Small Molecules for Cancer Immunotherapy

First-generation cancer immunotherapy agents being developed or approved are engineered T cells targeting tumors or mostly antibody-based biologics that target the immune checkpoint cascade. The success of these biologics in the clinic is now inspiring the discovery and development of small molecules that act on intracellular targets affecting immuno-modulatory pathways in cancer. Cambridge Healthtech Institute’s 2nd Annual Small Molecules for Cancer Immunotherapy conference brings together discovery chemists and biologists to talk about these new intracellular oncology targets and immuno-modulatory small molecule inhibitors that are being developed to act alone or in combination with existing treatments.

Final Agenda


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Wednesday, September 26

7:00 am Registration Open and Morning Coffee

Update On Small Molecules In Development For Immunooncology

8:00 Welcome Remarks

Tanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

Paul Kassner, PhD, Vice President, Quantitative Biology, FLX Bio Inc.

8:10 Beyond PD-1 Axis: The Next Generation Oral Checkpoint Inhibitor Targeting the CD47/SIRPα Pathway for Cancer Immunotherapy

Sasikumar_PottayilPottayil G. Sasikumar, PhD, Associate Research Director and Head of the Peptide Chemistry group, Aurigene Discovery Technologies Limited

Encouraged by our success in discovering small molecule immune checkpoint inhibitors predominantly impacting T cells, we are now focusing on next generation checkpoint inhibitors. In this presentation, we will discuss successful identification of oral agents targeting the CD47/signal regulatory protein alpha (SIRPα) axis, a critical regulator of myeloid cell activation and a checkpoint for macrophage and dendritic-cell mediated phagocytosis and antigen presentation.

8:40 Small Molecule Immune Oncology Therapies from Ubiquitin Proteasome System

Kumar_SureshSuresh Kumar, PhD, Senior Director R&D, Progenra, Inc.

Progenra is developing small molecule inhibitors targeting deubiquitinases and ubiquitin ligases that promote tumor growth and immune evasion. The deubiquitylase (DUB) USP7 stabilizes several pro-tumorigenic proteins and plays an essential in Treg function by regulating post-translational modification of Foxp3 and TIP60. Progenra has developed potent USP7 inhibitors that exhibit direct anti-tumor activity in multiple xenograft tumor models. Most importantly, USP7 inhibitors also impair Treg functions and are efficacious in syngeneic solid tumor models.

9:10 Purine Nucleoside Phosphorylase Inhibitors as Novel, First-in-Class Small Molecule Immunotherapy

Shanta Bantia, PhD, President and CEO, Nitor Therapeutics

We have discovered, contrary to all previous literature, that purine nucleoside phosphorylase (PNP) inhibitors are immune potentiators and represent a new class of orally bioavailable, small molecule immuno-oncology therapeutics. Increase in the endogenous metabolite, guanosine, with PNP inhibition leads to activation of TLR2, 4 and 7. Potential attributes for differentiation of PNP inhibitor (NTR001) are: less adverse events from targeted immune activation in tumor micro-environment; human safety known and doses defined, and immune activation in clinical/preclinical studies confirmed.

9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:25 The Network-Driven Drug Discovery (NDD) Approach and Lead Generation: Novel Immune-Modulatory Small Molecules Case Study

Sree_VadlamudiSree Vadlamudi, PhD, Programme Manager, e Therapeutics plc

The majority of drug discovery approaches involve the search for a single binding target in a well-characterized pathway. But while pathways are easy to envisage, they do not reflect the complexity of biological systems. A more realistic way to describe the underlying interactions which occur is as a network. We have implemented and validated a highly productive NDD approach to identify NCEs in diverse areas of biology. We will describe a case study highlighting the discovery and optimization of small molecules modulating tumor micro environment (TME) with a novel mechanism of action.

10:55 Epigenetic Control of Immune Checkpoint Inhibitor Responses

Hargreaves_DianaDiana Hargreaves, PhD, Assistant Professor, Molecular and Cell Biology, Salk Institute for Biological Sciences

Mutations in subunits of the SWI/SNF chromatin remodeling complex are known to potentiate responses to checkpoint therapies and are thus attractive targets for the development of small molecules for cancer therapy. Here we describe a key role for the SWI/SNF subunit ARID1A in controlling chromatin accessibility and histone modifications at transcriptional enhancers and discuss our efforts to identify novel SWI/SNF complex inhibitors.

11:25 Development of CCR4 Antagonists for Cancer Immunotherapy

Kassner_PaulPaul Kassner, PhD, Vice President, Quantitative Biology, FLX Bio Inc.

Regulatory T cells (Treg) suppress anti-tumor immunity in the tumor micro environment (TME). CCR4 is highly expressed on Treg and responsible for recruitment of Treg to the TME. FLX475 is a potent and selective CCR4 antagonist in Phase I clinical trials. The preclinical development, patient selection strategy and biomarker plan for FLX475 will be discussed.

11:55 Sponsored Presentation (Opportunity Available)

12:25 pm Session Break

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

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

IMPACTING TLRs, CYTOKINES AND PRO-INFLAMMATORY PATHWAYS

1:50 Chairperson’s Remarks

David Ferguson, PhD, Professor, Medicinal Chemistry, University of Minnesota

1:55 Targeting Myeloid Cell Suppressor Function through Inhibition of GCN2

Ravishankar_BuvanaBuvana Ravishankar, PhD, Scientist, Discovery Biology, FLX Bio Inc.

Myeloid-derived suppressor cells (MDSC) are a major component of the tumor microenvironment with potent immune-suppressive activity. MDSC within the tumor mediate local depletion of amino-acids that induce suppression of T cell proliferation and activation. GCN2 kinase is a stress response kinase that detects amino-acid deprivation leading to T cell anergy and apoptosis. GCN2 inhibitors abrogated the suppressive function of MDSCs leading to restoration of proliferation and effector function of CD8 T cells.

2:25 A New Approach for the Selective Suppression of Regulatory T Cell Development with Small Molecules

Ersmark_KarolinaKarolina Ersmark, PhD, Principal Scientist and Project leader Medicinal Chemistry, Medivir AB

Selective suppression of regulatory T cells (Tregs) has previously been demonstrated to enhance the anti-tumor immune response. We have identified a biological target involved in the regulation of Tregs as a novel approach to improve responses to cancer immunotherapy. This presentation will show data demonstrating selective suppression of Tregs in vitro by small molecule inhibition of this target. Optimization of two separate classes of inhibitors is currently in progress with the aim of selecting a final molecule for clinical development.

2:55 Discovery of Small Molecule AhR Antagonists to Overcome Local Tumor Immunosuppression

Christoph Steeneck, PhD, Director, Medicinal Chemistry, Phenex Pharmaceuticals AG

The Aryl Hydrocarbon Receptor (AhR) is widely known for mediating toxicity and tumor-promoting activities of halogenated hydrocarbons and polycyclic aromatic hydrocarbons. However in recent years, ample evidence emerged that AhR activation causes immunosuppression and that AhR antagonism could represent a treatment for cancer complementary to checkpoint inhibitors. An overview on Phenex` series of small molecule AhR antagonists and their optimization will be given. The lead molecules show high potency, favorable ADME/PK and in vivo efficacy.

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

4:05 IDO1 as a Promoter of Inflammatory Neovascularization

Alexander J. Muller, PhD, Associate Professor, Lankenau Institute for Medical Research

IDO1 is a tryptophan catabolizing enzyme implicated in maintaining pregnancy and tumoral immune escape. This may, however, be just one aspect of a multifaceted role for IDO1. Our studies have determined that, by triggering the integrated stress response, IDO1 can support inflammatory neovascularization through its positioning at the regulatory interface between the inflammatory cytokines IFNγ and IL6. These insights have important ramifications for the therapeutic development of IDO1 inhibitors.

4:35 Toll-Like Receptor 7 and 8 Agonists with Direct Inflammasome Activation

Ferguson_DavidDavid Ferguson, PhD, Professor, Medicinal Chemistry, University of Minnesota

The basic structural features of small molecule ligands that confer selectivity to Toll-like receptors 7 and 8 will be discussed in the context of immunomodulation and the design of cancer vaccines. An SAR analysis will be presented to identify structural features that confer selectivity to TLR7 and TLR8 and ligand specific activation of key cytokines in producing antigen-specific cellular responses in model systems. Finally, in vivo data will be shown that demonstrates the potential of TLR7/8 stimulation in designing advanced vaccines for cancer treatment.

5:05 Interactive Breakout Discussion Groups - View Details

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.

Exploring Diverse Target Classes for Cancer Immunotherapy

Moderators: Paul Kassner, PhD, Vice President, Quantitative Biology, FLX Bio Inc.

Buvana Ravishankar, PhD, Scientist, Discovery Biology, FLX Bio Inc.

  • Enzyme targets vs. protein-protein interactions and approaches to target them
  • Immuno-metabolism targets
  • Kinase inhibitors for immunotherapy
  • TLRs
  • Chemokines

The Chemistry of Small Molecule Immunomodulators in the Clinic

Moderator: David Ferguson, PhD, Professor, Medicinal Chemistry, University of Minnesota

  • Single agents
  • Vaccine adjuvants
  • Combination therapies
  • Drug delivery and formulation 

6:05 Welcome Reception in the Exhibit Hall with Poster Viewing

7:10 Close of Day

Thursday, September 27

7:30 am Registration Open and Morning Coffee

Emerging Targets And Combinations For Cancer Immunotherapy

8:00 Chairperson’s Remarks

Amar Natarajan, PhD, Professor, Eppley Institute for Cancer Research, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center

8:05 Exhausted CD8 Cells May Predict Response to Immune Checkpoint Inhibitors in Breast Cancer

Munster_PamPamela Munster, MD, Professor, Department of Medicine; Director, Early Phase Clinical Trials Unit, and Leader, Developmental Therapeutics Program, University of California San Francisco

Immune checkpoint inhibitors have limited efficacy in estrogen receptor (ER)+ breast cancer. Implicated factors include scarcity of tumor infiltrating lymphocytes (TILs), low PD-L1 expression, female gender and liver involvement. Evaluation of in vitro and in vivo effects of epigenetic modulation with HDACi on Tregs, change in TIL composition and data from a clinical trial in patients with (ER)+ metastatic breast cancer suggests that HDACi induced Treg regulation and the presence of exhausted CD8+ cells in a small subset of patients (ER)+ breast cancer patients were predictive of response.

8:35 Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti-Apoptotic Proteins for Cancer Therapy

Natarajan_AmarnathAmar Natarajan, PhD, Professor, Eppley Institute for Cancer Research, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center

Systematic CRISPR studies defined signaling arms in the apoptosis network that can be targeted for cancer therapy. Using a pair of doxycycline (Dox)-inducible cell lines that specifically report on targeting either the Mcl-1 arm or the Bcl-2/Bcl-xL/Bcl-w arm we identified unique combination of inhibitors that synergistically induce apoptosis. Here we will present preclinical studies that validate these combinations that can be rapidly translated to the clinics.

9:05 Discovery of Scaffold/Platform for the Development of Dual Kinase/Epigenetic Inhibitors for the Activation of Innate and Adaptive Antitumor Immunity

Donald Durden, MD, PhD, Professor, Department of Pediatrics, University of California, San Diego; Director of Operations, SignalRx Pharmaceuticals

A novel thienopyranone molecular scaffold has been discovered to selectively inhibit PI3 kinase as well as the bromodomain protein BRD4. Molecular modeling studies and a robust PI-3K and BRD4 BD1 homology model has been developed and will be presented to describe how these single small molecules can bind to inhibit such distinctly different proteins and their functions. As a cancer therapeutic, this dual inhibition mechanism allows for a unique and powerful way to modulate critical components of cancer cells. Finally, other inhibitors developed in silico against other targeted kinases e.g. BTK in combination with PI3K-gamma and PI3K-delta will be presented as novel immuno-oncological agents.

9:35 Coffee Break in the Exhibit Hall with Poster Viewing

10:20 Plate-Based Approach to Identify PROTACS Molecules and Protein Degraders

Gianni_DavideDavide Gianni, PhD, Team Leader, Discovery Sciences, AstraZeneca

PROTACS provide a new modality to drug previously challenging targets and much evidence indicates that protein degraders are a mode of inhibition that can be pursued post HTS. Western Blot is mostly used to characterize PROTACS molecules, but it has a number of obvious limitations. The adoption of plate-based approaches is essential in PROTACS and several options are available such as, antibody-based and non-antibody based approaches. We will present two case studies building plate-based, HTS-friendly protein degradation assays potentially applicable for PROTACS identification campaigns.

10:50 PROTACS: The Chemical Equivalent of CRISPR

Shanique Alabi, Graduate Student, Laboratory of Dr. Craig Crews, Department of Molecular, Cellular and Developmental Biology, Yale University

Induced protein degradation offers several advantages over traditional inhibition strategies and has emerged recently as a potential therapeutic option. For the past 16 years, we have helped develop this fast-growing field, shepherding our initial chemical biology concept into a drug development strategy that is on the verge of clinical validation. PROTACs with high target selectivity, potency, and oral bioavailability will be discussed as well as a system to address the ‘PROTACability’ of particular E3 ligases.

11:20 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

11:50 Conference Registration Open


12:20 pm Plenary Keynote Program

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

2:45 Close of Conference


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