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 (Foyer)
12:20 pm Plenary Keynote Program (Constitution Ballroom)
2:00 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)
2:45 Welcome Remarks
Ngoc Emily Le, PhD, 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 NEW: Targeting Myeloid Immune Checkpoints and Signatures of Macrophage Activation
Kipp Weiskopf, MD, PhD, Resident Physician, Internal Medicine, Brigham and Women’s Hospital
4:25 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)
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 Inhibition of STAT3 by Antisense Oligonucleotide Treatment Decreases the Immune Suppressive Tumor Microenvironment in Syngeneic Tumor Models
Theresa Proia, PhD, Associate Principal Scientist, 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 syngeneic murine tumor models. Our data indicate that inhibition of STAT3 has immunomodulatory activity, specifically
through reduction of suppressive CD163+ cells and in combination with anti-PDL1, increased cytotoxic activity of CD8+ T cells in CT26 tumors, leading to significant tumor growth inhibition. These data demonstrate the opportunity to effectively combine
STAT3 ASO with antibodies such as those targeting PD-L1 to enhance the activity of immune checkpoint inhibitors.
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 (Foyer)
9:30 Close of Day
Friday, September 28
7:00 am Registration Open (Foyer)
7:30 Interactive Breakfast Breakout Discussion Groups
Room: Constitution A
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.
Table 6: Therapeutic Targeting of Myeloid Derived Suppressor Cells
Moderator: David A. Eavarone, PhD, Senior Scientist, Siamab Therapeutics
- In vitro assays
- Specific targeting of MDSC
- Effective payloads
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 (Grand Ballroom)
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.
There is growing interest in the role of CSF1 in cancer. CSF1 driven M2 macrophages mediate immune suppression in the tumor microenvironment and therefore CSF1R inhibition provides a viable therapeutic strategy for augmenting established tumor immunotherapeutics
such as anti-PD-1 and anti-CTLA4. ARRY-382 is a potent, selective CSF1R kinase inhibitor that could have utility in immune-oncology. In a phase I study in cancer patients ARRY-382 induced a 28X increase in circulating CSF-1 while simultaneously reducing
non-classical (M2) macrophages by 96% from baseline. The design and discovery of ARRY-382 along with additional clinical results will be presented.
EMERGING TECHNOLOGIES AND MODEL ADVANCEMENT
Hampton
11:45 Chairperson’s Remarks
Donald L. Durden, MD, PhD, Director, SignalRx Pharmaceuticals, Inc.
11:45 Macrophage Syk-PI3Kg-HIF Axis Controls Tumor Immune Suppression
Donald L. Durden, MD, PhD, Director, SignalRx Pharmaceuticals, Inc.
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 (Grand Ballroom)
1:55 Chairperson’s Remarks
Donald L. Durden, MD, PhD, Director, SignalRx Pharmaceuticals, Inc.
2:00 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.
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 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.
4:00 Close of Conference