2017 Archived Content
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 tumor myeloid cells to eliminate or convert them to their immunostimulatory state has emerged as a new and complementary strategy in the suite of cancer immunotherapy approaches.
Cambridge Healthtech Institute’s Inaugural Targeting Tumor Myeloid Cells conference will convene immuno-oncology researchers, cancer immunotherapy developers, and technology providers to discuss current challenges and opportunities in this rapidly emerging space.
Final Agenda
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Wednesday, September 27
11:50 am Conference Registration Open
12:35 pm Plenary Keynote Program
(click here for details)
2:00 Refreshment Break in the Exhibit Hall with Poster Viewing
2:45 Welcome Remarks
Kip Harry, Senior Conference Director, Cambridge Healthtech Institute
2:50 Chairperson’s Opening Remarks
Jennifer Guerriero, Ph.D., Instructor of Medicine, Lead Scientist of the Immuno-Oncology Group, Letai Laboratory, Dana-Farber Cancer Institute
2:55 KEYNOTE PRESENTATION: Tumor-Associated Macrophages as a Therapeutic Target
Alberto Mantovani, M.D., Professor, Pathology, Humanitas University; Scientific Director, Istituto Clinico Humanitas
Macrophages are key orchestrators of chronic inflammation. They respond to microenvironmental signals with polarized genetic and functional programmes. M1 and M2 cells represent simplified extremes in a universe of functional states. Available information suggests that some TAM are an M2 population. Polarization of phagocytes sets these cells in a tissue remodeling and repair mode and orchestrate the smoldering and polarized chronic inflammation associated to established neoplasia. Intrinsic metabolic features and orchestration of metabolism are key components of macrophage polarization and function. Recent studies have begun to address the central issue of the relationship between genetic events causing cancer and activation of protumor, smoldering, non-resolving tumor-promoting inflammation. New vistas have emerged on molecules associated with M2 or M2-like polarization and its orchestration in cancer. Recently, proof-of-principle has been obtained that targeting TAM can be beneficial in human cancer. Moreover, complement has emerged as a key component of tumor-promoting inflammation. Classic and novel therapeutic targets will be discussed.
3:25 Macrophage-Targeted Cancer Immunotherapy
Carola Ries, Ph.D., Head, Cancer Immunotherapy I, Pharma Research and Early Development (pRED), Roche Innovation Center Munich
To therapeutically target TAMs, we harnessed their dependence on the key survival factor, macrophage colony-stimulating factor 1 (CSF1), and developed a monoclonal antibody (Emactuzumab/RG7155) that blocks dimerization and activation of human CSF1R. Treatment of cancer patients with Emactuzumab substantially reduces the intratumoral TAM infiltrate. We will present data on a cancer immunotherapy combination, which targets TAMs and stimulates an anti-tumoral T cell response leading to tumor remission in preclinical mouse models.
3:55 Selected Poster Presentation: Targeting Tumor-Associated Macrophages by Melittin Suppresses Tumor Progression in a Lewis Lung Carcinoma Mouse Model
Chanju Lee, Research Scientist, Kyung Hee University
4:25 Refreshment Break in the Exhibit Hall with Poster Viewing
5:00 A First-in-Class Selective Class IIa Histone Deacetylase (HDAC) Inhibitor, TMP195
Michael Nolan, Ph.D., Director, GlaxoSmithKline
We recently reported that a first-in-class selective class IIa HDAC inhibitor (TMP195) influenced human monocyte responses to colony stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumor microenvironment and reduces tumor burden and pulmonary metastases through macrophage modulation. TMP195 induces recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumors.
5:30 Discovery and Development of DCC-3014, a Highly Specific Inhibitor of CSF1R Kinase
Bryan Smith, Ph.D., Senior Director of Biology, Deciphera Pharmaceuticals
The discovery and development of DCC-3014 will be presented, including the use of Deciphera’s switch control platform to identify highly specific inhibitors of CSF1R kinase. DCC-3014 potently inhibits CSF1R, while sparing near neighbor kinases FLT3, KIT, and PDGFRs by >100 to >1,000 fold, and additionally sparing a 300 kinase panel by >1,000 fold. Cellular studies, in vivo PK/PD studies, and in vivo efficacy studies in syngeneic cancer models (single agent and in combination with anti-PD1) will also be presented.
6:00 Class IIa HDAC Inhibition Promotes an Anti-Tumor Macrophage Phenotype that Induces Breast Tumor Regression and Inhibits Metastasis
Jennifer Guerriero, Ph.D., Instructor of Medicine, Lead Scientist of the Immuno-Oncology Group, Letai Laboratory, Dana-Farber Cancer Institute
We recently reported that a first-in-class selective class IIa HDAC inhibitor (TMP195) influenced human monocyte responses to colony stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumor microenvironment and reduces tumor burden and pulmonary metastases through macrophage modulation. TMP195 induces recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumors.
6:30 Close of Day
6:30 Dinner Short Course Registration
Click here for details on short courses offered.
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Thursday, September 28
7:30 am Registration Open
8:00 Interactive Breakout Discussion Groups with Continental Breakfast
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 below. Please click here for full details on all breakouts.
Preclinical Efficacy Assessment of Drug Candidates Targeting Tumor Myeloid Cells
Moderator: Bernard Vanhove, Ph.D., COO, OSE Immunotherapeutics
- Cell-based assays for myeloid function
- Setting up “in sitro” assays from patient tissues
- Surrogate animal models and drugs
- Humanized mice models
Combination Cancer Immunotherapy and New Immunomodulatory Targets
Moderator: Kipp A. Weiskopf, M.D., Ph.D., Resident Physician, Medicine, Brigham and Women's Hospital
- What are emerging strategies for immunotherapy combinations?
- How can preclinical and clinical data determine rational combinations?
- How can we use biomarkers to inform new combinations?
9:00 Chairperson’s Remarks
Michael M. Goldberg, M.D., President and CEO, Navidea Biopharmaceuticals, Inc. & Macrophage Therapeutics, Inc.
9:05 A Portfolio of Humanized Anti-CD47 Monoclonal Antibodies with Diverse Combinations of Functional Properties and Preclinical Anti-Tumor Activity
Robert W. Karr, M.D., CSO, Tioma Therapeutics
Anti-CD47 antibodies have also been shown to promote an anti-tumor adaptive immune response. Ti-061, Tioma’s first generation humanized anti-CD47 antibody, has preclinical anti-tumor activity in vitro and in vivo and is being studied in a Phase I trial. Tioma’s second generation anti-CD47 antibodies have novel combinations of functional properties, including direct killing of tumor cells, minimal RBC binding and increasing phagocytosis of tumor cells, potentially enhancing their anti-tumor activity.
9:35 TTI-621 (SIRPαFc): A Checkpoint Inhibitor of the Innate Immune System that Blocks the CD47 “Do Not Eat” Signal
Lisa Johnson, Ph.D., Research Scientist, Trillium Therapeutics, Inc.
Trillium Therapeutics is developing TTI-621 (SIRPαFc), a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG1. It is designed to block the CD47 “do not eat” signal and engage activating Fc receptors on macrophages to enhance phagocytosis and anti-tumor activity and is currently being evaluated in two Phase I clinical studies. This presentation will discuss the preclinical rationale and emerging clinical data for this novel innate immune system checkpoint inhibitor.
10:05 Selective Targeting of SIRP Alpha Induces Potent Memory Anti-Tumor Immune Responses in Mice and Does Not Prevent SIRP Gamma Dependent Human T Cell Responses
Bernard Vanhove, Ph.D., COO, OSE Immunotherapeutics
Using murine models of TNBC and HCC, we noticed a preclinical efficacy of antagonistic anti-SIRPalpha mAbs in monotherapy or in combination with anti-PDL-1 and 4-1BB mAbs. Combinations elicited anti-tumor T cell responses. In humans, but not in mice, CD47 also interacts with SIRPgamma expressed by T cells, playing a role in human T cell proliferation. We show here that blocking CD47/SIRPgamma interaction is deleterious for T cell responses in vitro while specifically targeting SIRPalpha is “T cell friendly”.
10:35 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
11:20 Targeting CD47 with High-Affinity SIRPα Fusion Protein to Enhance Both Innate and Adaptive Immunity against Cancer without Hematological Toxicity
Hong I. Wan, Ph.D., Chief Scientific Officer, Alexo Therapeutics, Inc.
CD47 is a widely expressed cell surface protein that functions as a marker of self. Interaction of CD47 with signal regulatory protein-α (SIRPα), its receptor on macrophages, inhibits phagocytosis. CD47 blockade may enhance both innate and adaptive immunity against cancer and is being evaluated as a new immunotherapy. Fusion proteins comprised of the N-terminal D1 domain of SIRPα and inactive Fc domains were engineered to bind CD47 with high affinity and prevent interaction of CD47 with wild type SIRPα. These high-affinity SIRPα fusion proteins enhanced the activity of multiple anti-cancer antibodies and have minimal effect on normal blood cells both in vitro and in vivo. ALX148, a high-affinity CD47 blocker designed to avoid toxicity on CD47-expressing blood cells, is currently in clinical development in a broad spectrum of malignancies (NCT03013218).
11:50 Targeting the Tumor Microenvironment by Selectively Depleting the Tumor Supporting M2 Macrophages
Michael M. Goldberg, M.D., President and CEO, Navidea Biopharmaceuticals, Inc. & Macrophage Therapeutics, Inc.
Macrophage Therapeutics has developed a highly targeted agent that can deliver therapeutic payloads with extremely high Kds, on the order of 10-11 or higher, targeted to the mannose receptor (CD206). The mannose receptor is only expressed on activated macrophages and internalizes and recycles every 15 minutes. MT1002 targets CD206 and delivers a therapeutic agent linked to the targeted dextran backbone with a pH sensitive linker. Data will be presented that demonstrates that MT1002 depletes the TAMs via apoptosis, without any effect on non-activated macrophages.
12:20 pm Enjoy Lunch on Your Own
1:50 Refreshment Break in the Exhibit Hall with Poster Viewing
2:35 Chairperson’s Remarks
Bernard Vanhove, Ph.D., COO, OSE Immunotherapeutics
2:40 Overcoming Resistance to Checkpoint Blockade by Selectively Targeting PI3K-Gamma in Tumor Myeloid Cells
Jeffery Kutok, M.D., Ph.D., CSO, Biology and Translational Medicine, Infinity Pharmaceuticals
IPI-549 is an investigational, orally administered immuno-oncology development candidate that selectively inhibits PI3K-gamma which is highly expressed in tumor associated myeloid cells. In preclinical studies, IPI-549 increases anti-tumor immunity by reprogramming tumor-associated myeloid cells from the M2, pro-tumor phenotype to the M1, anti-tumor phenotype and activating anti-tumor T cell responses. IPI-549 also overcomes immune checkpoint blockade resistance in preclinical tumor models.
3:10 Novel Targeting of Tumor Infiltrating Myeloid Derived Suppressor Cells (MDSCs) Through Expression of the Tumor-Specific Glycan Antigen Sialyl Tn (STn)
David Eavarone, Ph.D., Scientist II, Siamab Therapeutics, Inc.
MDSCs are major regulators of immune responses in cancer and other pathological conditions. MDSCs are functionally defined by their capacity to suppress T cell immunity; therefore inhibiting these cells is of great interest for immuno-oncology applications. We have further evaluated the correlation between MDSC STn expression and tumor STn expression using murine xenograft models of tumors with controlled STn expression. Using anti-STn antibody-drug conjugates (ADCs), we have demonstrated that STn provides a uniquely glycan-specific and potent targeting mechanism for treatment of solid tumors. STn expression on MDSCs offers the potential to go beyond tumor targeting with an anti-STn therapeutic to also directly target and deplete immune-suppressive MDSCs, fostering immune re-engagement and possibly better patient outcomes. The emerging understanding of glycans in immunology and specifically MDSC biology suggests the potential for a functional role of STn as well and provides a compelling opportunity to directly impact MDSC function with immuno-therapeutic applications.
3:40 Session Break
3:55 Imprime PGG - A Yeast-Derived Pathogen-Associated Molecular Pattern (PAMP) Triggers the Anti-Cancer Immunity Cycle to Potentiate the Efficacy of Immune Checkpoint Inhibitors
Jeremy R. Graff, Ph.D., CSO and Senior Vice President, Research, Biothera Pharmaceuticals, Inc.
Imprime has been safely administered to >400 human subjects. Imprime triggers a cascade of immune activating events that re-polarize the immunosuppressive tumor microenvironment and elicit maturation of antigen presenting cells. Unlike other PAMPs (TLR and STING agonists), Imprime is administered systemically. In preclinical tumor models, Imprime robustly enhances the anti-tumor efficacy of CPIs. Accordingly, Imprime is now being explored in multiple Phase II clinical trials in combination with pembrolizumab.
4:25 Effective Combinatorial Immunotherapy for Castration-Resistant Prostate Cancer
Xin Lu, Ph.D., John M. and Mary Jo Boler Assistant Professor, Department of Biological Sciences, Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame
Targeted therapy against myeloid-derived suppressor cells (MDSCs), using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumor activities. Strikingly, primary and metastatic CRPC showed robust responses to the synergistic effect when ICB was combined with MDSC-targeted therapy. Mechanistically, the combination efficacy was due to the upregulation of IL-1RA and suppression of MDSC-promoting cytokines secreted by mCRPC cells.
4:55 Close of Conference
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The quick brown fox jumps over the lazy dog.