Cambridge Healthtech Institute 第3回

Small Molecules for Cancer Immunotherapy
( がん免疫療法のための低分子医薬品 )

がん免疫療法の標的に対応する新たな分子と併用療法の設計

2019年4月9日~10日

これまでに開発が成功し、承認を受けた第1世代のがん免疫療法薬は、腫瘍を標的とする改変T細胞、または免疫チェックポイントカスケードを標的とする抗体ベースの生物製剤のいずれかでした。しかし、現在前臨床研究段階や早期臨床開発段階にある第2世代と第3世代の新薬は、がんの免疫調節パスウェイに影響を及ぼしている細胞内標的や受容体に対して作用する低分子医薬です。がん免疫療法のための低分子医薬品をテーマにしたこのカンファレンスプログラムでは、創薬化学や生物学の研究者が一堂に会し、新たな細胞内腫瘍標的、および単独あるいは既存治療薬との併用により作用する免疫調節低分子阻害剤について議論します。現在腫瘍治療のための低分子医薬品の標的として盛んに研究が行われているのが、IDO1、USP7、STING、TIM-3、VISTA、LAG-3、KIR、ブロモドメインです。今度の学会では、これらの標的に関連するプログラムの開発、トランスレーショナル研究の課題、奏効率、薬剤耐性、安全性などのトピックが取り上げられる予定です。


Final Agenda

Tuesday, April 9

7:00 am Registration Open and Morning Coffee

単剤および併用がん免疫療法のための新たな化合物

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, Merachem

WNT/β-catenin signaling regulates key cellular functions, and aberrant WNT/ β-catenin signaling is found in multiple cancers. Recently it has been reported that the WNT/β-catenin pathway also regulates immune cell infiltration in the tumor micro-environment. We have developed unique inhibitors of Tankyrase 1 and 2, regulatory biotargets of the WNT/β-catenin and Hippo signaling pathway, for which we have demonstrated a promising immuno-oncology therapeutic potential in combination with check-point inhibitors.

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

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 Next-Generation Small Molecule Immunotherapeutic RRx-001 in Phase III

Corey A. Carter, MD, President and CEO, EpicentRx, Inc.

Next-generation immunotherapeutic RRx-001 is a first-in-class small molecule in Phase III which modulates the tumor microenvironment, repolarizes tumor-associated macrophages and induces an innate and adaptive immune anti-cancer response. RRx-001 lacks the toxicity of previous immunotherapies, has shown activity in multiple unmet need cancer indications and has the potential to resensitize and convert tumors from treatment resistant to treatment-sensitive, making it an ideal combination agent for chemotherapy, radiation and immunotherapy.

11:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:20 pm Session Break

腫瘍微小環境の調節

1:15 Chairperson’s Remarks

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

1:20 “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.

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 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.

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 Sponsored Presentation (Opportunity Available)

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


4:30 Welcome Remarks from Lead Conference Director

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

4:35 Plenary Technology Spotlight Presentation to be Announced

5:05 Plenary Keynote Introduction (Sponsorship Opportunity Available)

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

腫瘍治療におけるPROTACの新たな役割

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

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。