Emerging Approaches to Cancer Immunotherapy

Agenda

* Presentation titles and times are subject to change.

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, MS^1,2,3

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

Travel & Lodging

Our Location

The New York Academy of Sciences

7 World Trade Center
250 Greenwich Street, 40th floor
New York, NY 10007-2157
212.298.8600

Directions to the Academy

Hotels Near 7 World Trade Center

Recommended partner hotel

Club Quarters, World Trade Center
140 Washington Street
New York, NY 10006
Phone: 212.577.1133

The New York Academy of Sciences is a member of the Club Quarters network, which offers significant savings on hotel reservations to member organizations. Located opposite Memorial Plaza on the south side of the World Trade Center, Club Quarters, World Trade Center is just a short walk to the Academy.

Use Club Quarters Reservation Password NYAS to reserve your discounted accommodations online.

Other nearby hotels