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 focused 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 introduces the 2nd Annual Small Molecules for Cancer Immunotherapy symposium, 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

Kip Harry, Senior Director, Conferences, Cambridge Healthtech Institute

1:35 Chairperson's Opening Remarks

Rogier C. Buijsman, PhD, Head, Chemistry, Netherlands Translational Research Center B.V. (NTRC)

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

Alexander_DomlingAlexander Domling, 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, 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 Sponsored Presentation (Opportunity Available)

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

4:30 Discovery of PF-06840003, a Novel IDO Inhibitor for Cancer Immunotherapy

Stefano_CrosignaniStefano Crosignani, PhD, Director, Medicinal Chemistry, iTeos Therapeutics

Tumors use Indoleamine 2-3 dioxygenase to induce an immunosuppressive environment by promoting immune tolerance, effector T cell anergy and enhanced Treg function. We have identified and characterized a new, highly selective, orally bioavailable IDO-1 inhibitor, PF-0684003. PF-0684003 reverses human T cell anergy in vitro. It shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties. These studies highlight the strong potential of PF-0684003 as a clinical candidate in immuno-oncology.

5:00 Talk Title to be Announced

Rogier C. Buijsman, PhD, Head, Chemistry, Netherlands Translational Research Center B.V. (NTRC)

5:30 Breakout Discussions

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 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 Sponsored Plenary Keynote Introduction (Opportunity Available)

8:55 PLENARY KEYNOTE: Activity-Based Proteomics: Protein and Ligand Discovery on a Global Scale

Benjamin F. Cravatt, PhD, Professor and Co-Chair, Department of Molecular Medicine, The Scripps Research Institute

To address uncharacterized proteins, we have introduced chemical proteomic technologies that globally profile the functional state of proteins in native biological systems. Among these methods is activity-based protein profiling (ABPP), which utilizes chemical probes to map activity states of large numbers of proteins in parallel. I will discuss the application of ABPP to discover and functionally annotate proteins in mammalian physiology and disease, and the generation and implementation of advanced ABPP platforms for proteome-wide ligand discovery.

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 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.

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.

11:45 Sponsored Presentation (Opportunity Available)

12:00 pm A First-in-Class Selective Class IIa Histone Deacetylase (HDAC) Inhibitor, TMP195

Michael_NolanMichael Nolan, PhD, 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.

12:30 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

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 Leniolisib (CDZ173) - The Discovery of a New Generation of Selective PI3Kδ Inhibitors

Nicolas_SoldermannNicolas Soldermann, PhD, Senior Investigator and Group Leader, Global Discovery Chemistry, Novartis Institutes for BioMedical Research

The discovery and characterization of leniolisib (CDZ173), a potent and selective inhibitor of Phosphoinositide 3-kinase delta (PI3Kd) will be presented. We report how innovative medicinal chemistry efforts led to the identification of a novel and promising tetrahydro-pyrido-pyrimidine lead series that could be rapidly further optimized into a favorable physicochemical space and resulted in the identification of leniolisib, currently in clinical development as an anti-inflammatory therapeutic agent.

3:20 Discovery of a PI3Kβ/δ Inhibitor for the Treatment of PTEN-Deficient Tumors: Building PI3Kβ Potency in a PI3Kδ-Selective Template

Stephane_PerraultStephane Perreault, PhD, Research Scientist II, Medicinal Chemistry, Gilead Sciences, Inc.

The design, optimization, and in vivo evaluation of a novel series of PI3Kβ/δ inhibitors in which PI3Kβ potency was built in a PI3Kδ-selective template will be presented. This work led to the discovery of a highly selective PI3Kβ/δ inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model. Phosphoinositide 3-kinase β (PI3Kβ) signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated.

3:50 Refreshment Break


4:20 Tumor Immune Modulation following Intratumoral Therapy with Small Molecule TLR7/8 Ligands

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

* The program is subject to change without notice, due to unforeseen reason.