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October 1-2, 2020

Dr Ronald Germain on using multiplexed imaging and machine learning to better understand tumors

A patient perspective: What Steve Hamilton, IO patient, wants doctors and researchers to know

Dr Teresa (Teri) Foy on BMS’s approach to collaboration and partnerships

Summaries on all the conference main topics

And more!

Event RecapIO

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Dear Reader,

This edition of the IO360° Newsletter is dedicated to providing you with a recap of the Immuno-Oncology Combinations 360° program that took place October 1-2, virtually.

We are pleased to share summaries of the keynote presentations and the main topics covered throughout the conference. These include:

Ronald Germain, MD, PhD, NIAID, NIH, on Detailed Cellular and Functional Analysis of the Tumor Microenvironment in the Context of Immunotherapy Using Highly Multiplexed Imaging and Machine Learning.

Steve Hamilton, Cancer Veteran, on his pathway participating in a clinical trial with an IO combination therapy and advice for physicians and researchers.

Teresa (Teri) Foy, PhD, BMS, on BMS’s approach to collaborations and partnerships.

Additionally, this recap includes summaries on the conference sessions including Discovery/Preclinical Science, Translational Science & Emerging Biomarkers, IO Novel Technologies, Cell Therapy & Bispecifics, Clinical Operations, Business Aspects, and Clinical Developments.

If you are interested in contributing to a future newsletter, please contact andrew@tcfllc.org

Enjoy the recap.

Welcome Letter

Kate WodaConference Director, IO Combinations 360°

Valerie BowlingExecutive Director Conference Forum

Meredith SandsExecutive Director, Business Development Conference Forum

Bre BugbeeMarketing Manager, IO Combinations 360°

Elizabeth BardBusiness Development Manager,IO Combinations 360°

Adam KolankoBusiness Development Manager,IO Combinations 360°

Meg GouldSenior Conference Planner,IO Combinations 360°

Eforsini ZambasConference Planner,IO Combinations 360°

Andrew GoldsteinIO Combinations 360° Writer

Mary O’ConnorGraphics and Marketing Associate

IO COMBOS 360°The Conference Forum1430 BroadwaySuite 1510New York, NY 10018 (646)-350-2580

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Dr Germain explained that all immune function occurs in a complex lymphoid or parenchymal tissue context and cannot be fully explored by examining just isolated cells or molecules. The only real way to collect that tissue-based information with high spatial resolution is imaging. Dr Germain then discussed multi-photon dynamic methods for imaging, histo-cytology, the IBEX multiplex imaging platform, AI enabled reduced-complexity analysis of pixel-based imaging data (RAPID), and combination sectional and 3D imaging. Using these methods, Dr Germain and his team were able to quantify cellular interactions and clarify that auto-responsive PD-1+ CD4 T-cells sit in microdomains of Tregs while other CD4 cells do not. This effector phenotype was dependent on IL-2. Additionally, Dr Germain and his team could identify, quantify and perform spatial statistics on T cells. They found that Tregs don’t prevent T-cell proliferation but prune out autoreactive cells rather than preventing them from being activated in the first place. As a result of using both static and volume imaging and connecting it with dynamic imaging researchers can get more useful information than using any of these tools individually. Dr Germain concluded, “It’s this suite of approaches that will contribute to understanding what is happening in the TME and why certain treatments work in patients or not.”

Opening Keynote: Detailed Cellular and Functional Analysis of the Tumor Microenvironment in the Context of Immunotherapy Using Highly Multiplexed Imaging and Machine Learning

Dr Ronald Germain, National Institute of Allergy and Infectious Diseases, National Institutes of Health, presented the opening keynote talk on Detailed Cellular and Functional Analysis of the Tumor Microenvironment in the Context of Immunotherapy Using Highly Multiplexed Imaging and Machine Learning.

Dr Omid Hamid of The Angeles Clinic and Research Institute and Cedars-Sinai CANCER chaired the Discovery & Preclinical Plenary Session, which focused on the future of improving checkpoint inhibiting therapies with rational combinations. Individual sessions included:

Discovery & Preclinical Plenary Expert Discussion

Dr Eytan Ruppin of the National Cancer Institute presented on IO Synthetic Lethality and IO Combination Studies, where he explained how NCI is harnessing synthetic lethal interactions

to analyze patient tumor bulk expression and stratify patients to new targets and combinations, as well as analyzing single-cell tumor transcriptomics to identify effective modular treatment combinations tailored for individual patients.

Patricia Soulard and Dr Frank Zenke of Merck KGaA shared a presentation on Targeting DNA Damage Response Signaling to Improve the Anti-Tumor Efficacy of Immune Checkpoint Inhibitors. They demonstrated how Merck ATR inhibitors showed strong antitumor activity in combinations with DNA damaging chemotherapies as well as other targeted DDR inhibitors, suggesting that ATRi/platinum/avelumab combination could work in immunologically “cold” tumors.

DAY 1

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The Translational Science and Emerging Biomarkers Plenary Session was chaired by Dr Theresa LaVallee, Parker Institute for Cancer Immunotherapy (PICI).

In her introductory remarks, Dr LaVallee said, “We’re all aware of the impact that checkpoint inhibitors and CAR-Ts have had on patient survival but we can build on that because there is still a minority of patients who benefit. Combination therapy will improve on these.” The session focused on the topics of dual targets with bispecifics or combination treatments, TME modulation, CAR-T agents, and biomarker technologies. Dr LaVallee then kicked off the session with Biomarker Approaches to Inform Combinations, where she explained how PICI interrogates biomarkers to inform adaptive and flexible trials to advance treatment in prostate cancer.Dr Scott Turner, PLIANT

Therapeutics, spoke on the topic of Small Molecule Integrin Inhibitors to Reduce TGF-Beta and Enhance Checkpoint Inhibitor Efficacy.

Dr Omid Hamid,The Angeles Clinic and Research Institute and Cedars-Sinai CANCER, Dr Eytan Ruppin, National Cancer Institute, Dr Stephen Baylin, Johns Hopkins University, Dr Alex Franzusoff, PACT Pharma, and Dr Scott Turner, PLIANT Therapeutics, discussed combination approaches outside of PD-1/PD-L1, improving treatments based on patient-specific response data, learning more from clinical trials, triplet combinations, and inter-company collaborations. Additionally, the panelists addressed analyzing cell types that impact response as targets; priming and boosting versus synchronous delivery of combination therapies; deciphering the molecular signatures of patients who achieved stable disease; and partial response versus deep partial response as a way to determine future combinations.

Dr Stephen Baylin, Johns Hopkins University, presented on DNA-MTi and HDACi with Immunotherapy. After explaining the need to understand the integration

of epigenomic regions and their alterations throughout the cancer life history, Dr Baylin spoke about the combination of DNMTis and HDACis to enhance checkpoint therapy.

In a presentation on Personalized Neoantigen-Targeted T-Cell Therapies Engineered for Each Person with (Solid) Cancer ,PACT Pharma’s Dr Alex Franzusoff shared how PACT Pharma is leveraging pre-existing T-Cells to engineer personalized Neo-TCR-T-cells to treat solid tumors.

Translational Science and Emerging Biomarkers Plenary Session

Dr Genevive Hernandez, IGM Biosciences, presented on Biomarker for Bispecific T-Cell Engager Studies: Teasing Individual Contribution of Each Combination Partner. Dr Hernandez explained how to use learnings from biomarkers to inform the next steps for bispecific T-Cell engagers as well as combinations.

In the session Comprehensive Immunogenomics to Enable Composite Biomarkers for Immunotherapy Response Using a Sample Sparing

Approach, Dr Travis Yates, Personalis, shared a case study on combining highly sensitive, exome-scale DNA and RNA sequencing with advanced analytics to provide a broad view of the tumor and the immune-related components of the tumor microenvironment from a single sample preparation.

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Dr Jane Anne Healy, Merck Research Labs spoke on TIGIT Combinations in Advanced Solid Tumors where she introduced vibostolimab as an anti-TIGIT monoclonal antibody

that was well tolerated as a combination therapy with pembrolizumab in patients with advanced solid tumors and NSCLC. The combination demonstrated promising antitumor activity.

A discussion on Redefining Biomarker Approaches for Combinations vs Predictive Biomarkers moderated by Dr Alexandra Snyder, Merck Research Labs, with panelists Dr Sharon Benzeno, Adaptive Biotechnologies, Dr Omid Hamid,The Angeles Clinic and Research Institute and Cedars-Sinai CANCER, and Dr Raluca Verona, Janssen R&D, addressed how patient selection is changing in as new combination data comes out; using companion diagnostics and biomarkers to define patient population of need or interest; studying auto-antibodies; creating the necessary data to use biomarkers as surrogate endpoints; understanding the relative contribution of each agent in a combination regimen; using biomarkers to inform dynamic trials; combinations outside of IO; and building out biomarker libraries through collaboration.

In her presentation on Translational Learnings from ide-cel, a BCMA-directed CAR-T Cell Therapy for Multiple Myeloma, Dr Kristen Hege, BMS, shared conclusions from the KarMMa trials indicating that ide-cel demonstrated frequent, deep and durable responses in heavily pretreated, highly refractory multiple myeloma patients and the development of a next generation BCMA CAR-T cell therapy.

Luis Voloch, Immunai, shared how his team developed an integrated platform that enables high-quality analysis of single-cell multi-omics data on real-world clinical samples.

Dr Dimitriy Zamarin, Memorial Sloan Kettering Cancer Center, evaluated the potential for oncolytic viruses to activate tumor-specific immune responses, overcome the TME heterogeneity, and

potentiate the efficacy of immune checkpoint blockades in his session, Oncolytic Virus in Combination with Immunotherapy.

Dr Nadim Ajami of MD Anderson Cancer Center presented on Combinations Between Agents that Modulate the Microbiome and Checkpoints. Dr Ajami explained the efforts of MD Anderson to utilize microbiome research for biomarker discovery, modulation, and prevention and interception to improve outcomes in combination with checkpoint therapy.

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The Cell Therapy and Bispecifics Plenary Session was chaired by Dr Daniel Chen, IGM Biosciences. The session focused on combining CAR-T cell therapies, bispecific T-cell engagers, oncolytic viruses, checkpoint therapies, neoantigen-specific TCRs and allogeneic cell therapies from red blood cells. Individual sessions included:

Dr Saul Priceman, City of Hope, presented on Advancing Immunotherapy Platforms for Solid Tumors. Dr Priceman shared how City of Hope is treating patients with solid tumors using autologous CAR-T cell therapies.

Dr Anjali Sharma, Amgen, shared Updates on BCMA BiTE Combinations including the relevance of BCMA in Multiple Myeloma, how BiTE technology can be utilized to target MM cells and clinical trials investigating BCMA-targeted BiTE molecules for RRMM.

Dr Mark O’Hara, University of Pennsylvania, spoke on the topic of Immunotherapy Combinations & CAR-T Cells in Pancreatic Cancer: CD40 and Beyond, where he explained that lentiviral-transduced CAR-T meso cells have increased expansion but

lack persistence and significant trafficking to pancreatic cancer and explored combinations with CD40 agonists and oncolytic adenoviruses expressing IL-2 and TNF-a.

Cell Therapy and Bispecifics Plenary Session

Dr Sharon Benzeno of Adaptive Biotechnologies presented on High Throughput Identification of Naturally-Occurring TCRs for Cellular Therapies Oncology. Dr Benzeno explained how Adaptive Biotechnologies sequences, maps, pairs and characterizes the immune repertoire in order to develop neoantigen-specific TCRs.

Dr Christina Coughlin of Rubius Therapeutics spoke to the development of an allogeneic cellular therapy from red blood cells to broadly stimulate the adaptive and innate immune systems to generate immune response to improve anti-tumor activity

and overcome resistance to immunotherapy in patients with solid tumors in combination with anti-PD-1 in her presentation titled Realizing the Power of Red: Cellular Therapy Combination Trials in Solid Tumors.

On the topic of Addressing Operational Challenges and Leveraging innovative Trial Designs for IO Combinations: Next Steps, led by Karen May, AstraZeneca, with panelists Alice Donnelly, PPD, Iris Sison, IGM Biosciences, and Jim Wise, PRA Health Sciences, the group discussed innovative trials designs in the face of COVID-19 including master protocols, umbrella and basket trials, and adapting based on safety and efficacy signals; operational strategies to drive the speed and quality of trials; risk-based and remote monitoring; expanding trials into community centers; dosing strategies; working with regulatory agencies for protocol amendments due to COVID-19; engaging in telehealth to enhance clinical trials and reduce patient burden; and data quality and completeness. The panelists also discussed what inspections will look like after COVID-19 and efforts to increase patient diversity in clinical trials.

The fireside chat was led by Daniel Chen. Steve Hamilton, melanoma cancer survivor, shared his pathway with an IO vaccine involving the MAGE-A3 protein with IL-2 that ultimately saved his life.

When asked about advice for researchers and physicians, Mr Hamilton said, “If there’s communication, education, and transparency behind a clinical trial, that goes a long way. The fewer questions you have, the more the trial is set up for success”

Mr Hamilton concluded by saying, “Keep focused and know that there are people like me who have survived and started in a very dark and unknowing place of what the future holds. Patients looking for treatments rely on you to help them survive. There are so many people that rely on you. Please keep doing what you’re doing.”

VIP Fireside Chat: Steve Hamilton’s Combination Immunotherapy Trial Pathway

DAY 2

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On the topic of Public-Private Partnerships Between Research Organizations and BioPharma to Accelerate Cancer Immunotherapies, Dr Michael Salgaller, National Institutes of Health, Dr Jill O’Donnell-Tormey, Cancer Research Institute, and Dr Marc Hurlbert, Melanoma Research Alliance, discussed traditional and non-traditional collaborations between Pharma, Biotech and research organizations to propel research, initiate clinical trials and get treatments to patients and on the market.

In a panel on Investment Decision Making For IO Combinations led by Asthika Goonewardene, Truist Securities, along with Dr John Connolly, Parker Institute for Cancer Immunotherapy, Geraldine O’Keeffe, Life Science Partners, and Dr Alessandra Polara, Genentech, considerations when investing in combination therapies including investing in assets versus platforms, what data needs to be seen before investing, the stage of the drug, exit strategies and what you are looking to get out of the investment in terms of unmet need were discussed.

Clinical Developments Plenary SessionDr James Gulley, National Cancer Institute, chaired the Clinical Developments Plenary Session, which focused on data from combinations in clinical trials. Individual sessions included:

Dr Roy Baynes, Merck Research Labs presented recent datasets on the increase of therapeutic options and improved outcomes due to precision medicine informed combination therapies.

Dr Dimitris Skokos of Regeneron Pharmaceuticals, Inc presented on Human Costimulatory Bispecific Antibodies in Cancer Immunotherapy. Dr Skokos explained the background of costimulatory bispecifics

and described a combination therapy using PSMAxCD28 costimulatory bispecifics with anti-PD-1.

Dr Christina Derleth, Seagen, presented on Enfortumab Vedotin + Pembrolizumab: Combining Antibody-Drug Conjugates and Immunotherapy. Dr Derleth explained that studies demonstrated enfortumab vedotin induces early hallmarks of ICD resulting in recruitment and activation of innate immune cells and increases HLA/MHC Class I and II to activate the adaptive immune response. In combination with pembrolizumab, it led to rapid and durable responses and encouraging PFS and OS trends with manageable toxicity in advanced urothelial cancers.

Dr Raphaël F Rousseau, Gritstone Oncology, presented triple and quadruple combination data including neoantigen vaccines in combination with nivolumab + ipilimumab in Combining Neoantigen Vaccines with Checkpoint Inhibitors.

Dr Mark Cobbold, AstraZeneca, addressed mechanisms of primary and secondary resistance using combinations and navigating the challenges of combinatorial possibilities using preclinical and in vitro approaches in his talk on Combination Mixed-Mode Immunotherapy.

Business Aspects Plenary Session

The Business Aspects Plenary Session began with a Keynote Fireside Chat between Dr Teresa (Teri) Foy, BMS, and Asthika Goonewardene, Truist Securities, on the topic of External Collaborations and Combination Strategies.“It’s a little ironic that the long awaited success for checkpoint inhibitors that now there is some [investment] fatigue for the modality after breaking through the challenge,” Dr Foy said.Going forward, she expects this first wave of CPIs to expand into new indications and as earlier therapies, as well as a second wave of approved therapies, with targets like TIGIT to follow. Also, the industry is exploring complementary mechanisms and pathways that attack other elements of the tumor microenvironment. Dr Foy said that she expects the leveraging the innate immune system with the adaptive immune system in a tumor-specific – rather than immune-specific – way will add value in the future.BMS typically doesn’t enter a collaboration with the thought of acquisition but determines whether to do so based on the scope of the collaboration and the value of the company. Dr Foy said that BMS collaborates with the idea of developing the drugs that come out of the collaboration. BMS is interested in partnering with companies that bring interesting molecules to combine with PD-1 that have scientific clinical rational and single-agent safety data. Concluding with her thoughts on interesting areas, Dr Foy spoke about cell therapy, non-viral delivery, and editing genes that enhance T-cell persistence.

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June, 2021

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