporaries studying B cells in the early 1900s.

 

Efforts to understand how we could make antibodies from B cells against almost any foreign surface while usually avoiding making them against self, led to Burnet’s clonal selection theory. This was followed by the molecular definition of how a diversity of immunoglobulins can arise by gene rearrangement in developing B cells. Recombination activating gene (RAG)-dependent processes of V-(D)-J rearrangement of immunoglobulin (Ig) gene segments in developing B cells are now known to be able to generate an enormous amount of antibody diversity (theoretically at least 1016 possible variants).

 

With so much already known, B cell biology might be considered ‘‘done’’ with only incremental advances still to be made, but instead, there is great activity in the field today with numerous major challenges that remain. For example, efforts are underway to develop vaccines that induce broadly neutralizing antibody responses, to understand how autoantigen- and allergen-reactive antibodies arise, and to harness B cell-depletion therapies to correct non-autoantibody-mediated diseases, making it evident that there is still an enormous amount we do not know about B cells and much work to be done.

 

Multiple self-tolerance checkpoints exist to remove autoreactive specificities from the B cell repertoire or to limit the ability of such cells to secrete autoantigen-binding antibody. These include receptor editing and deletion in immature B cells, competitive elimination of chronically autoantigen binding B cells in the periphery, and a state of anergy that disfavors PC (plasma cell) differentiation. Autoantibody production can occur due to failures in these checkpoints or in T cell self-tolerance mechanisms. Variants in multiple genes are implicated in increasing the likelihood of checkpoint failure and of autoantibody production occurring.

 

Autoantibodies are pathogenic in a number of human diseases including SLE (Systemic lupus erythematosus), pemphigus vulgaris, Grave’s disease, and myasthenia gravis. B cell depletion therapy using anti-CD20 antibody has been protective in some of these diseases such as pemphigus vulgaris, but not others such as SLE and this appears to reflect the contribution of SLPC (Short lived plasma cells) versus LLPC (Long lived plasma cells) to autoantibody production and the inability of even prolonged anti-CD20 treatment to eliminate the later. These clinical findings have added to the importance of understanding what factors drive SLPC versus LLPC development and what the requirements are to support LLPCs.

 

B cell depletion therapy has also been efficacious in several other autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, and rheumatoid arthritis (RA). While the potential contributions of autoantibodies to the pathology of these diseases are still being explored, autoantigen presentation has been posited as another mechanism for B cell disease-promoting activity.

 

In addition to autoimmunity, B cells play an important role in allergic diseases. IgE antibodies specific for allergen components sensitize mast cells and basophils for rapid degranulation in response to allergen exposures at various sites, such as in the intestine (food allergy), nose (allergic rhinitis), and lung (allergic asthma). IgE production may thus be favored under conditions that induce weak B cell responses and minimal GC (Germinal center) activity, thereby enabling IgE+ B cells and/or PCs to avoid being outcompeted by IgG+ cells. Aside from IgE antibodies, B cells may also contribute to allergic inflammation through their interactions with T cells.

 

B cells have also emerged as an important source of the immunosuppressive cytokine IL-10. Mouse studies revealed that B cell-derived IL-10 can promote recovery from EAE (Experimental autoimmune encephalomyelitis) and can be protective in models of RA and type 1 diabetes. Moreover, IL-10 production from B cells restrains T cell responses during some viral and bacterial infections. These findings indicate that the influence of B cells on the cytokine milieu will be context dependent.

 

The presence of B cells in a variety of solid tumor types, including breast cancer, ovarian cancer, and melanoma, has been associated in some studies with a positive prognosis. The mechanism involved is unclear but could include antigen presentation to CD4 and CD8 T cells, antibody production and subsequent enhancement of presentation, or by promoting tertiary lymphoid tissue formation and local T cell accumulation. It is also noteworthy that B cells frequently make antibody responses to cancer antigens and this has led to efforts to use antibodies from cancer patients as biomarkers of disease and to identify immunotherapy targets.

 

Malignancies of B cells themselves are a common form of hematopoietic cancer. This predilection arises because the gene modifications that B cells undergo during development and in immune responses are not perfect in their fidelity, and antibody responses require extensive B cell proliferation. The study of B cell lymphomas and their associated genetic derangements continues to be illuminating about requirements for normal B cell differentiation and signaling while also leading to the development of targeted therapies.

 

Overall this study attempted to capture some of the advances in the understanding of B cell biology that have occurred since the turn of the century. These include important steps forward in understanding how B cells encounter antigens, the co-stimulatory and cytokine requirements for their proliferation and differentiation, and how properties of the B cell receptor, the antigen, and helper T cells influence B cell responses. Many advances continue to transform the field including the impact of deep sequencing technologies on understanding B cell repertoires, the IgA-inducing microbiome, and the genetic defects in humans that compromise or exaggerate B cell responses or give rise to B cell malignancies.

 

Other advances that are providing insight include:

  • single-cell approaches to define B cell heterogeneity,
  • glycomic approaches to study effector sugars on antibodies,
  • new methods to study human B cell responses including CRISPR-based manipulation, and
  • the use of systems biology to study changes at the whole organism level.

With the recognition that B cells and antibodies are involved in most types of immune response and the realization that inflammatory processes contribute to a wider range of diseases than previously believed, including, for example, metabolic syndrome and neurodegeneration, it is expected that further

  • basic research-driven discovery about B cell biology will lead to more and improved approaches to maintain health and fight disease in the future.

 

References:

 

https://www.cell.com/cell/fulltext/S0092-8674(19)30278-8

 

https://onlinelibrary.wiley.com/doi/full/10.1002/hon.2405

 

https://www.pnas.org/content/115/18/4743

 

https://onlinelibrary.wiley.com/doi/full/10.1111/all.12911

 

https://cshperspectives.cshlp.org/content/10/5/a028795

 

https://www.sciencedirect.com/science/article/abs/pii/S0049017218304955

 

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Immunoediting can be a constant defense in the cancer landscape


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

 

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

 

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

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Immunotherapy may help in glioblastoma survival


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. But, in a glimmer of hope, a recent study found that a drug designed to unleash the immune system helped some patients live longer. Glioblastoma powerfully suppresses the immune system, both at the site of the cancer and throughout the body, which has made it difficult to find effective treatments. Such tumors are complex and differ widely in their behavior and characteristics.

 

A small randomized, multi-institution clinical trial was conducted and led by researchers at the University of California at Los Angeles involved patients who had a recurrence of glioblastoma, the most common central nervous system cancer. The aim was to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab (checkpoint inhibitor) in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone.

 

Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhanced both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

 

Immunotherapy has not proved to be effective against glioblastoma. This small clinical trial explored the effect of PD-1 blockade on recurrent glioblastoma in relation to the timing of administration. A total of 35 patients undergoing resection of recurrent disease were randomized to either neoadjuvant or adjuvant pembrolizumab, and surgical specimens were compared between the two groups. Interestingly, the tumoral gene expression signature varied between the two groups, such that those who received neoadjuvant pembrolizumab displayed an INF-γ gene signature suggestive of T-cell activation as well as suppression of cell-cycle signaling, possibly consistent with growth arrest. Although the study was not powered for efficacy, the group found an increase in overall survival in patients receiving neoadjuvant pembrolizumab compared with adjuvant pembrolizumab of 13.7 months versus 7.5 months, respectively.

 

In this small pilot study, neoadjuvant PD-1 blockade followed by surgical resection was associated with intratumoral T-cell activation and inhibition of tumor growth as well as longer survival. How the drug works in glioblastoma has not been totally established. The researchers speculated that giving the drug before surgery prompted T-cells within the tumor, which had been impaired, to attack the cancer and extend lives. The drug didn’t spur such anti-cancer activity after the surgery because those T-cells were removed along with the tumor. The results are very important and very promising but would need to be validated in much larger trials.

 

References:

 

https://www.washingtonpost.com/health/2019/02/11/immunotherapy-may-help-patients-with-kind-cancer-that-killed-john-mccain/?noredirect=on&utm_term=.e1b2e6fffccc

 

https://www.ncbi.nlm.nih.gov/pubmed/30742122

 

https://www.practiceupdate.com/content/neoadjuvant-anti-pd-1-immunotherapy-promotes-immune-responses-in-recurrent-gbm/79742/37/12/1

 

https://www.esmo.org/Oncology-News/Neoadjuvant-PD-1-Blockade-in-Glioblastoma

 

https://neurosciencenews.com/immunotherapy-glioblastoma-cancer-10722/

 

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Original Tweets Re-Tweets and Likes by @pharma_BI and @AVIVA1950 at #kisymposium for 17th annual Summer Symposium: Breakthrough Cancer Nanotechnologies: Koch Institute, MIT Kresge Auditorium, June 15, 2018, 9AM-4PM

 

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CHI’s 5th ImmunoModulatory Therapeutic Antibodies for Cancer Conference, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA

Reporter: Aviva Lev-Ari, PhD, RN

ANNOUNCEMENT

Leaders in Pharmaceutical Business Intelligence (LPBI) Group will cover the event in

REAL TIME

Aviva Lev-Ari, PhD, RN will be streaming live from the floor of the Sheraton Hotel in Boston on August 28 and August 29, 2017

@pharma_BI

@AVIVA1950

 

Cambridge Healthtech Institute’s 5th Annual

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

http://www.immuno-oncologysummit.com/Immunomodulatory-Antibodies-Cancer/

 

MONDAY, AUGUST 28

7:30 am Registration & Morning Coffee

8:25 Chairperson’s Opening Remarks

Yan Qu, Ph.D., Senior Principal Scientist, Pfizer

 

8:30 KEYNOTE PRESENTATION: Enabling Effective Immuno-Oncology

Greg_AdamsGregory Adams, Ph.D., CSO, Eleven Biotherapeutics

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_DahanRony 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.

TD2 tagline9:30 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_BetofAllison 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_KanedaMegan 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_QuYan 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.

ProImmune11:30 Epitope Identification and Clinical Immune Monitoring in Immune Oncology Programs

Emilee KnowltonEmilee Knowlton, Ph.D., Immunology Sales Specialist, ProImmune

 

12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:30 Session Break

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_ThrosbyMark 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

Nicola_WallisNicola Wallis, Ph.D., Senior Director, Biology, Astex Therapeutics, Ltd.

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.

TD2 tagline3:00 Refreshment Break

 

IMMUNE SYSTEM PRIMING AND ACTIVATION

3:30 STING Adjuvants for Immune System Priming for Antibody Therapy

Stephen_BeersStephen 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_LeveyDaniel 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_MansourMarc 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.

5:00 End of Day

 

 

TUESDAY, AUGUST 29

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_WhitingChan 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_HansenAaron 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_ChangKen 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.

MaxCyte no tagline10:00 Accelerated Production of Immunomodulatory Therapeutic Antibodies & Bispecific Molecules Using Scalable Cell Engineering

James_BradyJames Brady, Ph.D., Vice President, Technical Applications & Customer Support, MaxCyte

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_AdlerAdam 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_GuptaRuchi 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

 

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