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.
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Wednesday, September 26
7:00 am Registration Open and Morning Coffee
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
Pottayil 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
Suresh 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 Vadlamudi, PhD, Programme Manager, e Therapeutics
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
Diana 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
Paul Kassner, PhD, Vice President, Quantitative Biology, FLX
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
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
Buvana 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
2:25 A New Approach for the Selective Suppression of Regulatory T Cell Development with Small Molecules
Karolina 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
David 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
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
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Thursday, September 27
7:30 am Registration Open and Morning Coffee
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
Pamela 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
Amar 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
Davide Gianni, PhD, Team Leader, Discovery Sciences,
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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