Cancer immunotherapy has ushered in a new era in the development of anti-cancer agents. The remarkable clinical response demonstrated by first-generation checkpoint antibodies has garnered significant interest by developers, quickly creating a broad and robust cancer immunotherapy development landscape. One very exciting area focuses on finding novel ways to modulate the immune response beyond or in combination with checkpoint inhibition. These new approaches are poised to significantly enhance the potential of obtaining durable clinical effects in a wider range of cancers, and particularly solid tumors.

Cambridge Healthtech Institute’s inaugural Cancer Immunotherapy and Combinations meeting will convene immuno-oncology researchers, cancer immunotherapy developers, and technology providers to discuss next-generation approaches and combinations, including small molecule development, to enhance the efficacy of checkpoint inhibitors and adoptive therapies.

Final Agenda

Wednesday, June 15

7:00 am Registration and Morning Coffee

BISPECIFIC ANTIBODIES – DUAL TARGETING

8:25 Chairperson’s Opening Remarks

9:05 In vivo Efficacy of Bispecific Antibodies Targeting Two Immune-Modulatory Receptors

Jacqueline Doody, Ph.D., Vice President, Immunology, F-star Biotechnology, Ltd

The bispecific antibody format that allows a “plug and play” modular strategy. I will discuss the enhancement of in vivo activity in a bispecific format over combination therapy in a murine system, as well as novel in vivo biology using bispecific antibodies.

9:35 Dual-Targeting Bispecific Antibodies for Selective Neutralization of CD47 on Cancer Cells

Krzysztof Masternak, Ph.D., Head, Biology, Therapeutic Antibody Discovery, Novimmune

CD47 is a ubiquitously expressed cell surface molecule that serves as a universal "don’t eat me" signal of phagocytosis. To evade immune surveillance, hematological and solid cancers up-regulate the expression of CD47. We generated dual-targeting bispecific antibodies capable of selectively inhibiting CD47 on cancer cells. The dual-targeting antibody design helps to avoid potential hematological toxicities and poor pharmacological half-life resulting from a non-selective blockade of CD47 (e.g., like with an anti-CD47 mAb), while allowing for effective cancer cell killing through antibody dependent cellular phagocytosis (ADCP) and antibody-mediated cell dependent cytotoxicity (ADCC). Phagocytosis of tumor cells by tumor associated macrophages was confirmed as one of the mechanisms of action utilized by dual-targeting anti-CD47 antibodies in vivo. Specifically, I will present the concept of anti-CD47/TAA dual-targeting bispecific antibodies, as well as some in vivo and in vitro data generated with two such dual targeting biAbs, a CD47/CD19 biAb and a CD47/mesothelin biAb.

10:05 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:50 Discovery and Characterization of Immunomodulatory Bispecific Antibodies

Mark Throsby, Ph.D., CSO, Merus

The Biclonics® platform is a robust and validated technology suite for the development of human full length IgG bispecific antibodies. In this presentation we will outline how the technology has been applied to generate bispecific antibody candidates against checkpoint inhibitory and costimulatory molecules.

11:20 Bi- and Tri-Functional Antibody-Cytokine Fusion Proteins for Cancer Immunotherapy

Dafne Müller, Ph.D., Group Leader, Institute of Cell Biology and Immunology, University of Stuttgart

IL-15 and costimulatory members of the B7- and TNF-superfamily have shown great potential to support the generation and development of an anti-tumor immune response. In order to improve the efficacy of such molecules at the tumor site we designed bi- and tri-functional antibody-fusion proteins, focusing on targeted presentation and combined mode of action of diverse immunomodulatory molecules, demonstrating enhanced immune responsiveness in vitro and anti-tumor activity in a mouse model in vivo.

11:50 High Content Screening Utilization for Innate Immune Studies

Steve Yang, Ph.D., Product Specialist/Sales Rep, Northeastern Territory, IDEA Bio-Medical

High content screening provides the combination of modern cell biology, automated high-resolution microscopy, robotic sample handling and sophisticated image analysis tools. Here we demonstrate how high content screening can be utilized for various immune studies, such as image based and time-dependent quantitative cytometry, HIV and Innate Immune Studies and more.

12:05 Sponsored Presentation (Opportunity Available) 

12:20 pm Luncheon Presentation: Immunosequencing: Generating a Potential New Class of Diagnostics

Sharon Benzeno, Ph.D., MBA, Vice President, Business Development, Adaptive Biotechnologies

Adaptive Biotechnologies’ technology combines bias-controlled multiplex PCR amplification with high-throughput sequencing and sophisticated bioinformatics. Adaptive’s immunoSEQ® Assays enable the accurate profiling of T cell and B cell receptor repertoires. In solid tumors, the immunoSEQ Assay accurately quantifies the density and clonality of tumor infiltrating lymphocytes, with preclinical and clinical applications to inform repertoire changes in response to single agent or combination immunomodulatory therapies that have potential prognostic and predictive value.

12:50 Session Break

RADIOTHERAPY AND CHEMOTHERAPY – PD-1 COMBINATIONS

1:40 Chairperson’s Remarks

Dan Duda, D.M.D., Ph.D., Associate Professor, Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School

1:50 Rational Development of Combinations of Antiangiogenic Therapy with Immune Checkpoint Blockers Using Mouse Models of HCC and Cirrhosis

Dan Duda, D.M.D., Ph.D., Associate Professor, Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School

Immunotherapies targeting the programmed death 1 (PD-1) co-inhibitory receptor have shown promise in hepatocellular carcinoma. One challenge will be incorporation of checkpoint blockade with existing, standard anti-angiogenic therapy. I will discuss several strategies addressing this important issue in liver cancer treatment using preclinical models.

2:20 Harnessing the Immune Microenvironment of Gastrointestinal Cancers Using Combined Modalities

Osama Rahma, M.D., Assistant Professor, Center for Immune-Oncology, Dana-Farber Cancer Institute

We are currently investigating the combination of anti-PD-1 inhibitor (Pembrolizumab) and CRT in patients with pancreatic cancer and rectal cancer. Testing this combined modality in the neoadjuvant setting will allow us to study the safety of this approach and its effect on the tumor microenvironment by comparing TILs and other effector (NK, macrophages) and suppressor immune cells (T-regs, MDSCs) and receptors (PD-L1, CTLA-4) pre- and post- treatment. Finally, we will study the correlation between these immune biomarkers and clinical outcomes.

2:50 Refreshment Break in the Exhibit Hall with Poster Viewing

AGONIST – PD-1 AND CTLA-4 COMBINATIONS

3:35 The Role of the Target in the Disposition and Immunogenicity of an Anti-GITR Agonist Antibody

Enrique Escandón, Ph.D., Senior Principal Scientist, DMPK and Disposition, Merck

A detailed analysis of the biological responses to potent immunomodulatory drugs following extended exposure is critical to better understand and predict their therapeutic window. Here we examine the factors governing the dramatic target-mediated pharmacokinetic and pharmacological changes that follow repeated treatment with an anti-GITR agonist monoclonal antibody DTA-1 when dosed alone or in combination with the PD-1 antagonist antibody DX400.

4:05 Enhancing the Efficacy of Checkpoint Inhibition with TLR9 Agonist CpG Oligonucleotides

Art Krieg, M.D., Founder and CEO, Checkmate Pharma

Checkpoint inhibitor therapies such as anti-PD-1 antibodies induce dramatic tumor regression in a relatively small minority of patients, but are ineffective in most patients. Patients responding to anti-PD-1 therapy generally have tumors characterized by pre-existing TIL and a type I IFN signature (“hot tumors”) whereas patients with immunologically “cold” tumors tend to be non-responders. We hypothesize that modification of the tumor microenvironment by intratumoral injection of a Toll-like receptor 9 (TLR9) agonist CpG-A oligodeoxynucleotide will convert “cold” tumors into “hot” tumors, resulting in an increased response rate to anti-PD-1 therapy. This presentation will summarize the previous clinical experience with different TLR9 agonists, preclinical data supporting combination of TLR9 agonists with anti-PD-1 antibodies, and the design of a phase 1b clinical trial in patients with advanced melanoma to test the hypothesis.  

4:35 Label-Free Real-Time Monitoring of Immune Cell-Mediated Killing Using Cellular Impedance

Brandon Lamarche, Ph.D., Research Scientist, Research & Development, ACEA Biosciences

Development of novel cancer immunotherapies requires killing assays capable of predicting the long-term killing kinetics of immune cells in vivo. To address this unmet need, ACEA developed the label-free real-time xCELLigenceâ assay to quantify immune cell killing kinetics. Case studies on NK/T cell-mediated cytolysis, ADCC, BiTE and CAR-T will be discussed.

5:05 Combination Immunotherapy with Checkpoint Blockade, Agonist Anti-OX40 mAb, and Vaccination Rescues Anergic CD8 T Cells

William Redmond, Ph.D., Associate Member, Laboratory of Cancer Immunotherapy, Earle A. Chiles Research Institute, Providence Portland Medical Center

Overcoming tumor-induced tolerance is a major obstacle limiting the generation of anti-tumor immunity. Our studies revealed that dual anti-OX40/anti-CTLA-4 mAb immunotherapy plus tumor-specific vaccination elicited potent T cell responses, leading to significantly improved survival in a mammary carcinoma model. This strategy also restored the function of anergic CD8 T cells in a spontaneous model of prostate adenocarcinoma. Collectively, these data demonstrate that the addition of a vaccine with combined anti-OX40/anti-CTLA-4 immunotherapy significantly enhanced CD8 T cell function, while limiting Th2 polarization in CD4 cells and improving overall survival.

5:35 Welcome Reception in the Exhibit Hall with Poster Viewing

6:45 Close of Day

Thursday, June 16

7:00 am Registration

SMALL MOLECULE INHIBITORS AS SINGLE AND CHECKPOINT COMBINATION AGENTS

8:35 Chairperson’s Remarks

Joost Uitdehaag, Ph.D., Senior Investigator, Netherlands Translational Research Center B.V.

8:45 Selective Small Molecule Inhibitors of IDO1 and TDO for Cancer Immunotherapy

Joost Uitdehaag, Ph.D., Senior Investigator, Netherlands Translational Research Center B.V.

Recently approved immunotherapies are based on antibodies that block the immune checkpoints PD-1 and CTLA-4, while most experimental immune-therapeutics are also based on biologics. Synthetic small chemicals provide the potential of oral route of administration, and lower costs of manufacturing. IDO1 is the only small molecule drug target evaluated in clinical trials currently. IDO1 and TDO are two structurally unrelated proteins that both catalyze the degradation of the amino acid tryptophan, which, among other roles, regulates T cell response. Since several of the currently most advanced IDO1 inhibitors lack selectivity over TDO and have suboptimal drug-like properties, such as low in vivo stability or cross-reactivity with liver metabolic enzymes, we have started the development of best-in-class selective IDO1 inhibitors based on hits identified in an ultra-high throughput screen (uHTS) in the European Lead Factory (ELF) project. In the ELF a library of > 300,000 drug-like molecules has been collated from the internal compound collections of seven pharmaceutical companies. To enable high-throughput, low-volume miniaturized screening, we developed the NFK GreenScreen™ assay technology, which enables the quantitative determination of small molecule compound activity against either IDO1 or TDO by measuring the conversion of tryptophan into N-formyl kynurenine. During this presentation I will provide an update of our IDO1/TDO lead optimization project and a side-by-side comparison with clinical and preclinical reference inhibitors. 

9:15 Potent and Selective Small Molecule USP7 Inhibitors for Cancer Immunotherapy

Suresh Kumar, Ph.D., Director, R&D, Progenra, Inc.

Regulatory T cells (Tregs) suppress immune response against tumors and depletion of Tregs or impairment of Treg function is considered an attractive therapeutic approach. USP7, a deubiquitylase (DUB) implicated as a critical node in several cancer signaling pathways, has recently emerged as an essential factor in maintaining Treg functions. Treg-specific deletion of USP7 results in impairment of Treg function leading to immune activation. Using proprietary technologies, Progenra has identified USP7 inhibitors which were subjected to lead optimization and ADME/PK studies. Potent and selective candidate USP7 inhibitors impair Treg functions and exhibit powerful anti-tumor activity against syngeneic lung tumor models in immunocompetent mice as single agents and in combination with immunotherapies such as anti-PD1 antibodies and cancer vaccines.

9:45 Epigenetic Agents for Combination with Cancer Immunotherapy

Svetlana Hamm, Ph.D., Head, Biology, Translational Pharmacology, 4SC Group

The initiation and progression of cancer is controlled by both genetic and epigenetic events. Since epigenetic processes concurrently and concertedly regulate many cellular processes, their deregulation can contribute to a significant part of cancer hallmarks, including the capacity to avoid recognition and destruction by immune system. Several epigenetic drugs were shown to increase immunogenicity of tumor cells by up-regulating presentation of tumor antigens and enhancing expression of NK cell ligands. Here, I would like to provide a rationale and conclusive evidence for combination of the novel HDAC inhibitor resminostat with different cancer immunotherapy approaches such as immune checkpoint antibodies, opsonizing antibodies and immune stimulating therapies.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

VACCINES AND CHECKPOINT BLOCKADE Immunotherapy

11:00 Immunotherapy for Mesothelioma with an in vivo DC Vaccine and PD-1/PD-L1 Blockade

Huabiao Chen, M.D., Ph.D., Principal Investigator, Vaccine and Immunotherapy Center, Massachusetts General Hospital

The purpose of this work is to develop a combination immune therapy for malignant mesothelioma (MM), which involves the fusion protein VIC-008, which targets and evokes an immune response to mesothelin (MSLN), and the checkpoint blockade of PD-1/PD-L1 pathway to restore function of tumor antigen-specific cytotoxic T cells and to enhance cancer control. From this study we will provide a compelling logical background for further preclinical and ultimately clinical development of this combination of immunotherapy with an in vivo DC vaccine and PD-1/PD-L1 checkpoint blockade for the treatment of an otherwise hard-to-treat form of cancer.

11:30 Bringing Together Checkpoint Inhibition with Vaccines Using Customizing Capsids

Willie Quinn, President & CEO, Bullet Bio

Bullet Bio has pioneered the use of capsids to combine different affinities and create therapeutic vaccines as well as multi-specific antibodies. This talk will explore the potential for vaccines to improve response rates and the durability of effect for checkpoint inhibitors, presenting lessons learned from testing vaccines with various immune modulators, including anti-CTLA4 and anti-OX40, and seeing a strong abscopal effect in contralateral tumor models.

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

12:30 Session Break

1:00 Coffee and Dessert in the Exhibit Hall with Poster Viewing

1:45 PLENARY KEYNOTE SESSION

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

4:15 Close of Conference