Cambridge Healthtech Institute’s 2nd Annual

Small Molecules for Cancer Immunotherapy

Discovery and Development of Immune-Modulatory Small Molecules

April 4-5, 2018 | Hilton Bayfront | San Diego, California

First-generation cancer immunotherapy agents being developed or approved are mainly monoclonal antibodies that block protein-protein interactions between T cell checkpoint receptors and their ligands. Recently, discovery efforts have shifted to focus on the development of immune-modulatory small molecules, particularly for synergistic combinations with checkpoint antibodies, and addressing a wide array of new immune-modulatory targets.

Cambridge Healthtech Institute presents the 2nd Annual Small Molecules for Cancer Immunotherapy conference, designed to convene leading developers and discovery scientists to share new targets, novel immune-modulatory inhibitors, as well as preclinical and clinical studies in combination with checkpoint antibodies.

Final Agenda

Wednesday, April 4

12:30 pm Registration

12:45 Dessert Break in the Exhibit Hall with Poster Viewing


1:30 Welcome Remarks

Tanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute

1:35 Chairperson’s Opening Remarks

Alexander Dömling, PhD, Professor and Chair, Department of Drug Design, University of Groningen

1:40 Small-Molecule Inhibitors of PD-1/PD-L1

Alexander_DomlingAlexander Dömling, PhD, Professor and Chair, Department of Drug Design, University of Groningen

My research group is leading in the synthesis of macrocyclic compounds with non-peptidic character. We have not only devised 12 novel convergent straightforward synthetic ways to assemble very large macrocyclic libraries but we also applied them to antagonize protein-protein interactions such as PD1-PD-L1.

2:10 Tetraiodothyroacetic Acid (Tetrac), a Small Molecule Thyroid Hormone Antagonist, Disables Immune Checkpoint Defenses of Cancer Cells

Paul_DavisPaul Davis, MD, Professor, Department of Medicine, Pharmaceutical Research Institute, Albany Medical College

We have shown that the PD-1/PD-L1 immune checkpoint is regulated non-immunologically by thyroid hormone. A thyroid hormone antagonist, tetrac, acts as a hormone receptor on an integrin expressed by cancer cells to downregulate expression of PD-L1 and PD-1 genes. beta-Catenin activation mediates T cell exclusion from the cancer microenvironment and tetrac blocks catenin activation non-immunologically by inducing expression of miR-21 and CBY1 (Chibby). Thus, acting outside the traditional immune system and at the level of gene expression, tetrac disables immune defenses of tumor cells.

2:40 FEATURED PRESENTATION: Small Molecule Antagonists Targeting PD-1/PD-L1 and Other Immune Checkpoint Pathways

Murali Ramachandra

Murali Ramachandra, PhD, CSO, Aurigene Discovery Technologies Limited

We are developing small molecule oral agents dually targeting PD-L1 and another pathway to increase the response rate, and with a relatively shorter pharmacokinetic exposure for better management of irAEs. We have identified candidates potently targeting PD-L1 and VISTA or PD-L1 and TIM-3 pathways along with desirable physico-chemical profile, exposure upon oral dosing and pharmacological properties. CA-170, the first candidate from this approach dually targeting PD-L1 and VISTA, is now undergoing clinical trials.

3:10 Epigenetic Control of Immune Checkpoint Inhibitor Responses

Diana_HargreavesDiana 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.

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Network-Driven Drug Discovery (NDD) Approach in the Identification and Optimisation of Novel Immune-Modulatory Small Molecules

Sree Vadlamudi, PhD, Programme Manager, Discovery, e Therapeutics plc

The majority of drug discovery approaches involve the search for a single binding target in a well-characterised 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 successfully implemented and validated a highly productive network-driven drug discovery (NDD) approach to identify NCEs in diverse areas of biology. We will describe a case study highlighting the application of our proprietary NDD methodology in the discovery and optimisation of small molecules with a novel mechanism of action (MOA) for modulating tryptophan catabolism in tumour and immune cell populations. Our lead molecules, covered by two patents, show potency in that is comparable or superior to the existing clinical candidates in development.

5:00 A Small Molecule Multiple Checkpoint Inhibitor

Floyd Taub, MD, CEO, Medical, AxImmune

Ax 101 has been shown to decrease markers of severe checkpoint inhibition including PD1, Tim 3 and Lag 3. This correlates with tumor inhibition in animals of myeloma, melanoma, bladder cancer and breast cancer. It also correlates with all human Phase I/II lymphoma patients who are immune eligible meeting irRECIST and some meeting classic RECIST.

5:30 Breakout Discussions

In this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers.

Topic: Exploring Diverse Target Classes for Cancer Immunotherapy

Moderator: Murali Ramachandra, PhD, CSO, Aurigene Discovery Technologies Limited

Enzyme targets vs. protein-protein interactions and approaches to target them

  • Immuno-metabolism targets
  • Kinase inhibitors for immunotherapy
  • TLRs
  • Chemokines

Topic: 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


6:15 End of Day

6:30 Dinner Short Courses*

*Separate registration required

Thursday, April 5

8:00 am Breakfast Presentation: Improvements in NMR Approaches to Fragment Based Screening

Donna BaldisseriDonna Baldisseri, Senior Applications Scientist, Bruker BioSpin

FBDD is a powerful search engine for identification of fragments that bind to disease relevant target proteins ultimately leading to drug candidates. NMR-based FBDD screening requires compound library validation, preparation of hundreds of samples per campaign, automated acquisition, processing of thousands of spectra, and their analysis for binding assessment. Here is described the streamlined solutions offered by Bruker, automating this pipeline to improve the speed and productiveness of FBDD screening for the pharmaceutical industry.

8:45 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

8:50 Plenary Keynote Introduction

Chris PetersenChris Petersen, CTO,

8:55 PLENARY KEYNOTE: Targeting Ras and MYC for the Treatment of Cancer

Stephen Fesik
Stephen Fesik, PhD, Professor of Biochemistry, Pharmacology, and Chemistry, Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University School of Medicine
Two of the most important targets in cancer are Ras and MYC. However, both of these highly validated cancer targets are thought to be undruggable. In this presentation, I will discuss our approaches for targeting both of these proteins directly and indirectly using fragment-based methods and structure-based design.

9:45 Coffee Break in the Exhibit Hall with Poster Viewing


10:40 Chairperson’s Remarks

Suresh Kumar, PhD, Senior Director, Research and Development, Progenra

10:45 A New Approach for the Discovery of Immune Stimulating Drugs

Dennis A. Carson, MD, Director Emeritus, Moore University of California, San Diego Cancer Center, Sanford Consortium for Regenerative Medicine

11:15 Inhibiting Treg Trafficking into the Tumor Microenvironment

David_WustrowDavid Wustrow, Vice President, Drug Discovery, FLX Bio, Inc.

Recent longitudinal studies in patients receiving IO agents demonstrate an influx of Treg in responding patients which may dampen optimal anti-tumor responses. Understanding the mechanisms of Treg recruitment into the TME thereby preventing their ability to induce immune tolerance. This talk will describe the discovery of the key mechanism of such Treg recruitment as well as in vitro and in vivo validation of this small molecule approach to selectively decreasing immune tolerance in the TME.

Pelago11:45 Accelerated Drug Discovery with CETSA®

Mike DabrowskiMichael Dabrowski, CEO, Pelago Bioscience

Using CETSA, researchers can now measure directly how a compound interacts with target proteins in the cell. CETSA can be used against known targets or in an unbiased proteomic approach that makes it ideal for target deconvolution, safety studies and for biomarker discovery.

12:00 pm Targeting Tumor Microenvironment with Deubiquitinase Inhibitors for Cancer Immunotherapy

Suresh_KumarSuresh Kumar, PhD, Senior Director, Research and Development, Progenra

Immune suppressive Tregs and MDSCs in the tumor microenvironment correlate with poor prognosis. Suppression of Tregs or impairment of Treg function is an attractive cancer immunotherapy approach. Deubiquitinase USP7 is critical for Treg function by regulating Foxp3 and TIP60. Progenra has developed potent USP7 inhibitors that impair Treg functions and are efficacious in various syngeneic solid tumor models. USP7 inhibitors alone or in combination can improve the efficacy and expand the scope of cancer immunotherapy.

Bioduro 12:30 Lunch & Learn: Immune Metabolism: Targeting Mitochondria to Promote Antitumor Immunity

Hall BrettBrett Hall, PhD, CEO, Asellus Therapeutics

An expanding body of research has established that mitochondria are central players in coordinating immune response. Asellus is working on small molecule drug programs that promote antitumor immunity through targeted modulation of mitochondria function. We will discuss preclinical progress on one of our drug programs, AT-S-977.

1:30 Dessert Break in the Exhibit Hall with Poster Awards


2:15 Chairperson’s Remarks

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

2:20 Discovery of Scaffold/Platform for the Development of nM Potent Triple Inhibitor of PI3K/BRD4/CDK4/6 (Kinase/Epigenetic) Inhibitor, SRX3177 for Maximum Cancer Cell Synthetic Lethality, Safety and Efficacy

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

A novel thienopyranone molecular scaffold has been developed in silico to selectively inhibit PI3 kinase (PI3K) as well as two other targets, the bromodomain protein, BRD4 and CDK4/6. Molecular modeling studies employing crystal structure analysis and robust PI3K, BRD4 and CDK4/6 homology models have 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 triple inhibition mechanism allows for a unique and powerful way to modulate critical components of cancer cells.

2:50 Purine Nucleoside Phophorylase 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. PNP inhibitors activate the immune system through modulation of an endogenous metabolite. Increase in the endogenous metabolite, guanosine, with PNP inhibition leads to activation of TLR2, 4 and 7. Potential attributes for differentiation and value for PNP inhibitor (NTR001) are: (1) Immune activation occurring in tumor micro-environment (TME) more so than in other tissues (because of increased apoptosis and necrosis in TME causing increased levels of guanosine) and hence less likelihood of immune related adverse effects that is commonly seen with other immunotherapies (2) Rapid path to clinic as human safety is known and doses are defined (3) Evidence of immune activation in clinical studies and the concept of activation of immune system by PNP inhibitors confirmed in preclinical models of vaccines and cancer.

3:20 Selective Inhibitors of CLK and DYRK kinases

Lijun Sun, PhD, Director, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center; Associate Professor, Harvard Medical School

CDC2-like kinase (CLK) and dual specific tyrosine phosphorylation-regulated kinase (DYRK) control the mRNA splicing events via priming phosphorylation of key SF members of the spliceosome. CLK and DYRK are aberrantly activated in a number of cancers and are attractive targets for developing anticancer therapy. We describe our SAR results of a class of novel water-soluble benzimidazoles as selective CLK/DYRK inhibitors. In vitro activity in the NCI60 panel screen of the advanced lead candidates, as well as in vivo efficacy in established prostate cancer tumor models, will be presented.

3:50 Refreshment Break

4:20 Selective Activation of Toll-Like Receptor 7 and 8 in the Design of Cancer Vaccines

David_FergusonDavid 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 demonstrate the potential of TLR7/8 stimulation in designing advanced vaccines for cancer treatment.

4:50 Tumor Immune Modulation following Intratumoral Therapy with Small Molecule TLR7/8 Ligands

John_VasilakosJohn Vasilakos, PhD, Senior Research Immunologist and Business Director for TLR Agonists, TLR Department, Drug Delivery Systems Division, 3M

TLR7/8 ligands exhibit anti-tumor activity when injected into tumors, and synergize with checkpoint blockade therapies. Anti-tumor activity of TLR7/8 ligands requires or is associated with the infiltration of activated CD8 T cells, formation of lymphoid aggregates, and expression of cytokines and chemokines associated with Th1 immunity, CTL activity, T cell chemotaxis, and type I IFN inducible gene expression.

5:20 The Imipridone ONC201, a Selective DRD2 Antagonist, Exerts Immunostimulatory Activity in Advanced Cancer Patients

Joshua_AllenJoshua Allen, PhD, Vice President, Research and Development, Oncoceutics

ONC201 is an orally active small molecule antagonist of the G protein-coupled receptor DRD2 currently in Phase II clinical trials for advanced cancer. DRD2 is expressed by immune cells and ONC201 has shown immunostimulatory effects in preclinical studies, including increased intratumoral NK cell infiltration in xenografts. In agreement with preclinical observations, increase in circulating and intratumoral NK cells, cytokines and effector molecules was observed in prostate, endometrial, glioblastoma and mantle cell lymphoma patients.

5:50 End of Conference