Oligonucleotides for Cancer Immunotherapy


As waves of novel immunomodulatory agents continue to progress into clinical studies, much has focused on the development of antibodies, bi-specifics, and chimeric receptors where toxicity can be a concern. Advances in the discovery and development of nucleic acids with the ability to overcome immunosuppressive mechanisms, increase tumor immunogenicity and provide agonistic costimulation are now providing a safer and effective approach to modulate the tumor immune response.

Cambridge Healthtech Institute is proud to introduce the Inaugural Oligonucleotides for Cancer Immunotherapy symposium, designed to convene immuno-oncology researchers and drug developers to discuss advances in the development of oligonucleotides with application to cancer immunotherapy.

Final Agenda

Wednesday, March 29

7:45 am Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee

TOLL-LIKE RECEPTOR (TLR) AGONISTS
AND CHECKPOINT COMBINATIONS

8:25 Chairperson’s Opening Remarks

David Giljohann, Ph.D., CEO, Exicure

8:30 Creating a Beneficial Tumor Microenvironment for Effective Cancer Immunotherapy

Sudhir_AgrawalSudhir Agrawal, D.Phil., FRSC, President, Research, Idera Pharmaceuticals

We are evaluating the role of endosomal Toll-like receptors 3, 7, 8, and 9, in the TME by administering intratumorally an agonist of these receptors. IMO-2125, a TLR9 agonist, has shown potent anti-tumor activity following i.t. administration and has led to an abscopal effect. These anti-tumor activities are associated with beneficial changes in the TME, which potentiated the anti-tumor activity of anti-CTLA4, anti-PD1, and IDO-1 inhibitor. A Phase I/II trial of intratumoral IMO-2125 in combination with ipilimumab in PD-1 refractory melanoma patients is in progress.

 

 9:15 FEATURED PRESENTATION: Making “Cold” Tumors “Hot” with Intratumoral Injection of CpG-A Oligonucleotide

Art_KriegArt Krieg, M.D., Founder and CEO, Checkmate Pharmaceuticals

CMP-001 is a formulation of a CpG-A oligonucleotide, G10, within a virus-like particle, Qb. We are performing a Phase Ib dose escalation study of intratumoral CMP-001 given in combination with systemic pembrolizumab in advanced melanoma patients whose cancer has previously progressed on an anti-PD-1 Ab, or who have failed to respond to at least 12 weeks of such therapy.

10:00 Networking Coffee Break

NUCLEIC ACID DISCOVERY PLATFORMS FOR CANCER IMMUNOTHERAPY

10:30 Immunomodulatory Spherical Nucleic Acids

David_GiljohannDavid Giljohann, Ph.D., CEO, Exicure

Immunomodulatory nucleic acids act by agonizing or antagonizing endosomal toll-like receptors (TLR3, TLR7/8, and TLR9), proteins involved in innate immune signaling. Immunomodulatory spherical nucleic acids (SNAs) that stimulate immunity by engaging TLRs have been designed, synthesized, and characterized. Given the clinical potential of SNAs due to their potency, defined chemical nature, and good tolerability, SNAs are attractive new modalities for developing immunotherapies. We will provide an update on our preclinical work and clinical plans for AST-008, a TLR9 agonist.

11:00 Development of Pluripotent Stem Cell-Based Therapies for Neurologic and Oncologic Disorders

Casey_CaseCasey Case, Ph.D., Senior Vice President, Research and Nonclinical Development, Asterias Biotherapeutics

Our group has established protocols to produce oligodendrocyte progenitors that upon transplantation into animals with spinal cord injuries can remyelinate denuded axons, induce axonal sprouting, and improve locomotor activity. Extensive preclinical studies have been completed to examine the activity, biodistribution, dosing, delivery, and potential toxicity and tumorigenicity of the oligodendrocyte progenitors. In collaboration with Cancer Research UK, Asterias is preparing for a clinical trial using these hESC derived dendritic cells as a cancer immunotherapy in non-small cell lung carcinoma in the neoadjuvant setting.

11:30 RNAi-Mediated β-Catenin Inhibition Promotes T-Cell Infiltration and Anti-Tumor Activity in Combination with Immune Checkpoint Blockade

Shanthi Ganesh, Ph.D., Associate Director, Preclinical Oncology, Dicerna Pharmaceuticals, Inc.

Recent research strongly suggests an important role for Wnt/β-catenin signaling in mediating cancer immune evasion and resistance to immune checkpoint therapy.  The mechanism by which Wnt/β-catenin signaling causes checkpoint resistance involves suppression of specific cytokines which trigger immune cell recruitment to the tumor, resulting in the phenomenon of T-cell exclusion and rendering the tumor to a non-inflamed state.  Therefore, β-catenin inhibition might increase the low response rate to immunotherapy in numerous cancer populations.  In this presentation, we will introduce DCR-BCAT, a novel RNAi-based experimental drug targeting β-catenin.  DCR-BCAT is particularly effective at converting non-inflamed tumors to inflamed tumors in multiple, diverse preclinical models.  Additionally, DCR-BCAT sensitized tumors to checkpoint inhibition in both syngeneic and transgenic tumor models.  These data offer proof-of-concept for β-catenin inhibition as an effective strategy to improve responses to PD-1/PD-L1 therapy, and support clinical evaluation of this combination approach using a first-in-class RNAi-based agent.

12:00 pm Sponsored Presentation (Opportunity Available)

12:15 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

NOVEL IMMUNOMODULATORY NUCLEIC ACIDS

1:25 Chairperson’s Remarks

Alexey Eliseev, Ph.D., Chief Business Officer, RXi Pharmaceuticals

1:30 Targeting Immune Checkpoints Using Self-Deliverable RNAi Technology

Alexey_EliseevAlexey Eliseev, Ph.D., Chief Business Officer, RXi Pharmaceuticals

RNAi is a potent tool to regulate gene expression. Self-deliverable RNAi technology is based on chemical modification of siRNAs eliminating any need for transfection formulations or methods, emulating behavior of small molecule drugs. We have demonstrated efficient knockdown of multiple immune checkpoints in T cells and the increased antitumor efficacy of sdRNA-modified immune cells.

2:00 Development of SB 11285, a Highly Potent STING Agonist for Application in Immune-Oncology

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

Compounds that activate cellular pattern recognition receptors (PRRs) such as RIG-I, NOD2, and STING are of immense interest in the development of new generation antiviral and anticancer agents. STING is an intracellular adapter protein that activates IFN and NF-KB pathways to induce potent innate and adaptive response against cancer. We have discovered the cyclic dinucleotide SB 11285 as a highly potent STING agonist for immuno-oncology applications for a variety of cancers. This talk will focus on the key aspects of development of this next-generation anticancer agent.

2:30 FEATURED PRESENTATION: Selective Stimulation of RIG-1 with Novel Synthetic RNA Induces Strong Anti-Tumor Immunity in Mouse Tumor Models

Jim_BarsoumJim Barsoum, Ph.D., Chair, Scientific Advisory Board, Rigontec GmbH

We describe a novel immunotherapy approach in which a natural viral defense system is harnessed to stimulate anti-tumor immunity. The cytosolic RNA receptor RIG-I recognizes double-stranded RNA bearing a 5'-triphosphate. RIG-I activation induces apoptosis preferentially in tumor cells and activates the immune system via type I interferon signaling. We developed an optimized, synthetic oligonucleotide, RGT100, as a RIG-I selective ligand. RGT100 activates RIG-I leading to the induction of cytokines, including interferons. Treatment of tumor-bearing mice with RGT100 induced potent anti-tumor activity. Infiltration by both NK cells and CD8+ T cells was observed. Treatment of subcutaneous tumors by intratumor injection led to efficacy of both the treated tumors and untreated contralateral tumors. Systemic administration was efficacious against subcutaneous melanoma as well as lung metastases. Data support NK cell and T cell-mediated anti-tumor activities. RGT100 is progressing toward clinical evaluation in cancer patients and will be evaluated for single-agent activity as well as in combination with checkpoint inhibitors.

3:00 Networking Refreshment Break

APTAMER-BASED CANCER IMMUNOTHERAPY

3:15 Inducing Neoantigens in Therapeutic and “Prophylactic” Cancer Immunotherapy

Brett Schrand, Ph.D., Postdoctoral Research Associate, Gilboa Lab, Leonard Miller School of Medicine, University of Miami

Tumor recurrence remains a major challenge in cancer therapy and individuals with premalignant lesions, chronic infections, or genetic predisposition are at high risk of developing cancer. Whereas clinical experience with checkpoint blockade has underscored the importance of vaccinating against neoantigens, their identification on a patient-by-patient basis is facing significant hurdles. We have previously described an aptamer-targeted siRNA approach to induce neoantigens in tumor cells in situ that obviates the limitations of targeting endogenous neoantigens. Exploiting the ability to induce neoantigens de novo, here I will describe a vaccination strategy for patients in remission and for individuals at risk of developing cancer that will control the growth of the future tumor.

3:45 Targeting Co-Stimulation with Bi-Specific Aptamers to Melanoma Cancer Stem Cells

Fernando_RodriquezFernando Pastor Rodríguez, Ph.D., Principal Investigator, Aptamers, Molecular Therapy, CIMA

We have developed an aptamer that binds to multidrug-resistant protein 1 (MRP1), which is not only expressed in tumor variants with higher resistance to chemotherapy but also in cancer stem cells. Anti-tumor effect with the systemic injection of the bi-specific-aptamer was proved in combination with peptide inhibition of Foxp3 in Treg or with CTLA4 blockade in an aggressive low-immunogenic melanoma tumor in mice. The bi-specific costimulatory aptamers could also be used to generate an ex vivo whole-cell cancer vaccine (Aptvax).

4:15 Close of Symposium