Emerging Approaches to Cancer Immunotherapy

Emerging Approaches to Cancer Immunotherapy

Monday, February 29, 2016

The New York Academy of Sciences

After decades of slow progress and significant barriers in the clinical application of immunotherapy in cancer research, landmark findings from studies of this treatment for metastatic melanoma have ushered in a new era of oncological inquiry and medicine. Targeting the body’s immune system to detect and destroy cancer cells, cancer immunotherapy is now being applied to hematological malignancies, non-small cell lung cancer, and other solid tumors. Areas of promising investigation such as checkpoint blockade inhibitors, specific T cell engagers (bi-specific antibodies), tumor cell directed vaccines, and adoptive T-cell therapies are significantly altering treatment and outcomes. Yet, issues with identification of optimal target antigens, understanding of mechanisms of action, and strategies to combat treatment resistance remain barriers to an in-depth understanding of this cancer therapy.

This symposium will convene leading experts in immunotherapy and immunology to discuss emerging approaches, challenges, and opportunities faced in this evolving field. Session topics will include: Biologics Based Therapies: Immune Checkpoint Modulators and Bi-Specific Antibodies and Cell Based Therapies: CAR-T Cell and Dendritic Cell Immunotherapy.

*Reception to follow.

Registration Pricing

Member$60
Student/Postdoc Member$25
Nonmember (Academia)$105
Nonmember (Corporate)$160
Nonmember (Non-profit)$105
Nonmember (Student / Postdoc / Resident / Fellow)$70

This event will also be broadcast as a webinar; registration is required.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.

Webinar Pricing

Member$30
Student/Postdoc Member$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45

Agenda

* Presentation titles and times are subject to change.


February 29, 2016

8:00 AM

Registration and Continental Breakfast

8:30 AM

Welcome and Introductory Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Renier Brentjens, MD, PhD, Memorial Sloan Kettering Cancer Center

8:40 AM

Historical Perspective: Coley's Mixed Bacterial Toxins
David B. Levine, MD, Hospital for Special Surgery

Session I: Biologics-based Therapies: Immune Checkpoint Modulators and Bi-Specific Antibodies

9:00 AM

Keynote Lecture
Immunologic Checkpoint Blockade
Jedd Wolchok, MD, PhD, Memorial Sloan Kettering Cancer Center

9:40 AM

Identification of Novel Immune Checkpoints in Cancer: From Keyboard to Clinic
John Hunter, PhD, Compugen Ltd.

10:10 AM

Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia (AML)
Roland Walter, MD, PhD, Fred Hutchinson Cancer Research Center

10:40 AM

Networking Coffee Break

11:10 AM

TBD
Jane Gross, PhD, Emergent Biosolutions, Inc.

11:40 AM

Bispecific Tetravalent TandAbs: High Specific Re-direction of NK-cells and T-cells to Fight Cancer
Jens-Peter Marschner, MD, Affimed

12:10 PM

Networking Lunch and Poster Session
Poster presenters are requested to be present at their posters at 12:40PM–1:10PM.

Session II: Cell-Based Therapies:  CAR T Cells and Dendritic Cell Immunotherapy

1:10 PM

Keynote Lecture
CAR T Cell Therapy of Cancer: Building a Better CAR
Renier Brentjens, MD, PhD, Memorial Sloan Kettering Cancer Center

1:50 PM

Targeting Undruggable Intracellular Targets with Antibodies
David A. Scheinberg, MD, PhD, Memorial Sloan Kettering Cancer Center

2:20 PM

NK Cell Receptor Based CAR T Cells as Immunotherapy for Cancer
Charles L. Sentman, PhD, Dartmouth Geisel School of Medicine

2:50 PM

Networking Coffee Break

3:20 PM

Molecular regulation of CAR-T cells: Evolving to Gas and Brake Pedal-Based Approaches
David Spencer, PhD, Bellicum Pharmaceuticals

3:50 PM

Active, Specific Immunization with AGS-003 and the Calculus of Combination Therapy
Charles Nicolette, PhD, Argos Therapeutics, Inc.

4:20 PM

Long Term Follow up of Patients with Acute Myelogenous Leukemia Receiving AST-VAS1: Future Directions
Jane Lebkowski, PhD, Asterias Biotherapeutics

4:50 PM

Poster Award Presentation and Closing Remarks
George Zavoico, PhD, Jones Trading

5:00 PM

Networking Reception and Poster Viewing

6:00 PM

Adjourn

Organizers

Renier Brentjens, MD, PhD

Memorial Sloan Kettering Cancer Center

Dr Renier J. Brentjens obtained an MD/PhD (microbiology) from SUNY Buffalo, completed residency in medicine at Yale New Haven Hospital, and a medical oncology fellowship at Memorial Sloan Kettering Cancer Center (MSKCC). Currently, Dr Brentjens is an associate member on the faculty at MSKCC and an attending physician on the leukemia service. Ongoing pre-clinical and clinical research in the focused on the further development of CAR modified T cells designed to overcome the hostile immunosuppressive tumor microenvironment through the generation of "armored CAR T cells."

George Zavoico, PhD

Jones Trading Institutional Services

Sonya Dougal, PhD

The New York Academy of Sciences

Caitlin McOmish, PhD

The New York Academy of Sciences

Keynote Speakers

Renier Brentjens, MD, PhD

Memorial Sloan Kettering Cancer Center

Dr Renier J. Brentjens obtained an MD/PhD (microbiology) from SUNY Buffalo, completed residency in medicine at Yale New Haven Hospital, and a medical oncology fellowship at Memorial Sloan Kettering Cancer Center (MSKCC). Currently, Dr Brentjens is an associate member on the faculty at MSKCC and an attending physician on the leukemia service. Ongoing pre-clinical and clinical research in the focused on the further development of CAR modified T cells designed to overcome the hostile immunosuppressive tumor microenvironment through the generation of "armored CAR T cells."

Jedd Wolchok, MD, PhD

Memorial Sloan Kettering Cancer Center

Dr. Wolchok is the Lloyd J. Old and Daniel K. Ludwig Chair in Clinical Investigation, Chief of the Melanoma and Immunotherapeutics Service, Attending Physician at Memorial Sloan-Kettering Cancer Center (MSKCC) with an expertise in the treatment of metastatic melanoma. He received his undergraduate degree from Princeton University and both M.D and Ph.D. from New York University, where he also fulfilled his residency program. He completed his fellowship at MSKCC and remained on faculty with an appointment in the Melanoma and Immunotherapeutics Service, which he now leads. Dr. Wolchok has helped establish MSKCC as a leader in the discovery and treatment of cancers with novel immunotherapies. Dr. Wolchok was instrumental in the clinical development leading to the approval of ipilimumab for advanced melanoma and recently designed and led a global phase 3 trial of combined checkpoint blockade for melanoma. He has been at the forefront of cancer immunotherapy, as an active clinician scientist exploring innovative immunotherapeutic strategies in laboratory models and as a principal investigator in numerous pivotal clinical trials. In 2011, he established the Immunotherapeutics Clinical Core, a specialized phase 1 outpatient unit at MSKCC that is focused on the conduct of novel immunotherapy trials, with a specific emphasis on pharmacodynamic biomarker identification. This group treats patients with a broad spectrum of malignancies and has become a model for similar efforts by other major cancer centers throughout the world.

Speakers

Jane Gross, PhD

Emergent Biosolutions, Inc

Dr. Jane Gross has been working in the field of immuno-therapeutics for over twenty years, leading groups at Emergent BioSolutions Inc. and ZymoGenetics Inc. She currently heads the research and development of bispecific antibody therapeutics at Emergent BioSolutions, focusing on retargeting T cells to kill tumors, a novel immuno-oncology approach for treating cancer. Dr. Gross received her Ph.D. in Immunology from the University of California at Berkeley under James P. Allison and completed her Post-Doctoral Fellowship at the University of Washington. Emergent BioSolutions recently announced the spin-off of an independent company, Aptevo Therapeutics, which will continue to develop bispecific therapeutics in immuno-oncology based on the ADAPTIRTM (a modular protein technology) platform as well as produce and sell four marketed hematologic products. Upon the successful completion of the spin-off, anticipated in mid-2016, Dr. Gross will become the Vice President of R&D for Aptevo Therapeutics.

John Hunter, PhD

Compugen Ltd

John Hunter is the Site Head and Vice President of Antibody R&D at Compugen USA, Inc, a wholly owned subsidiary of Compugen Ltd in Israel. He has primary responsibility for developing Compugen’s therapeutic antibody pipeline, which includes programs for both immunomodulatory and antibody drug conjugate (ADC) modalities in cancer. Prior to joining Compugen in 2012 he served as a Senior Director in the Preclinical Department at XOMA, where he managed early stage antibody development. Dr Hunter began his biotechnology career at Millennium Pharmaceuticals after receiving a PhD in Immunology from UCSF in 1996. While at Millennium he was involved in multiple aspects of oncology drug development, spanning target identification and validation to translational biomarker development for the Aurora kinase inhibitor program.

Jane S. Lebkowski, PhD

Asterias Biotherapeutics

Jane Lebkowski has been actively involved in the development of cell and gene therapies since 1986 and is currently Chief Scientific Officer and President of R&D at Asterias Biotherapeutics Inc, where she is responsible for all preclinical product development of Asterias’ products. From 1998 to 2012, Dr. Lebkowski was Senior Vice President of Regenerative Medicine and Chief Scientific Officer at Geron Corporation. Dr. Lebkowski led Geron’s human embryonic stem cell program, being responsible for all research, preclinical development, product development, manufacturing, and clinical development activities. Prior to Geron, Dr. Lebkowski was Vice President of Research and Development at Applied Immune Sciences. Following the acquisition of Applied Immune Sciences by Rhone Poulenc Rorer (RPR, currently Sanofi), Dr. Lebkowski remained at RPR as Vice President of Discovery Research. Dr. Lebkowski received her Ph.D. in Biochemistry from Princeton University in 1982, and completed a postdoctoral fellowship at the Department of Genetics, Stanford University in 1986.

Dr. Lebkowski has published over 70 peer reviewed papers and has 13 issued U.S. patents. Dr. Lebkowski has served as the co-chair of the Industrial Committee of the International Society for Stem Cell Research and serves on several scientific advisory boards and other professional committees.

David B. Levine, MD

Hospital for Special Surgery

David B. Levine, MD, Class of 1954 Dartmouth College, was awarded his medical degree from SUNY Upstate Medical College in 1957. He completed his orthopaedic residency at Hospital for Special Surgery in 1964 and a spine fellowship at USC the next year. Returning to HSS in 1966, he was appointed Chief of the Scoliosis Service (1968–1994), Director of the Department of Orthopaedic Surgery (1987–1990), and Chairman of the Orthopaedic Residency Training Program (1987–1990). Among honors and awards, were the Dartmouth Class of 1954 Award; HSS Distinguished Alumnus Award; and the David B. Levine, MD Chair in Scoliosis (HSS 2006). Appointed Professor of Clinical Surgery (Orthopaedics) at Cornell University Medical College in 1978, Levine retired from patient care in 1995. Returning to HSS in 2003, he became founder of the HSS Archives where he began a new career, writing medical history. He authored Anatomy of a Hospital: Hospital for Special Surgery (1863–2013), where he discovered HSS's third Surgeon-in-Chief Dr. William Coley. For the past ten years, Dr. Levine has been working closely with Bradley L. Coley, Jr., grandson of Dr. William Coley, and in the last year with Dr. Jedd Wolchok on the history of Coley's Mixed Bacterial Toxins.

Jens-Peter Marschner, MD

Affimed AG

Dr. Marschner is CMO of Affimed, a Biotech Company located in Heidelberg, Germany. He is trained and worked as a medical doctor before he became a board certified Clinical Pharmacologist. He has more than 20 years of professional experience in clinical development with a focus on biological compounds. Dr. Marschner led the clinical development team of cetuximab (Erbitux), which was successfully launched in 2004. Over the last 6 years his focus was on the clinical development of cancer immunotherapies, which include vaccines, immune modulators and antibodies. From 2012-2013 he was an active Board member of the Cancer Immunotherapy Consortium, an initiative of the Cancer Research Institute. Dr. Marschner is a member of ASCO and CIMT (Cancer ImmunoTherapy, Germany).

Charles Nicolette, PhD

Argos Therapeutics, Inc

Charles A. Nicolette, PhD, has served as Chief Scientific Officer for Argos Therapeutics, Inc. since December 2007 and as Vice President of Research and Development since December 2004. Dr. Nicolette served as Vice President of Research from July 2003 to December 2004. Prior to joining Argos Therapeutics, Inc., Dr. Nicolette served in various positions at Genzyme Molecular Oncology, Inc., a biotechnology company, from 1997 to 2003, most recently as Director of Antigen Discovery. Dr. Nicolette received a B.S. from the State University of New York at Stony Brook and a Ph.D. in biochemistry and cellular and developmental biology from the State University of New York at Stony Brook, completing his doctoral dissertation and post-doctoral fellowship at Cold Spring Harbor Laboratory.

David A. Scheinberg, MD, PhD

Memorial Sloan Kettering Cancer Center, New York, NY

Dr. Scheinberg is currently Vincent Astor Chair, and Chairman, Molecular Pharmacology, Sloan Kettering Institute (SKI). He founded and Chairs the Experimental Therapeutics Center. He is Professor of Medicine and Pharmacology and Co-chair of the Pharmacology graduate program at the Weill Cornell Medical College (WCMC). He is a founder and Director of the Therapeutics Discovery Institute, a non profit drug discovery corporation formed with WCMC, Rockefeller University and SKI. From 1992 until 2003, he was Chief of the Leukemia Service at Memorial Hospital. He has been elected into the American Society of Clinical Investigation the American Association of Physicians, and the Interurban Club. His other awards include the Doris Duke Distinguished Clinical Science Professorship, the Lucille P. Markey Scholarship, The Emil J. Freireich Award, Leukemia and Lymphoma Society Translational Investigator Awards, and CapCure Awards. Dr. Scheinberg is a physician-scientist, specializing in the care of patients with leukemia and also investigating new therapeutic approaches to cancer. The focus of his research is on the discovery and development of novel, specific immuno-therapeutic agents. Eight different therapeutic agents developed by Dr. Scheinberg in his laboratory have reached human clinical trials, which include the first humanized antibodies to treat acute leukemia, the first targeted alpha particle therapies and alpha generators, the first tumor specific fusion oncogene product vaccines. Dr. Scheinberg has published more than 250 papers, chapters, or books in these fields.

Charles L. Sentman, PhD

Dartmouth Geisel School of Medicine

Dr. Sentman is a Professor of Microbiology & Immunology and the Director of the Center for Synthetic Immunity at the Geisel School of Medicine at Dartmouth. He completed his training at the University of Texas Southwestern Medical Center (Dallas), Washington University Medical School (St. Louis), and the Karolinska Institute (Stockholm). He has held a medical faculty appointment at Umea University in Sweden and worked in Discovery at AstraZeneca R&D in Lund, Sweden. He joined the faculty at Dartmouth Medical School in 2001. His research program is focused on the development of novel cell and protein engineering approaches as immunotherapies to treat cancer and other complex diseases.

David M Spencer, PhD

Bellicum Pharmaceuticals

David Spencer joined Bellicum in 2012 as Chief Scientific Officer. Dr. Spencer is the co-inventor of CID technology, and together with Dr. Slawin, developed the first clinical applications of the technology, DeCIDe® and CaspaCIDe® that are now advancing in human clinical trials. Prior to joining Bellicum, he served as Professor and Vice Chairman of Pathology & Immunology, Baylor College of Medicine, during which time he was a scientific advisor to the Company. Dr. Spencer oversees a robust research program focused on CID clinical applications and supports clinical development of our CID-enabled products. He earned his Ph.D. at Massachusetts Institute of Technology and was a postdoctoral fellow at Stanford University.

Roland Walter, MD, PhD, MS

Fred Hutchinson Cancer Research Center

Dr. Walter is currently an Assistant Member in the Clinical Research Division at the Fred Hutchinson Cancer Research Center, an Associate Professor of Medicine in the Division of Hematology/Department of Medicine at the University of Washington (UW) School of Medicine, and an Adjunct Associate Professor in the Department of Epidemiology at the UW, School of Public Health. His research is centered on human acute myeloid leukemia (AML). A primary focus of his laboratory-based translational studies is the development of antigen-specific immunotherapies aimed at eradicating AML cells, including underlying progenitor and stem cell populations. Dr. Walter is particularly interested in the identification of the most suitable target antigen for such therapeutics, and an in-depth understanding of their mechanisms of action and resistance and, consequently, the development of rational strategies that can overcome relevant resistance factors. Much of this work is currently centered on small bispecific antibodies that engage immune effector cells in the elimination of AML cells. In clinical studies, Dr. Walter is involved in the early testing of novel drugs and innovative care approaches in patients with AML. Finally, he participates in collaborative projects utilizing large datasets that aim to improve diagnostic and prognostic tools in AML.

Abstracts

Father of Cancer Immunotherapies
David Levine, MD, Hospital for Special Surgery, New York

On October 1, 1890, seventeen year old, Bessie Dashiel, sought the advice of a young New York City surgeon, Dr. William Bradley Coley for a minor hand injury. A biopsy diagnosed a sarcoma. Coley performed a below elbow amputation. Widespread metastasis the next month resulted in Bessie's death in January 1891. Shocked, Dr. Coley vowed to devote his life to a cure for cancer. After reviewing 100 cases of advanced cancers operated by his mentor Dr. William Bull at New York Hospital, he found the case of Fred Stein, a 29 year old German House painter who had multiple surgeries by Bull for a sarcoma of his jaw. Stein developed erysipelas, survived that and his tumor disappeared a few weeks later. Coley found Stein seven years later free of disease. Dr. Coley decided to inject streptococcal bacteria into patients with advanced cancer. His first patient was a thirty five year old drug addict, Mr. Zola, whom he injected with live streptococcus pyogenes for recurrent tonsillar sarcoma. After multiple injections, the tumor regressed in size, and the patient lived for another eight years. Coley went on to inject bacteria into cancer patients in some 2,000 cases until he died in 1936. Many of his colleagues did not believe his published data including Dr. James Ewing and Dr. Cornelius Rhoads, both medical Directors at Memorial Hospital. His daughter, Helen Coley Nauts, with the tenacity of a terrier, carried on his work when she founded the Cancer Research Institute in 1953.
 
Coauthors: Jedd Wolchok, Memorial Sloan Kettering Cancer Center and Bradley Coley Jr, retired, West Palm Beach.

Keynote: Combination Checkpoint Blockade
Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center

Given the activity noted with both CTLA-4 or PD-1 blockade, clinical trials are now investigating combination checkpoint blockade. The most mature data with a combination of ipilimumab + nivolumab in melanoma showed a response rate of 40% across dose cohorts with >50% in some cohorts in the context of manageable toxicity. Such responses are generally durable, even when treatment was stopped early for toxicity. Unlike in studies of PD-1 blockade monotherapy, there was no significant difference in clinical activity based on tumor expression of PD-L1. Phase 2 and 3 trials of this combination have similarly shown high rates of activity in melanoma with phase 1 programs in numerous other tumor types. Attention is being paid to the reasons underlying the efficacy of checkpoint blockade in certain malignancies. One hypothesis has been that cancers having a high mutational load may be more amenable to immune modulation by virtue of the larger number of potential neo-epitopes present, fostering baseline immune recognition that can then be potentiated by checkpoint blockade. We have found that melanoma patients having long term clinical activity with ipilimumab have a significantly greater median number of non-synonymous passenger mutations, compared with patients who do not respond or those who have only short-term regression. Strategies to enhance baseline immune reactivity are therefore necessary to investigate as means to improve the impact of checkpoint blockade on a broad spectrum of cancers.

Targeting Undruggable Intracellular Targets with Antibodies
David A. Scheinberg, MD, PhD, Memorial Sloan Kettering Cancer Center

Many important mutated or oncogenic proteins are not expressed on the cell surface, nor are these proteins druggable by small molecules. Therapeutic solutions directed to such proteins may be achieved by vaccines to peptides that are processed and presented by major histocompatibility complex (MHC) molecules for recognition by the T Cell Receptor (TCR) on T cells, or by construction of TCR mimic mAb (TCRm). TCRm can bind to peptides from intracellular targets in the context of human leukocyte antigen (HLA) on the cell surface, even at extremely low density. The Wilms' tumor oncogene protein (WT1) is an intracellular, transcription factor, expressed in a wide range of human cancers and in leukemias. The preferentially expressed antigen of melanoma (PRAME) is an intracellular oncogenic retinoic acid receptor binding protein that is expressed in leukemias and in a wide range of human cancers. Neither protein is appreciably found in most normal tissues; both PRAME and WT1 are expressed on progenitor cells, and may be involved in the oncogenic process. A peptide based vaccine to WT1 is showing promising results in phase 2 clinical studies in hematopoietic and solid cancers. TCRm mAb have also been developed for WT1 and PRAME peptides. Such TCRm mAb are effective in preclinical models of cancer and leukemias. Bi-specific T-cell engager (BiTE) forms of TCRm have vaccinal effects. Issues related to efficacy, pharmacology, toxicity, and resistance to these approaches will be discussed.

Identification of Novel Immune Checkpoints in Cancer: From Keyboard to Clinic
John Hunter, PhD, Compugen USA Inc., South San Francisco

The B7/CD28 immune checkpoint proteins CTLA4, PD1, and PDL-1 play critical roles in T cell regulation, and have emerged as exciting drug targets for cancer immunotherapy. While dramatic clinical responses have been observed with therapeutics that antagonize these checkpoints, a majority of patients do not derive long term benefit, suggesting that additional molecules play an active role in suppressing anti-tumor immune response in those patients. Utilizing Compugen's predictive discovery platform we identified a number of novel checkpoint candidates that were then assessed as potential antibody targets for cancer treatment. Key assessment criteria included expression patterns in normal tissue and the tumor microenvironment, regulation of expression in tumor and immune cells, binding counterpart identification, and demonstration of immune modulatory function. Candidates meeting these validation criteria are being moved forward for therapeutic antibody development at Compugen, with CGEN-15029 the most advanced program in the therapeutic pipeline.

Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia (AML)
Roland B. Walter, MD, PhD, MS1,2,3

Despite aggressive therapies, acute myeloid leukemia (AML) has remained difficult to treat. There is thus a critical need to develop effective yet well-tolerated new therapies for this disease, and immunotherapy-based approaches have raised high expectations of accomplishing this goal. Indeed, recent randomized trials with the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO), which show improved survival for some patients validate this therapeutic strategy. Yet, many patients to not benefit from GO, or other monospecific antibodies, that have so far been clinically tested. Small bispecific antibodies that combine the minimal binding domains of a CD3 antibody and an antibody directed against a tumor cell surface antigen may overcome key limitations of unconjugated or conjucated monospecific antibodies. High efficacy of bispecific antibodies for acute leukemias is demonstrated in several recent trials with the CD19-directed bispecific T-cell engaging (BiTE) antibody, blinatumomab, in acute lymphoblastic leukemia. BiTE or DART (dual antigen re-targeting) molecules against a variety of leukemia cell antigens (e.g. CD33 and CD123) are currently in preclinical development or very early clinical testing for the treatment of AML. However, the antigenic heterogeneity characteristic of AML is a considerable limitation for all these therapeutics, and many important questions related to the ideal target antigen(s), disease situation in which to use these therapies, most suitable patient populations, exact treatment modalities, and details of supportive care needs remain open. Addressing such questions in upcoming studies will be required to ensure that bispecific antibodies become an effective tool for patients with AML.
 
1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle
2 Division of Hematology / Department of Medicine, University of Washington, Seattle
3 Department of Epidemiology, University of Washington, Seattle

ADAPTIR Immunotherapeutics: A Unique Bispecific Platform for Engaging T Cells to Treat Cancer
Jane A. Gross, PhD, Emergent BioSolutions Inc, Seattle

Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer, but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIRTM (modular protein technology) platform, to redirect T-cell cytotoxicity towards prostate cancer cells by specifically targeting T cells through CD3ε to prostate cancer cells expressing PSMA (Prostate Specific Membrane Antigen). In preclinical studies, MOR209/ES414 mediates potent T-cell cytotoxicity of cancer cells with minimal induction of cytokines with extended half-life compared to other formats. MOR209/ES414 is currently under clinical investigation for the treatment of mCRPC. A pipeline of ADAPTIR therapeutics is currently under development from early discovery to clinical stage, targeting both solid and hematologic malignancies. Case studies will be presented for the development of bispecific ADAPTIR therapeutics.
 
Coauthors: Gabriela Hernandez-Hoyos, Robert Bader, Jeannette Bannink, Ruth A. Chenault, Mollie Daugherty, Maria Dasovich, Hang Fang, Rebecca Gottschalk, Robert E. Miller, David Bienvenue, Catherine J. McMahan, and John W. Blankenship, Emergent BioSolutions Inc, Seattle; and Toddy Sewell.

Bispecific Tetravalent TandAbs: Highly Specific Re-Direction of NK-cells and T-cells to Fight Cancer
Jens-Peter Marschner, MD, Uwe Reusch, PhD, and Martin Treder, PhD, Affimed GmbH, Heidelberg

Bispecific tetravalent TandAbs consist of four variable domains with a molecular weight of 100-110 kDa. Therefore, TandAbs are not filtrated in the kidneys and have a half-life not requiring continuous infusion. TandAbs bind tumor targets and effector cells, each with two domains, resulting in a strong avidity effect. AFM11 is a CD19/CD3 T-cell-engaging TandAb currently in Phase 1 in relapsed/refractory (r/r) non-Hodgkin lymphoma. A phase 1 study in acute lymphocytic leukemia is being prepared. AFM11 has a higher in vitro potency compared to blinatumomab, which, together with the prolonged half-life, provide the rationale for clinical development. AFM13, a CD30/CD16A NK-cell-engaging TandAb, is in Phase 2 clinical development. A Phase 1 safety study in 28 patients demonstrated that NK-cell activation is well tolerated and active in r/r Hodgkin Lymphoma (HL). In 13 patients treated with effective doses of ≥1.5mg/kg, the rate of PR and SD was 23% and 77%, with tumor shrinkage in about 2/3 of patients. Of note, the vast majority of patients received four doses only. AFM13 was active in brentuximab vedotin-refractory patients. Combinations of AFM13 with different immunomodulators were investigated in translational PDX-models. AFM13 enhanced the efficacy of immunomodulators and the highest synergy was observed in combination with an anti PD-1 antibody. Further analysis showed that the combination resulted in increased cytokine production in the tumor and that the engagement of NK-cells led to an increased infiltration of cytotoxic T-cells. Studies with AFM13 alone and in combination with anti PD-1 in r/r HL are ongoing or in preparation.

Moving Car T Cell Therapy Forward: Cars and Armored Cars
Renier Brentjens, MD, PhD, Memorial Sloan Kettering Cancer Center

T cells may be genetically modified to express chimeric antigen receptors (CAR) targeted to antigens expressed by tumor cells. Treatment of patients with CD19 targeted CAR T cells has resulted remarkable remission rates in relapsed B cell acute lymphoblastic leukemia (B-ALL). Specifically, based on currently updated clinical outcomes, we have achieved CR rates in adult patients with relapsed B-ALL treated with CD19 targeted CAR T cells which far exceed historical expectations. Further, by deep sequencing analysis, most treated patients were MRD- after CAR T cell therapy. Significantly, remissions were observed in both patients with overt morphological residual disease at the time of therapy as well as in patients with only residual MRD+ disease. Clinical trials from other centers which confirm the presented clinical trial outcomes from our center and toxicities associated with CAR T cells therapy will be reviewed. In contrast, far more modest responses were seen in patients with relapsed chronic lymphocytic leukemia (CLL). The discordant clinical outcomes between B-ALL and CLL patients treated with CD19 targeted CAR T cells remains a subject of conjecture although the tumor microenvironment is a strong focus of further investigation. To this end, we will present novel data on a next generation of CAR T cells, termed "armored CARs" further genetically designed to overcome an immune suppressive tumor microenvironment through further genetic modification of CAR T cells. Promising preclinical studies utilizing these "armored CAR" T cell approaches and their role in future clinical trials will be discussed.

NK Cell Receptor Based CAR T Cells Mobilize the Host Immune System to Fight Cancer
Charles L. Sentman, PhD, The Geisel School of Medicine at Dartmouth, Center for Synthetic Immunity, Lebanon, New Hampshire

Adoptive T cell therapy is a powerful approach to harness the specific effector responses of the immune system to attack cancer leading to increased survival. Chimeric antigen receptor (CAR) T cell therapy is a method to create a large number of antigen-specific T cells for targeting tumor growth and survival. We have taken a unique approach to use natural killer cell receptors as a means to target many different types of tumors. These NK cell receptors recognize molecules over-expressed on many different hematological and solid tumor types, thus providing a means to potentially treat many types of cancer using these CAR T cells. CAR T cells are able to directly kill tumor cells, but in addition they also possess a variety of mechanisms to boost host anti-tumor immunity. This presentation will explore how NK cell receptor based CAR T cells activate local and systemic host immunity to enhance therapeutic efficacy and lead to long-term tumor-free survival.

CID-based Shaping of Activation, Expansion and Toxicity of T Cell-Based Therapies
David M. Spencer, PhD, Bellicum Pharmaceuticals, Inc., Houston

Use of tumor-specific T cell receptors (TCRs) or chimeric antigen receptors (CARs) to refocus adoptively transferred T cells has shown tantalizing clinical efficacy in solid and hematological tumors indications; however, durable responses have been limited by poor T cell persistence and expansion. Moreover, severe toxicities from hyperactivated T cells parallel efficacy. Therefore, we exploited our core technology, Chemically Induced Dimerization (CID) to develop molecular "safety" or "go" switches based on the small molecule ligand, rimiducid, to reign-in "overactive" T cells, or augment efficacy. Our clinically validated caspase-9-based safety switch, CaspaCIDe, demonstrates prompt termination of cellular toxicity after rimiducid administration while preserving therapy. Our novel, antigen-independent activation switch, "MC", based on signaling elements from MyD88 and CD40, can be used for constitutive costimulation or for "costimulation on demand" in the rimiducid-inducible MC variant, "iMC". When used with tumor-targeted CARs in animal models, intravenous administration of iMC-enhanced CAR-T ("GoCAR-T") therapy showed remarkable efficacy against both hematologic and solid tumors. Moreover, engineering T cells to co-express MC-enhanced CARs along with CaspaCIDe ("CIDeCARs") led to potent anti-tumor efficacy in vivo with rapidly controlled toxicity despite functional T cell persistence. Furthermore, by combining iMC with several classes of tumor-specific TCRs ("Go-TCRs"), we have demonstrated the broad applicability to multiple antigens. Additionally, antigen-independent iMC activation within a repressive tumor microenvironment can lead to reversal of commonly observed MHC class I downregulation, further improving therapeutic efficacy. Together, all three new platforms provide enhanced control over unpredictable cellular therapies, greatly expanding their utility into broader indications.
 
Coauthors: Aaron E. Foster, Tsvetelina P. Hoang, Joseph H. Bayle, and Kevin M. Slawin, Bellicum Pharmaceuticals, Inc., Houston

Long-term Relapse-free Survival of Patients with Acute Myeloid Leukemia (AML) Receiving a Telomerase-engineered Dendritic Cell Immunotherapy
Jane S Lebkowski, PhD, Asterias Biotherapeutics, Fremont

There are few treatment options for patients with intermediate and high risk AML. A Phase 2 clinical trial was conducted in subjects with AML to assess a dendritic cell immunotherapy (AST-VAC1) engineered to express a modified form of telomerase that is processed through the MHC Class I and II antigen presentation pathway. AML patients were enrolled if they were in complete remission with intermediate or high risk cytogenetics. AST-VAC1 containing 1 × 107 cells was administered as 6 weekly followed by 6 biweekly intradermal injections. Twenty one patients in complete remission (16 CR1 and 3 CR2) and or early relapse (2) received AST-VAC1. The majority of adverse events were transient including headache, fatigue, and erythema. Of the 19 patients that were in CR, 58% (11/19) developed hTERT-specific T cell responses. Eleven of 19 patients (median follow-up 52 mos.) were in remission as of last follow-up; seven developed detectable cellular immune responses to hTERT. Of the 19 CR patients, 7 were ≥60 years old at the time of AST-VAC1 immunotherapy. Four of 7 patients ≥60 years old remained relapse free 52–59 months post AST-VAC1 immunotherapy with all four developing immune responses to hTERT. The three patients that received AST-VAC1 while in CR2 were in remission as of their last follow-up of 24, 50 and 59 months with two having hTERT immune responses. The results suggest that immunotherapy with AST-VAC1 is safe, can stimulate immune responses to telomerase, and may extend relapse-free survival even in patients with high risk AML.
 
Coauthors: H. Jean Khoury2, Robert H. Collins Jr.3, William Blum4, Patrick Stiff5, Edward Wirth III1, Kevin Nishimoto1, and John F. DiPersio.6
 
1 Asterias Biotherapeutics, Fremont
2 Winship Cancer Institute, Emory University School of Medicine, Atlanta
3 UT Southwestern Med. Ctr. at Dallas, Dallas
4 The Ohio State University, Columbus
5 Medicine, Loyola University, Maywood
6 Washington University School of Medicine, Siteman Cancer Center, Saint Louis

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