Targeting Tumor Myeloid Cells

Recently, our understanding of the Tumor Microenvironment (TME) has shed light onto the importance of tumor-infiltrating myeloid cells, such as tumor-associated neutrophils TANs, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and tumor-associated dendritic cells (TADCs), as critical contributors to the suppression of innate and adaptive immune responses. Importantly, these cells exist in various states within the TME, producing either immunosuppressive or immunostimulatory responses. Therapeutically targeting of tumor myeloid cells to eliminate or to convert them to their immunostimulatory state has emerged as a new and complementary strategy in the suite of cancer immunotherapy approaches. However, our understanding of tumor-resident myeloid cell phenotype and their possible divergent function in the tumor microenvironment is still not elaborated.

 

Cambridge Healthtech Institute’s 2nd Annual Targeting Tumor Myeloid Cells conference will bring together experts in the field to examine their phenotypic complexity and possible functions in connection with the tumor microenvironment. We will also discuss evidences for their contribution to cancer pathogenesis from new clinical studies along with regulation mechanisms of myeloid cells by tumors.

Final Agenda

Thursday, September 27

11:50 am Conference Registration Open


12:20 pm Plenary Keynote Program

2:00 Refreshment Break in the Exhibit Hall with Poster Viewing

TUMOR MICROENVIRONMENT AND THE IMMUNE SYSTEM

2:45 Welcome Remarks

Ngoc Emily Le, PhD, Associate Conference Producer, Cambridge Healthtech Institute

2:50 Chairperson’s Opening Remarks

Kipp Weiskopf, MD, PhD, Resident Physician, Internal Medicine, Brigham and Women’s Hospital


2:55 KEYNOTE PRESENTATION: Reprogramming Tumor Microenvironment to Enhance Immunotherapy

Dai Fukumura, MD, PhD, Deputy Director of Edwin L. Steele Laboratory and Investigator, Massachusetts General Hospital; Associate Professor, Harvard Medical School

Immune checkpoint blocker immunotherapy has revolutionized oncology. However, its efficacy is limited to small fraction of patients. Our laboratory has been dissecting the role of tumor microenvironment (TME) in tumor progression and therapeutic response. We found that TME suppresses anti-tumor immunity via two components – abnormal ECM and infiltrated myeloid cells – resulting in hypoperfusion, hypoxia and immunosuppression. We developed strategies to reprogram immune TME and enhance immunotherapy by targeting these mechanisms.

3:25 Chemotherapy-Induced Metastasis: Mechanisms and Translational Opportunities

George S. Karagiannis, DVM, PhD, Anatomy and Structural Biology, Albert Einstein College of Medicine Anatomy and Structural Biology

A better understanding of the mechanistic underpinnings of chemotherapy-induced metastasis will allow us to better predict which patients are more likely to exhibit pro-metastatic responses to chemotherapy and will help develop new therapeutic strategies to neutralize chemotherapy-driven prometastatic changes.

3:55 Sponsored Presentation (Opportunity Available)

4:25 Refreshment Break in the Exhibit Hall with Poster Viewing

TUMOR MICROENVIRONMENT AND THE IMMUNE SYSTEM (CONT.)

5:00 Targeting the ATP: Adenosine Pathway in Cancer

Tim Sullivan, PhD, Vice President, Business Development, Arcus Biosciences, Inc.

In many tumors, extracellular adenosine contributes to an immunosuppressed tumor micro-environment (TME) via activation of the A2a receptor (A2aR), expressed on lymphocytes, and the A2b receptor (A2bR), expressed on myeloid cells. AB928 is a novel and selective dual A2aR/A2bR antagonist designed to potently block the immunosuppressive effects of adenosine in the TME.

5:30 Targeting Stat3 in the Tumor Microenvironment

Corinne Reimer, PhD, Director, In Vivo Bioscience, Oncology IMED Biotech Unit, AstraZeneca

We explored the ability of a mouse STAT3 targeted antisense oligonucleotide (ASO) to enhance the antitumor activity of an anti-PD-L1 mAb in a syngeneic murine tumor model. Our data indicate that, in these models, inhibition of STAT3 has immunomodulatory activity, and can enhance the activity of immune checkpoint inhibitors, such as those targeting PD-L1.

6:00 Targeting Myeloid Cells in the Microenvironment

David C. Linehan, MD, Seymour I. Schwartz Professor, Chairman, Surgery, University of Rochester Medical Center Objective

Targeting tumour-associated CXCR2+neutrophils (TAN) or tumour-associated CCR2+ macrophages (TAM) alone improves antitumour immunity in preclinical models. However, a compensatory influx of an alternative myeloid subset may result in a persistent immunosuppressive TME and promote therapeutic resistance. Here, we show CCR2 and CXCR2 combined blockade reduces total tumour-infiltrating myeloids, promoting a more robust antitumour immune response in PDAC compared with either strategy alone.

6:30 Dinner Short Course Registration

9:30 Close of Day

Friday, September 28

7:00 am Registration Open

7:30 Interactive Breakfast Breakout Discussion Groups

Grab a cup of coffee and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are available on the conference website.

TARGETING MYELOID CELLS IN CANCER – CLINICAL APPROACHES

8:30 Chairperson’s Remarks

Jeffery Kutok, MD, PhD, CSO, Infinity Pharmaceuticals

8:35 A Drug Development Perspective on Targeting Tumor-Associated Myeloid Cells

Majety Meher Vinay Krishna Mohan, PhD, Principal Scientist, Cancer Immunotherapy, Discovery Oncology, Pharma Research and Early Development (pRED), Roche Innovation Center Munich

Myeloid cells represent one of the most abundant immune cell populations within the tumor stroma and are equipped with a broad functional repertoire that promotes tumor growth by suppressing cytotoxic T cell activity, stimulating neo-angiogenesis and tissue remodeling. There are several pharmacological approaches to therapeutically target tumor-associated myeloid cells, each of which has unique advantages and challenges that need to be considered to achieve clinical benefit.

9:05 Targeting Tumor Infiltrating Myeloid Cells for Effective Immunotherapy

Alan Wang, PhD, Associate Professor, Cancer Biology, The University of Texas MD Anderson Cancer Center

Both human cancers and mouse tumors are heavily infiltrated with various types of myeloid cells. Their immune suppressive roles in GEM models, including castration resistance prostate cancer, colon cancer, pancreatic cancer and GBM will be discussed. Results on combinations of MDSCs targeting agents and immune checkpoint blockade will be presented.

9:35 Reprogramming Tumor-Associated Macrophages by Targeting PI3K- γ with IPI-549

Jeffery Kutok, MD, PhD, CSO, Infinity Pharmaceuticals

IPI-549 is a first-in-class, oral, selective PI3K-γ inhibitor that in preclinical studies reprograms macrophages from an immune-suppressive to an immune-activating phenotype and can overcome resistance to checkpoint inhibitors. We are conducting a Ph 1/1b study IPI-549-01 (NCT02637531) evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunomodulatory activity of IPI-549 to determine its recommended Phase II dose and preliminary efficacy, as monotherapy and combined with nivolumab, in ~200 advanced solid tumor patients.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

10:45 Blocking the CD47 “Do Not Eat” Signal with SIRPaFc Fusion Proteins

Bob Uger, PhD, CSO, Trillium Therapeutics, Inc.

CD47 is an innate immune checkpoint that binds to SIRPα and delivers a “do not eat” signal to suppress macrophage phagocytosis. Many tumors express high levels of CD47 to escape macrophage-mediated immune surveillance. Trillium Therapeutics is developing SIRPaFc fusion proteins to block the CD47 “do not eat” signal. The preclinical rationale and emerging clinical data for this novel class of innate immune system checkpoint inhibitors will be discussed.

11:15 The Development of ARRY382

John E. Robinson, PhD, Director, Array BioPharma, Inc.

11:45 Sponsored Presentation (Opportunity Available)

12:15 pm Session Break

12:25 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

EMERGING TECHNOLOGIES AND MODEL ADVANCEMENT

1:55 Chairperson’s Remarks

Jeffery Kutok, MD, PhD, CSO, Infinity Pharmaceuticals

2:00 Re-Programming Tumor Myeloid Compartment

Karrie Wong, PhD, Investigator II, Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, Inc.

Granulocyte-macrophage colony-stimulating factor (GM-CSF), a pleiotropic cytokine that modulates the differentiation and maturation of innate immune cells, has a complex role in cancer immunotherapy. In the tumor microenvironment, GM-CSF contributes to immunosuppression in the tumor microenvironment in a context dependent manner by inducing myeloid suppressor cells and regulatory T cells. Using an in vitro assay and in vivo syngeneic tumor models, we explored targets of GM-CSF mediated myeloid cell immunosuppression.

2:30 Sialyl Tn: A Novel Therapeutic Target for Myeloid Derived Suppressor Cells

David A. Eavarone, PhD, Senior Scientist, Siamab Therapeutics

Tumor expression of the glycan Sialyl Tn (STn) is well established and can be leveraged for therapeutic intervention. We have detected the presence of STn on the surface of infiltrating myeloid derived suppressor cells (MDSCs) in a panel of human tumor samples. Data from in vivo tumor models links tumor and MDSC STn expression and supports the use of anti-STn therapeutics for targeting MDSCs and reducing tumor immune suppression.

3:00 TIM-3 Regulates CD103+ Dendritic Cell Function and Response to Chemotherapy in Breast Cancer

Brian Ruffell, Assistant Member, Immunology, H. Lee Moffitt Cancer Center and Research Institute

Immunotherapeutic approaches are particularly lacking in breast cancer. Here we describe that TIM-3 expression by intratumoral CD103+ DCs regulates chemokine expression during paclitaxel treatment, with anti-TIM-3 antibody administration leading to an immune-mediated response to chemotherapy in murine models. These findings expand upon the potential targets of TIM-3 antibodies currently in clinical trials and offer a rationale for combinatorial studies with chemotherapy.

3:30 Cancer Immunotherapy Getting Brainy: Visualizing the Distinctive CNS Metastatic Niche to Illuminate Therapeutic Resistance

Bryan Ronain Smith, PhD, Associate Professor, Instructor, Radiology and Molecular Imaging Program, Stanford University

Current methods to examine the immunobiology of metastases in the brain are constrained by tissue processing methods that limit spatial data collection, omit dynamic information, and cannot recapitulate the heterogeneity of the tumor microenvironment. In the current review, we describe how high-resolution, live imaging tools, particularly intravital microscopy (IVM), are instrumental in answering these questions.

4:00 Close of Conference