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 expanded 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 introduces the Inaugural Immunomodulatory Small Molecules 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

Monday, September 25

7:00 am Registration Open and Morning Coffee

KINASE, UBIQUITIN AND EPIGENETIC INHIBITORS FOR CANCER IMMUNOTHERAPY

7:55 Welcome Remarks

Kip Harry, Senior Conference Director, Cambridge Healthtech Institute

8:00 Chairperson’s Opening Remarks

Jonathan Pachter, Ph.D., CSO, Translational Research, Verastem

8:10 Immunologic Effects of Clinical Stage FAK and PI3K-Delta/Gamma Inhibitors

Jonathan Pachter, Ph.D., CSO, Translational Research, Verastem

The efficacy and long term survival observed with our FAK inhibitor in combination with PD-1 antibody across preclinical models has led to 3 ongoing clinical trials combining our FAK inhibitor defactinib with anti-PD-1 and anti-PD-L1 in solid tumor indications. Additionally, in preclinical models, PI3K-delta inhibition has been shown to confer selective inhibition of Tregs, while PI3K-gamma inhibition confers selective inhibition of MDSCs. Accordingly, immuno-oncology applications of our Phase III PI3K-delta/gamma inhibitor duvelisib will be discussed.

8:40 A Novel Dual PI3K/BRD4 Inhibitor, SF2523 for Combinatorial Activation of Anti-Tumor Immunity in Cancer Via the Orthogonal Inhibition of MYCN and MYC

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

We have developed a dual inhibitory chemotype which blocks MYC via two orthogonal independent pathways: 1) PI3K inhibition induces MYCN degradation and 2) BRD4 blocks MYCN transcription. We demonstrate that this small molecule, SF2523, blocks MYCN transcription and induces MYCN degradation and abrogates the macrophage immunosuppressive effects on tumor immunity via the blockade of the M1-M2 transition in vivo.

9:40 Networking Coffee Break with Poster Viewing

10:10 A First-in-Class Selective Class IIa Histone Deacetylase (HDAC) Inhibitor, TMP195

Michael Nolan, Ph.D., 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.

10:40 Inhibition of Kinase-Mediated Signaling in Myeloid Cells Suppresses Peritumoral Immune Suppression in Pancreas Cancer

Michael Burnet, Ph.D., Managing Director, Oncology Discovery, Synovo GmbH

We have identified small molecule kinase inhibitors that act on myeloid cells infiltrating tumors. These compounds promote the tumor-specific local secretion of interferon gamma leading to activation of CD8+ and NK cells. Tumor specificity appears to be due to a reliance on tumor co-signalling for target pathways to be expressed. The agents have safety margins in the range of 15-30x and are effective in very low doses in mice in the order of 3 to 5 mg/kg/day. The compounds synergize both cytotoxic agents and checkpoint antibodies.

11:10 Enjoy Lunch on Your Own 

SMALL MOLECULES TARGETING PD-1, IDO1, TDO2, AND STING

1:10 pm SPEAKER CANCELLATION: Chairperson’s Remarks

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

1:20 SPEAKER CANCELLATION: Design and Synthesis of IDO1 and TDO2 Inhibitors

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

We conducted in silico screens to identify novel and selective IDO1 and TDO2 inhibitors, respectively. Enzymatic hIDO1 and hTDO2 assays were utilized to confirm inhibitory activity and selectivity. Among the confirmed inhibitors, a series of oxan-4-carboxamides selectively inhibited hIDO1, while a series of substituted 9H-fluorenes were identified as TDO2 selective inhibitors (IC50: 1 µM). In this presentation, we will discuss the in silico approach and provide updates on characterization data of the inhibitors.

1:50 Development of SB 11285, a Highly Potent STING Agonist for Application in Immuno-Oncology

R.P. (Kris) Iyer, Ph.D., Co-Founder & CSO, Spring Bank Pharmaceuticals

Immunotherapy has emerged as a transformative approach for the treatment of cancer. Evidence suggests that the activation of Stimulator of Interferon Genes (STING) pathway in tumor cells and/or immune cells induces type I Interferon production leading to apoptosis of tumor cells as well as induction of adaptive immune response thereby providing a powerful anti-cancer strategy. Herein, we describe the discovery of highly potent and selective first-in-class STING agonist SB 11285 for application in immuno-oncology.

2:20 Small Molecule Ubiquitin Protease (USP7) Inhibitors with Immune Cell Based Anti-Tumor Activity Superior to that of Biologicals

 Tauseef R. Butt, Ph.D., President and CEO, Progenra, Inc.
In immune competent animal models, USP7 inhibitors are potent anti-tumor agents, not only blocking tumor growth but also eliminating tumor metastasis. These results constitute the first example of a small molecule single agent that works by targeting both the tumor itself and the host immune system and also by eliminating tumor metastasis. In animal models, the USP7 inhibitor demonstrates activity that is superior to that of PD1 and CTLA4 antibodies.

2:50 Networking Refreshment Break with Poster Viewing

NOVEL IMMUNOMODULATORY SMALL MOLECULES

3:30 Chairperson's Remarks

David Ferguson, Ph.D., Professor, Medicinal Chemistry, University of Minnesota

3:30 Selective Activation of Toll-Like Receptor 7 and 8 in the Design of Cancer Vaccines

David Ferguson, Ph.D., 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.

4:00 Anti-Cancer Therapy by Inducing Immunogenicity in Tumors with Small Molecules

Weiwen Ying, Ph.D., Co-Founder and President, Drug Discovery, Capten Therapeutics

Capten Therapeutics is developing a new class of drugs that enhance the immunogenicity of cancer cells in a novel way. Our technology uses analogs of the active substance in natural produces to bond with proteins in cancer cells to produce highly immunogenic haptenated proteins. These haptenated proteins stimulate an adaptive immune response that opens the door to effective therapeutic options.

4:30 Novel Natural Immunomodulatory Peptide Synergistic with Chemotherapy

Raghu Pandurangi, Ph.D., Founder & President, Drug Design, Sci-Engi-Medco Solutions, Inc.

Loss of immunity protein beta defensin is responsible for the onset of cancer. A fragment of beta defensin modulates immunofunction which when delivered selectively to cancer cells resulted in the regression of tumor. The peptide fragment also synergizes with standard FDA-approved chemotherapeutics in vitro/in vivo. This novel peptide can be used as neoadjuvant to chemotherapy to expand the therapeutic index of existing treatments.

5:00 Close of Symposium

5:00 Pre-Conference Dinner Short Course Registration

Click here for details on short courses offered.