Stem Cell Clinic

Adoptive T Cell Therapy 2: Development

Cambridge Healthtech Institutes 5th Annual August 30-31, 2018

In 2017, two CAR T cell therapies were approved by the Food and Drug Administration (FDA). With multiple engineered receptors making preclinical impact, many biotech and pharma companies are already entering other clinical trials in a race to get to market. Has this promising field finally reached a tipping point? Technical considerations and translational challenges relating to cell therapy development, manufacturing practicability, clinical trial approaches, cell quality and persistence, and patient management remain. Cambridge Healthtech Institutes 5th Annual Adoptive T Cell Therapy 2: Development conference focuses on the steps needed to deliver CAR, TCR, NK, and TIL therapies to the clinic. Overall, this event addresses clinical progress, case studies, and the critical components for making adoptive T cell therapy work.

Final Agenda

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THURSDAY, August 30

7:45 am Registration & Morning Coffee (Harbor Level)

8:25 Chairpersons Opening Remarks

Amy Hines, BSN, RN, Director, Collection Network Management, Be The Match BioTherapies

8:30 FEATURED PRESENTATION: A Translational Perspective of Development of Yescarta (Axicabtagene Ciloleucel), a First-in-Class CAR T Cell Product for Diffuse Large B Cell Lymphoma

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

Yescarta (Axicabtagene Ciloleucel) is an anti-CD19 CAR T cell therapy that received approval for treatment of relapsing or refractory DLBCL. This presentation describes key elements of the translational program, correlates of toxicities and durable objective response, product characteristics, patient conditioning, and importance of tumor microenvironment. It also showcases major lessons learned and challenges in developing cell-based immunotherapies.

9:00 NEW: Selected Poster Presentation: TAC-T, A Novel T Cell Therapy, Co-Opts the Endogenous T Cell Receptor for Effective, Safe, and Persistent Tumor Rejection

Christopher W. Helsen, PhD, Director, R&D and Head, Platform Development, Triumvira Immunologics, Inc.

9:30 Predictors of Response to CD19-Specific CAR T Therapy in B-CLL

Jun Xu, PhD, Associate Director, Product Development Laboratory, Center for Advanced Cellular Therapeutics, Perelman Center for Advanced Medicine, University of Pennsylvania

To date, it has not been possible to identify patient- or disease-specific factors that predict why some B-CLL patients and not others have such dramatic responses to CAR T cell treatment. We explored the mechanisms associated with clinical response and lack of response to CAR T therapy, providing evidence for intrinsic T cell fitness in mediating durable anti-tumor responses and long-term complete remissions.

10:00 Coffee Break in the Exhibit Hall (Last Chance for Poster Viewing) (Commonwealth Hall)

10:45 Facing the Challenges of Apheresis Network Management

Amy Hines, BSN, RN, Director, Collection Network Management, Be The Match BioTherapies

For companies working in cell therapies, managing and maintaining your apheresis (cell collection) network is a critical challenge. How do you know which center is best equipped to handle your needs? How do you evaluate their compliance with FDA and international regulations? Hines discusses the key questions to ask and gives you the tools youll need to evaluate centers, secure your supply chain and advance your cell therapy program.

11:15 Solving the Challenges of Large-Scale GMP T Cell Manufacturing

Steven L. Highfill, PhD, Assistant Director, Product Development and Management, Center for Cellular Engineering, Clinical Center, National Institutes of Health

This presentation covers current, ongoing GMP manufacturing efforts at the NIH. Highlights focus on CAR T cell manufacturing and some of the challenges that we had to overcome specifically when using autologous patient-derived starting material. In addition, I discuss some newer closed-system manufacturing platforms that will make it easier for academic institutes to provide cell therapy options to their patients.

11:45 Sponsored Presentation (Opportunity Available)

12:15 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:45 Session Break

1:40 Chairpersons Remarks

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

1:45 FEATURED PRESENTATION: Stress-Resistant T Cell Therapy for Solid Tumors

Prasad S. Adusumilli, MD, FACS, FCCP, Associate Attending and Deputy Chief, Thoracic Surgery; Head, Solid Tumors Cell Therapy, Cellular Therapeutics Center; Director, Mesothelioma Program, Memorial Sloan Kettering Cancer Center

CAR T cell therapy efficacy in solid tumors is limited by PD-1/PD-L1 pathway. We have shown that exhausted CAR T cells can be rescued by anti-PD1 agents or by a decoy receptor, PD-1 dominant negative receptor cotransduced with CAR T cells to promote functional persistence. The presentation focuses on cell-intrinsic and extrinsic methods in overcoming checkpoint blockade in cellular immunotherapy.

2:15 TRAP CAR T & Related Cell Therapies: Can Local Delivery Solve Efficacy and Safety Challenges in Solid Tumor Immuno-Oncology?

Janet R. Rea, MSPH, RAC, Senior Vice President, Regulatory, Quality & Clinical Affairs, Atossa Genetics

This presentation reviews cell therapy evolution and challenges. It includes considerations of local delivery options using breast cancer as a model.

2:45 Selected Poster Presentation: Phase I Study of an Adoptive Cellular Immunotherapy by Silencing cbl-b in Autologous Peripheral Blood Mononuclear Cells

Kathrin Thell, PhD, MSc, In Vivo Scientist, Apeiron Biologics AG

3:15 Refreshment Break (Commonwealth Hall)

3:45 Eutilexs 4-1BB CTL Adoptive T Cell Therapy: Clinically Safe and First Efficacy in Solid Tumors

Agustin de la Calle, PhD, CBO, Eutilex Co., Ltd.

Eutilexs 4-1BB CTL therapy is the autologous T cell therapy proven safe in man without treatment-related toxicity and no CRS. Efficacy in hematological cancers and solid tumors: brain, breast, lung, tracheal, pancreatic cancers, CRC and melanoma. Complete remissions were observed in Hodgkins and NK/T cell lymphomas. Phase I safety accepted single dose in terminal patients but relapsed patients became responsive again to further treatments. Leader in COGS: simple outpatient procedure.

4:15 Engineering NK Cells for Enhanced Potency and Persistence

James B. Trager, PhD, Senior Vice President, R&D, Nkarta, Inc.

NK cells form a first line of defense against cancer, and they can be formidable mediators of cytotoxicity and adaptive immunity. Efforts to maximize their potential as cancer therapeutics are hampered by difficulty in expanding NK cells, relatively short in vivo persistence, and the ability of tumor cells to evade NK recognition. We discuss recent progress in overcoming these barriers to successful therapeutic application of NK cells.

4:45 FEATURED PRESENTATION: Tricked-Out CARs: Next-Generation Approaches to Enhance and Optimize CAR T Cell Function

Benjamin Boyerinas, PhD, Senior Scientist, Immunotherapy, bluebird bio

Genetically engineered CAR T cells can be further engineered to survive and overcome immune evasion mechanisms employed by tumors. We have been developing a novel TGF- signal conversion platform that provides a T cell supportive signal upon exposure to TGF- within the hostile tumor microenvironment. This approach, combined with other methodologies such as gene editing and drug-regulated activation, have the potential to enhance specific activity within solid tumors.

5:15 End of Day

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FRIDAY, August 31

7:45 am Registration (Plaza Level)

8:00 Breakout Discussion Groups with Continental Breakfast (Beacon Hill)

This session features discussion groups that are led by a moderator who ensures focused conversations around the key issues listed. Attendees choose to join a specific group, and the small, informal setting facilitates sharing of ideas and active networking. Details on the topics and moderators are available on the conference website.

9:00 Chairpersons Remarks

Paul Rennert, PhD, President & CSO, Aleta Biotherapeutics, Inc.

9:05 GOLD: Activation-Induced Payload Delivery for T Cell Therapies

Gus Zeiner, PhD, CSO, Chimera Bioengineering

GOLD is an endogenous post-transcriptional gene regulatory node that couples T cell metabolic states to transgenic payload outputs. Conditional payload expression is induced by signaling through either the native T cell receptor or a CAR. GOLD is payload-agnostic, and enforces low basal payload expression in resting T cells with a wide dynamic range in activated T cells. GOLD-mediated regulation is non-immunogenic, making GOLD-enabled T cell therapeutics compatible with long-term persistence.

9:35 Developing Tumor Infiltrating Lymphocytes for the Treatment of Cancer

Maria Fardis, PhD, President & CEO, Iovance Biotherapeutics

Recent FDA approvals of Kymriah and Yescarta show that cell therapies are viable options for treatment of hematological malignancies. Incidence of solid tumors are, however, approximately 10 times higher than hematological malignancies. Available therapies for solid tumors include chemotherapy, radiotherapy, and immunotherapy. Immunotherapies, such as Anti-PD-1 antibodies, have shown promise, but in many cases, although the overall response rate is not high, discontinuation due to adverse events remains an issue. Iovance is developing -infiltrating lymphocytes (TIL), a one-time cell therapy treatment that leverages and enhances the bodys natural defenses against certain aggressive solid tumors. TIL is currently under investigation in several multi-center Phase II clinical trials and preliminary results have demonstrated safety and efficacy in melanoma, head and neck and cervical cancer patients with multiple prior therapies which constitutes unmet medical need.

10:05 PM21-NK Cells for Cancer Therapy

Robert Igarashi, PhD, President, CytoSen Therapeutics

CytoSen is advancing NK cell therapy for treatment of cancer. CytoSens methods for stimulating NK cells with membrane bound (IL21), originally developed by Dr. Dean A. Lee, produces NK cells with high anti-tumor potency and can generate the highest doses. We plan to leverage our particle-based platform, that has logistical advantages, to pursue clinical studies in leukemia.

10:35 Coffee Break (Plaza Level)

11:00 A TCR-Based Chimeric Antigen Receptor

Even Walseng, PhD, Staff Scientist, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health; Department of Immunology, Hospital Radiumhospitalet, Institute for Cancer Research, University of Oslo

Although CARs are very potent, the recognition is limited to membrane antigens which represent around 1% of the total proteins expressed, whereas TCRs have the advantage of targeting any peptide resulting from cellular protein degradation. To expand the horizon of TCR use, we have successfully fused a soluble TCR construct to a CAR-signaling tail. We demonstrate that the TCR-CAR redirection is not restricted to T cells and hence opens therapeutic avenues combing the killing efficiency of NK cells with the diversified target recognition of TCRs.

11:30 Hijacking CAR19 T Cells to Address Critical Issues in Cell Therapy: Application to Diverse Indications

Paul Rennert, PhD, President & CSO, Aleta Biotherapeutics, Inc.

The Aleta platform addresses critical issues in cell therapy including CAR persistence, antigen escape and antigen heterogeneity, and provides important solutions for treating both hematologic and solid tumors. The key element of our technology is the use of novel fusion proteins to redirect CAR T specificity. Our lead programs are directed to B cell malignancies, AML and solid tumors.

12:00 Close of Adoptive T Cell Therapy 2: Development

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Adoptive T Cell Therapy 2: Development

Chimeric Antigen Receptor (CAR) T-Cell Therapy | Leukemia …

Possible Side Effects of CAR T-Cell Therapy

Cytokine-ReleaseSyndrome (CRS). This potentially seriousside effectis frequently associated with CAR T-cell therapy. Cytokines (chemical messengers that help the T cells carry out their functions) are produced when the CAR T cells multiple in the body and kill the cancer cells. CRS symptoms can range from mild flulike symptoms that include nausea, fatigue, headache, chills and fever to more serious symptoms, such as a low blood pressure, tachycardia (abnormally rapid heart rate), capillary leakage (fluid and proteins leak out of tiny blood vessels and flow into surrounding tissues, resulting in dangerously low blood pressure), cardiac arrest, cardiac arrhythmias, cardiac failure, hemophagocytic lymphohistiocytosis (life-threatening immunodeficiency)/macrophage activation syndrome (life-threatening complication of rheumatic disease) (HLH/MAS), hypoxia (lack of oxygen reaching the tissue), renal insufficiency (poor function of the kidneys), poor lung oxygenation and multiple organ failure. Severe CRS requires intensive care treatment. Some patients may also experience neurological symptoms (see Neurologic Toxicities, below). Although most symptoms are reversible, the potential life-threatening risk of CAR T-cell therapy should not be underestimated. Deaths have been reported in CAR-T cell trials.

Depending on the patient and the CAR T cells, CRS may occur within 1 to 21 days of CAR T-cell infusion. The duration of CRS is variable and it depends on the type of intervention used to manage it, typically resolving within 1 to 2 weeks after CAR T-cell infusion.

Neurologic Toxicities. The frequency, severity and nature of neurological effects appear different between CAR-T products. Common symptoms include language impairment (aphasia), confusion, delirium, involuntary muscle twitching, hallucinations, or unresponsiveness. Seizures have also been reported.

Neurotoxicity has been reversible in most cases and the symptoms have resolved over several days without intervention or apparent long-term effects. However there can be life-threatening adverse neurological events. The cause of neurotoxicity is the subject of intense investigation by researchers.

B-CellAplasia.CAR T-cell therapy targeting antigens found on the surface of B cells not only destroys cancerous B cells but also normal B cells. Therefore, B cell aplasia (low numbers of B cells or absent B cells) is an expected result of successful CD19-specific CAR T-cell treatment and has served as a useful indicator of ongoing CAR T-cell activity. This effect results in less ability to make the antibodies that protect against infection. Intravenous or subcutaneous immunoglobulin replacement therapy may be given with the aim of preventing infection. Long-term follow-up study is needed to assess the late effects of B-cell aplasia.

TumorLysisSyndrome (TLS).Another known side effect of CAR T-cell therapy is tumor lysis syndrome (TLS), a group of metabolic complications that can occur due to the breakdown of dying cellsusually at the onset of toxic cancer treatments. However, TLS can be delayed and may occur one month or more after CAR T-cell therapy. TLS can cause organ damage and can be a life-threatening complication of any treatment that causes breakdown of cancer cells, including CAR T cells. The complication has been managed by standard supportive therapy.

Anaphylaxis (Life-threatening Allergic Reaction). There is potential for a patient receiving CAR T-cell therapy to have an overwhelming immune response against the CAR itself, called anaphylaxis. Symptoms associated with anaphylaxis include hives, facial swelling, low blood pressure and respiratory distress. There have been a few reports of acute anaphylaxis. Thorough monitoring and immediate treatment of this life-threatening side effect are critical for patients receiving CAR T-cell therapy.

Early outcomes from CAR T-cell trials have generated impressive results in patients with blood cancers.

Acutelymphoblasticleukemia (ALL).).With the FDA approval of tisagenlecleucel (KymriahTM), CAR T-cell therapy represents an option for B-cell acute lymphoblastic leukemia (B-ALL) patients who have relapsed after intensive chemotherapy or a stem cell transplant. In some studies, up to 90 percent of children and adults with B-cell acute lymphoblastic leukemia who had either relapsed multiple times, or failed to respond to standard therapies, achieved remission after receiving CAR T-cell therapy. Relapses may be due to the tumor cells losing the expression of the CD19 antigen, to the limited persistence of CAR T-cells, or inhibition of CAR T-cell activity.

Other blood cancers.Studies of CAR T-cell therapy in other blood cancers, including chronic lymphocytic leukemia (CLL), as well as multiple myeloma, also show potential. Research is also under way, exploring the application of CAR T-cell therapy in the treatment of solid tumors.

While data is fast emerging as to the early responses to CAR T-cell therapy, most of the patients participating in these clinical trials have only been followed for a relatively short time. Following these trial participants over the long term will provide information as to the length of their responses. It is important for more pediatric and adult patients to be enrolled in clinical trials. Larger study samples, evaluated over more extended periods, will help researchers further understand the impact of this type of therapy, ways to reduce its toxicity and improve the management of adverse side effects.

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