Cambridge Healthtech Institute’s 3rd Annual

Small Molecules for Cancer Immunotherapy

Design of New Molecules and Combinations for Immuno-oncology Targets

April 9-10, 2019

First-generation cancer immunotherapy agents being developed or approved were either engineered T cells targeting tumors or antibody-based biologics targeting the immune checkpoint cascade. However, novel second and third-generation drugs that are in preclinical or early-stage clinical development are small molecules that act on intracellular targets and receptors affecting immuno-modulatory pathways in cancer. Cambridge Healthtech Institute’s 3rd 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. IDO1, USP7, STING, TIM-3, VISTA, LAG-3, KIR, bromodomains are examples of some oncology targets that are being actively pursued by small molecule drugs. The development of programs around these targets and discussions on translational challenges, response rates, drug resistance and safety will certainly be covered in this conference.

Final Agenda

Tuesday, April 9

7:00 am Registration Open and Morning Coffee (20 C/D Foyer) 

NEW COMPOUNDS FOR SINGLE AND COMBINATION IO THERAPY
30 D/E

8:00 Welcome Remarks

Tanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

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

8:10 Modulation of Immune Response with Porcupine Inhibitor RXC004 in Preclinical Cancer Models

Inder Bhamra, PhD, Research Fellow, Medicinal Chemistry, Redx Pharma

RXC004 is a potent and selective Porcupine inhibitor currently undergoing Phase I clinical evaluation in cancer patients. Porcupine is a membrane bound O-acyltransferase responsible for post-translational modification of all Wnt ligands. Porcupine inhibitors are efficacious in preclinical models of Wnt ligand driven cancers. Preclinical models demonstrate that RXC004 has an anti-tumour effect via immuno-stimulatory mechanisms, both as a single agent or in combination with anti-PD1 antibodies.

8:40 Toll-Like Receptor (TLR) 7 and 8 Agonists with Direct Inflammasome Activation

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

TLR 7 and 8 agonists are potent modulators of proinflammatory cytokine induction but may also induce regulatory cytokines leading to the upregulation of PD-L1 and activation of MDSCs and Tregs. The benefits of combining sunitinib with and without an anti-PD-L1 antibody and a TLR-based nanovaccine evaluated using in vitro and in vivo models show reductions in MDSCs and Tregs can be afforded through co-administration of sunitinib with vaccination. Gains in antigen specific CD8 T cell responses were also noted by addition of anti-PD-L1 antibodies resulting in improved anti-tumor response of the TLR-based vaccine in vivo.

9:10 Tankyrase Inhibitors: Evidence for Therapeutic Potential in Immuno-Oncology

Luc Van Hijfte, PhD, Senior Vice President, Medicinal Chemistry, Mercachem

WNT/β-catenin signaling regulates key cellular functions including proliferation, differentiation, migration, apoptosis, stem cell renewal and immune system modulation. Abberrant WNT/ β-catenin signaling is found in multiple cancers. In particular, the recently described role of the WNT/β-catenin pathway in regulating immune cell infiltration in the tumor micro-environment suggests an impact of the pathway on immunotherapy. Hence, WNT-directed therapeutic intervention represents an area of significant developmental focus. The Poly-ADP-ribosylases tankyrase 1 and 2 are central biotargets in the WNT/β-catenin signaling pathway, regulating the turnover of the protein complex that controls β-catenin stability and in adition impacting the hippo signaling pathway. Several small molecules have been identified that inhibit tankyrases 1 and 2, and we have earlier shown efficacy of tankyrase inhibitors in WNT dependent adenoma and tumor models. The successful discovery of novel, selective tankyrase inhibitors from a hit stage to an advanced lead stage, and in vivo data that these compounds demonstrate a promising new approach in immuno-oncology in combination with check-point.

9:40 Networking Coffee Break

10:05 In silico Design of a “First-in-Class” Novel Dual Syk/PI3K Inhibitor to Block the Immunosuppressive Tumor Microenvironment

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

Macrophages (MQs) play a critical role in tumor growth, immunosuppression and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MQs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kg has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that a macrophage Syk-PI3K axis drives polarization of immunosuppressive macrophages which establish an immunosuppressive tumor microenvironment in  in vivo syngeneic tumor models. Genetic or pharmacological inhibition of Syk and/or PI3Kg in MQs promotes a pro-inflammatory MQ phenotype, restores CD8+ T cell activity, destabilizes HIF under hypoxia, and stimulates antitumor immune response. Moreover, we have developed in silico the “first in class” dual Syk/PI3K inhibitor, SRX3207, for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.

10:35 Small-Molecule Therapeutics Targeting Immunosuppressive TIGIT and Adenosine Signaling Pathways

Murali Ramachandra, PhD, CSO, Aurigene Discovery Technologies Limited

Potential advantages of small molecule agents include oral dosing, greater response rate due to better tumor distribution, potential for simultaneously targeting closely related checkpoint proteins, and possibility of better management of adverse events. After succeeding in identifying agents targeting PD-L1, VISTA, TIM3 and CD47, which are at different stages of development (most advanced CA-170 in Phase II clinical trial), we have now focused our attention in discovering agents targeting newer checkpoint protein such as TIGIT and immunosuppressive adenosine signaling. The talk will cover our approaches and status of these programs.

11:05 SELECTED POSTER PRESENTATION: 3PO - Small Molecule PFKFB3 Inhibitor Induce Apoptosis and Cell Cycle Arrest in A375 Human Melanoma Cell Line with Endogenous BRAFV600E Mutation

Krzysztof Kotowski, Medical Student, Faculty of Medicine, Wroclaw Medical University

11:35 Enjoy Lunch on Your Own

12:20 pm Session Break

MODULATING THE TUMOR MICROENVIRONMENT

1:15 Chairperson’s Remarks

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

1:20 Targeting the Tumor Microenvironment with TGFβ Inhibitors

Rikke B. Holmgaard, PhD, Principal Research Scientist, Oncology Research, Eli Lilly and Company

Inhibiting the immune suppressive effects of TGFβ is an emerging strategy as a way to increase benefit of cancer immunotherapy. We explored the impact of the clinical stage TGFβ pathway inhibitor, galunisertib on anti-tumor immunity at clinically relevant doses. Our data show strong dose-dependent anti-tumor activity with immunological memory in preclinical mouse models with established tumors; as well as combinatorial activity with anti-PD-L1 resulting in tumor regressions associated with enhanced T-cell activation. A second generation, more potent and selective TGFβRI inhibitor, LY3200882, is currently in Phase I.

1:50 Targeting the CBP/P300 Bromodomain for Immuno-Oncology

Karen Gascoigne, PhD, Scientist, Discovery Oncology, Genentech, Inc.

The histone acetyl-transferases CBP/P300 are critical regulators of gene expression in both tumor and immune cells. We describe a novel CBP/P300 bromodomain inhibitor, and its use to probe the role of the bromodomain in CBP/P300 activity at chromatin and in tumor & immune cell function. CBP/P300 bromodomain inhibition impacts the function of MDSC and Treg cells, and directly impairs tumor growth in vitro and in vivo.

2:20 “It Takes Guts to Rev Up CARs”: Harnessing the Power of Gut Microbiome to Modulate Responses of Novel Cancer Therapies

Muhammad Bilal Abid, MD, MRCP, Clinician-Scientist, Medical College of Wisconsin

Preclinical and human studies establishing a clear relationship between antigen presentation machinery, gut microbiome diversity, and certain microbial taxa, coupled with preclinical studies highlighting the suppressive role of Tregs on CAR T-cells, postulate that modulating gut microbiota may very well impact responses to CAR T-cells.

2:50 GCN2 Mediates Response to Stress Caused by Amino Acid Deprivation Influencing both Immunological Function and Cell Growth in the Tumor Microenvironment

David Wustrow, PhD, Vice President, Drug Discovery, FLX Bio

GCN2 plays a key role in the regulation of T cell anergy and apoptosis caused by amino acid depletion in the tumor microenvironment. Inhibition of GCN2 abrogates immune suppression by increasing proliferation and effector function of T cells and via reversal of the suppressive function of MDSCs. GCN2 inhibitors have also been shown to potentiate the anti-tumor effects of the amino acid depleting agent asparaginase. Efforts to discover and assess novel GCN2 inhibitors will be described.

3:20 CETSA® Enabled Drug Discovery

Michael Dabrowski, PhD, CEO, Pelago Bioscience

CETSA allows quantification of target engagement under relevant physiological conditions, which is prerequisite for achieving the intended efficacy. Over the last 8 years CETSA has been applied in hundreds of studies from early target validation to analysis of clinical samples. In his talk Michael will explore examples of applications and also discuss future perspectives in enabling drug discovery using the CETSA method.

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

4:35 Plenary Technology Spotlight: Molecular Modelling for the Masses: Orion

Paul Hawkins, Head, Scientific Solutions, OpenEye Scientific

The advent of cloud computing has been transformative for many fields that utilize computation, including drug discovery. The cloud offers robust, elastic, and scalable compute resources through a browser, decreased IT overhead, costs, and time to obtain actionable results. In this presentation I illustrate how the cloud, and in particular OpenEye’s web-based platform Orion, is democratizing molecular modelling by providing easy to use access to cutting-edge molecular design tools coupled with essentially unlimited compute resources.

5:05 Plenary Keynote Introduction

Vicky Steadman, PhD, Business Line Leader, Integrated Drug Discovery, Eurofins Discovery (formerly Eurofins Pharma Discovery Services)

5:10 PLENARY KEYNOTE: Chemical Biology of Proteostasis

Jack Taunton, PhD, Professor, Department of Cellular and Molecular Pharmacology, University of California San Francisco

We have recently discovered several macrocyclic compounds that potently and selectively modulate protein homeostasis. I will discuss our recent efforts to unravel their molecular mechanisms.

6:00 Welcome Reception in the Exhibit Hall with Poster Viewing

7:00 Close of Day

Wednesday, April 10

7:30 am Continental Breakfast Breakout Discussions - View All Breakouts

EMERGING ROLE OF PROTACs IN ONCOLOGY

8:30 Chairperson’s Remarks

Markus Queisser, PhD, Scientific Leader, Protein Degradation DPU, R&D Future Pipelines Discovery, GlaxoSmithKline

8:35 Proteolysis Targeting Chimeric Molecules (PROTACs) as Small Molecule Modality in Immuno-Oncology

Markus Queisser, PhD, Scientific Leader, Protein Degradation DPU, R&D Future Pipelines Discovery, GlaxoSmithKline

Targeted protein degradation using bifunctional small molecules known as proteolysis targeting chimeric molecules (PROTACs) is emerging as a novel modality. PROTACs redirect ubiquitin-ligases to target specific proteins for degradation. The advantages of the PROTAC technology lie in its modular, rationally designed molecules, capable of producing a cellular protein knock-down as demonstrated in both cellular and in vivo with the ligase ligand and targeting warhead combine to exert a synergistic effect in oncology.

9:05 FEATURED PRESENTATION: Empirical & Structure-Based PROTAC Design: Lessons Learned with VHL-Based PROTACs

Peter Ettmayer, PhD, Scientific Director, Cancer Research, Boehringer Ingelheim RCV GmbH & Co KG

Current PROTAC design is driven by screening exit vectors and linkers until a suitable degrader is identified. We will present an alternative rational PROTAC optimization based on high-resolution ternary complex crystal structures and cooperativity considerations. The case study will exemplify a successful structure driven campaign to degrade targets previously considered undruggable and pave the way towards new therapeutics for the treatment of genetically-defined tumors.

9:35 Coffee Break in the Exhibit Hall with Poster Awards Announced

Poster Awards Sponsored by Domainex

10:30 TIP60 Inhibition and Cancer Therapy

Wayne W. Hancock, MD, PhD, Professor, Pathology and Chief of Transplant Immunology, Children’s Hospital of Philadelphia and University of Pennsylvania

Foxp3+ Tregs predominate in the microenvironment of many “hot” tumors where they impair antitumor immunity. There are currently no approved strategies that specifically focus on targeting intratumoral Foxp3+ Tregs. We have found that newly developed conventional and PROTAC forms of Tip60 inhibitors (Tip60i) can impair Treg function and boost anti-tumor immunity in syngeneic lung tumor models. Given that mouse Tip60 shares 99.6% identity (511 of 513 amino acids) with human Tip60, the relevance of our mechanistic studies in murine models to human disease appears compelling.

11:00 Targeted Protein Degradation for Treatment of Cancer

Michael Plewe, PhD, Vice President, Medicinal Chemistry, Cullgen, Inc.

Targeted protein degradation using bifunctional molecules to remove specific proteins by hijacking the ubiquitin proteasome system has emerged as a novel drug discovery approach. These bifunctional degrader molecules consist of a ligand that binds to the protein targeted for degradation, a linker and a ligand for recruitment of an E3 ligase. We will present case studies for developing degraders for oncology targets such as anaplastic lymphoma kinase (ALK) that could lead to novel therapeutics with minimal toxicity.

11:30 Dual Role of USP7 Inhibitors in Treatment of Malignant Diseases

Tauseef Butt, PhD, CEO, Progenra

USP7 is a multifaceted DUB that mediates immune evasion by promoting aggressive Treg functions in tumor tissue as well as direct tumor growth. Progenra’s USP7 inhibitors eradicate experimental tumors in syngeneic models by suppressing regulatory T cells to unleash Teffector anti-tumor responses as well as direct anti-tumor action. USP7 inhibitors have been reported by other pharma companies. However, these molecules have poor therapeutic efficacy as compared to Progenra molecules. Molecular mechanisms that differentiate USP7 inhibitors will be discussed.

12:00 pm Close of Conference