Cambridge Healthtech Institute’s 6th Annual

Adoptive Cell Therapy – ACT 2

Engineering the Second Generation of CAR Ts, NKs, TCRs, and TILs

August 5-6, 2019

Efforts to engineer CAR Ts, NKs, TCRs, and TILs with greater precision, safety profiles, and efficacy are leading to the second generation of improved adoptive cell therapies (ACT 2). With multiple engineered receptors already making preclinical impact, many biotech and pharma companies are preparing for the next wave of clinical trials. The end goal is still the same: improved patient outcomes. However, there remain technical considerations and translational challenges relating to cell therapy development, manufacturing practicability, clinical trial approaches, cell quality and persistence, and patient management. Cambridge Healthtech Institute’s Sixth Annual Adoptive Cell Therapy – ACT 2 conference focuses on the next steps needed for engineering CAR and delivering T Cells, NKs, TCR, and TIL therapies into the clinic.

Final Agenda

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MONDAY, AUGUST 5

7:30 am Registration Open and Morning Coffee

ACT2: TARGETING THE TUMOR

8:25 Chairperson’s Opening Remarks

Eric Smith, MD, PhD, Director of Translational Development, Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center

8:30 KEYNOTE PRESENTATION: Tumor Immune Microevironment and Pre-Treatment Tumor Burden Influence Clinical Efficacy of Anti-CD19 CAR T Cells in Large B Cell Lymphomas

Adrian Bot, MD, PhD, Vice President, Translational Sciences, Kite, a Gilead Company

To date, there are two approved CAR T cell interventions, both applicable to a range of B cell malignancies. We gathered showing that while anti-CD19 CAR T cells can be effective across large cell lymphomas with a broad range of characteristics including those with poor prognostic markers routinely utilized in clinic (c-myc, bcl-2 and bcl-6). Nevertheless, an immunologically involved tumor biology in conjunction with reduced pre-treatment tumor burden, may facilitate durable clinical responses. Such data point to strategies to overcome hurdles in front of CAR T cell therapies by building new features into CAR products and by optimizing clinical protocols.

9:00 Advances in CAR T Cell Therapy for Multiple Myeloma, Present and Future

Eric Smith, MD, PhD, Director of Translational Development, Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center

Early results with BCMA targeted CAR T cell therapy by our group and others appear promising in multiply relapsed or refractory MM. Preclinical studies of novel CAR design and rational combination therapies may lead the way to further enhance the dramatic efficacy for patients with limited other options.

9:30 Overcoming Resistance to CAR T Therapy for Hematologic Malignancies

Marco Ruella, MD, Assistant Professor of Medicine and Scientific Director, Lymphoma Program, Division of Hematology and Oncology and Center for Cellular Immunotherapies, University of Pennsylvania

Adoptive T cell therapies and in particular chimeric antigen receptor T cells (CAR T) are leading to significant responses in cancer patients, in particular B-cell leukemias and lymphomas. However, a significant subset of patients still does not respond or eventually relapse after this therapy. In his talk, Dr. Ruella will highlight recent finding in the pathogenesis of relapse after CAR T19 and discuss novel therapeutic approaches aimed to increase CAR T feasibility and efficacy.

10:00 Coffee Break

10:30 Clinical Predictors of T Cell Fitness for CAR T Cell Manufacturing and Efficacy in Multiple Myeloma Using RShiny, FlowType, Citrus and Spade

Iulian Pruteanu-Malinici, PhD, Investigator III, Lab Head, Immuno-Oncology, Novartis

11:00 TALEN-Mediated Gene Editing of CAR T-Cells for Improved Adoptive Cell Therapies

Laurent Poirot, PhD, Vice President, Immunology, Cellectis

Despite early success of CD19-targeted CAR T-cell therapy in acute lymphoblastic leukemia (ALL), recent clinical results in other diseases show that extending this success to more patients and in other diseases will require additional cellular features. We will discuss our strategy focused on allogenic CAR T-cells and TALEN-based gene editing to extend the applicability of CAR T-cells.

11:30 Bruteforcing Immune Oncology Discovery with Computational Immuno-Engineering

Jacob Glanville, PhD, Co-Founder, CSO, Chairman, Distributed Bio

A decade of iterative improvement in rational antibody repertoire design resulted in antibody libraries that are > 1000x larger than previously possible. We review the practical consequences of this enhanced diversity on antibody discovery against challenging oncology targets, discovery of GPCR antagonists, personalized anti-cancer antibodies, immune-checkpoint inihbitors; PD1 case study were we have generated > 6500 unique anti-PD1 antibodies, including picomolar binders, mouse/cyno/human triple cross-reactive epitopes, antagonists, agonists, and saturated epitope coverage of the target.

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

12:30 Session Break

ACT 2: THERAPEUTIC T-CELLS

1:25 Chairperson’s Remarks

Christopher Helsen, PhD, Director, R&D, Triumvira

1:30 Altering T Cell Metabolism to Improve the Efficacy of Adoptive Cell Therapies

Sam Saibil, MD, PhD, Translational Research Fellow, Tumour Immunotherapy Program, Princess Margaret Cancer Centre

Memory T cells are superior mediators of adoptive cell therapy (ACT) compared with effector T cells due to increased persistence in vivo. Underpinning this survival is a shift in cellular metabolism away from aerobic glycolysis towards fatty acid oxidation (FAO). We have identified an agonist of the peroxisome proliferator activated receptors alpha and delta that shifts T cell metabolism to FAO and results in improved efficacy of ACT in preclinical models.

2:00 A Rare Population of Tumor Antigen-Specific CD4+CD8+ Double-Positive αβ T Lymphocytes Uniquely Provide CD8-independent TCR Genes for Engineering Therapeutic T Cells

Junko Matsuzaki, PhD, Assistant Professor, Oncology; Director, Immune Analysis Shared Resource, Roswell Park Comprehensive Cancer Center

High affinity TCR gene is required for manufacturing a potent therapeutic T-cell product by gene engineering. However, most of naturally occurring tumor antigen-specific TCR is of low affinity. Here we discovered naturally occurring high-affinity tumor antigen-specific TCR gene from CD4+CD8+ T cells in peripheral blood of an ovarian cancer patient. Our study demonstrates that the TCR gene is a promising for effective and safe adoptive T-cell therapy in cancer patients.

2:30 Pre-Clinical Evaluation of a CD19-Directed TAC T Cell Therapy Candidate for First-in-Human Clinical Trials

Christopher Helsen, PhD, Director, R&D, Triumvira

Triumvira develops a CD19-targeted TAC-T cell product and generated preclinical data in preparation of a Phase I/II clinical trial. The data show that CD19-directed TAC-T cells selectively eliminate CD19-positive cancer cells in vitro and in vivo in multiple models of hematological malignancies. These in vivo effects correlate with an initial expansion of T cells and suggest the presence of long-term memory T cells in tumor re-challenge experiments.

3:00 Breakout Discussion Groups and Refreshment Break

4:00 Calibration of CAR Activation Potential Directs Alternative T Cell Fates and Therapeutic Potency

Judith Feucht, PhD, Research Fellow, Laboratory for Gene Transfer and Gene Expression, Memorial Sloan Kettering Cancer Center

We hypothesized that excessive signal strength arising from redundancy of combined CD3z and CD28 signaling in 1928z CARs might foster terminal T cell differentiation and exhaustion. To differentially reprogram T cell function and differentiation, we calibrated the activation potential of CD28-based CARs by mutating CD3z ITAMs. We demonstrate that the number and position of ITAMs in 1928z CAR T cells influence functional, phenotypic and transcriptional programs, resulting in profound effects on therapeutic potency.

4:30 KEYNOTE PRESENTATION: Novel Luciferase-Based Assays for Determining the Expression of CAR T Cells and Cytotoxicity of Adoptive Cell Therapies

Preet M. Chaudhary, MD, PhD, Professor and Chief of Hematology and Director of Blood and Marrow Transplant, Jane Anne Nohl Division of Hematology, University of Southern California Keck School of Medicine

The talk will describe novel non-radioactive marine luciferase-based assays (Topanga and Matador Assays) for detection of CAR T cells and for measuring the cytotoxicity of CAR T cells and other forms of adoptive cell therapies.

5:00 Close of Day

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TUESDAY, AUGUST 6

7:30 am Registration Open and Morning Coffee

ACT 2: ENHANCING CAR CONSTRUCTS

8:25 Chairperson’s Remarks

Michael C. Milone, MD, PhD, Associate Professor, Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania

8:30 Improving CAR T Cell Therapy through Reverse Engineering from Nature’s Designs

Michael C. Milone, MD, PhD, Associate Professor, Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania

Chimeric antigen receptors (CARs) based upon a single chimeric molecule bearing an antigen binding domain linked in cis to the cytoplasmic domains of CD3ζ and costimulatory receptors CD28 or 4-1BB provide a potent method for engineering T cell cytotoxicity towards tumors. While effective, most natural immunoreceptors utilize a multichain design where the ligand binding and signaling activities are contained within different polypeptide chains. We will describe a simple, alternative approach to constructing a chimeric immunoreceptor based with a killer immunoglobulin-like receptor (KIR) with DAP12. This novel design is capable of inducing regression of tumors in which second generation CD3ζ-based CARs show limited activity supporting a benefit to evaluating alternative CAR designs that reflect natural immunoreceptor structure.

9:00 Unraveling the CAR T Cell Signaling Circuitry

Daniel Abate-Daga, PhD, Assistant Member, Immunology Program, H. Lee Moffitt Cancer Center

Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of blood cancers. Despite major advances, receptor optimization relies largely on empirical testing. To provide new tools for the rational design of next-generation CARs, we conducted a structure-function analysis of variations of an anti-PSCA CAR, which displayed different antitumor efficacy. This strategy unveiled previously unknown phosphorylation sites with direct relevance to CAR function and identified new parameters that affect their performance.

9:30 The Functional Capacity of Immune Cells as Measured by Single Cell Proteomics Is Predictive of Clinical Outcome in IO

Will Singleterry, PhD, Director, Business Development, IsoPlexis

Using single cell proteomics to measure the functional capacity or “fitness” of immune cells has correlated with and been predictive of clinical outcome in CAR-T, TIL, Cancer Vaccine and Checkpoint Inhibitor therapy. This talk will review several of these data sets and discuss applications of IsoPlexis’ single cell technology.

9:45 Sponsored Presentation (Opportunity Available)

10:00 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

11:00 BOXR: A T-Cell Therapy Solution to the Challenges of the Solid Tumor Microenvironment

Greg Motz, PhD, Director, Immunopharmacology, Unum Therapeutics

A key challenge facing T-cell therapy in solid tumors is immunosuppression in the tumor microenvironment. Unum has developed the BOXR technology (Bolt-On Chimeric Receptor) as a T-cell platform that enables engineered T-cells to overcome specific mechanisms of TME immunosuppression that include metabolic competition, immunosuppressive cell types (Treg, MDSC), and exhaustion due to chronic stimulation.

11:30 PANEL DISCUSSION: ACT2: Translationg from Preclinical to Clinical Proof of Concept

This panel shares insights for discovering new target spaces, engineering novel antigen receptors, and validating leads for promising cancer-beating patient-centric immunotherapies.

Moderator: Michael C. Milone, MD, PhD, Associate Professor, Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania

Panelists: Daniel Abate-Daga, PhD, Assistant Member, Immunology Program, H. Lee Moffitt Cancer Center

Greg Motz, PhD, Director, Immunopharmacology, Unum Therapeutics

12:00 pm Close of Adoptive Cell Therapy – ACT 2

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