The immunotherapies industry is currently dominated by antagonist antibodies such as PD-1 and CTLA-4. However, it is clear that antagonists alone are not enough to elicit response in the majority of patients, hence a rising interest in agonists targets.
CHI’s Agonist Immunotherapy Targets conference will examine these modalities and their treating disease. Agonists showing the most promise, including OX40, CD27, GITR, and 4-1BB, will be covered in clinical case studies by examining the data as well as the biology and mechanisms. Emerging agonists, including TNFR receptors, ICOS, STING, and VISTA will also be discussed. Focus will be given throughout to potential combination immunotherapies to ensure durable antitumor response. Overall, this event will emphasize strategies for target discovery to ensure continued growth and success for immunotherapies.
Day 1 | Day 2
THURSDAY, APRIL 11
12:00 pm Registration
12:35 Luncheon in the Exhibit Hall with Poster Viewing
LATEST DEVELOPMENTS IN AGONIST IMMUNOTHERAPY - CYTOKINES AND OX40 TARGETS
1:40 Chairperson’s Opening Remarks
Peter Ellmark, PhD, Vice President, Discovery, Alligator Bioscience
1:50 KEYNOTE PRESENTATION: Harnessing Potent Cytokine Agonist Pathways by Polymer Engineering to Develop Novel Immune Therapeutic Agents
Loui Madakamutil, PhD, Vice President, Head of Discovery, Nektar Therapeutics
We have engineered cytokines using polymer technology to enable viable medicines. NKTR-214 is in Phase 3 clinical trials and a key example of how polymer conjugation can bias the well-known IL-2 receptor pathway to favor CD8 T cell tumor infiltration over Tregs. On the other hand, NKTR-358 selectively grows T regs in vivo. Finally, NKTR-255, an IL-15 receptor agonist stimulates NK cells. Each agent is conjugated in unique ways to elicit desirable and controlled pharmacological and immunological outcomes.
2:20 Agonists in Combination Immunotherapy
William L. Redmond, PhD, Associate Member, Laboratory of Cancer Immunotherapy, Director, Immune Monitoring Laboratory, Providence Portland Medical Center
Our previous studies helped elucidate the mechanisms by which OX40 agonist immunotherapy plus checkpoint blockade synergized with a novel cancer vaccine to boost the function of killer CD8 T cells and cause tumor regression. We are investigating how combination immunotherapy restores the function of killer CD8 T cells that have been paralyzed, or rendered anergic, by tumors. Additional studies seek to understand the mechanisms by which immunotherapy enhances the efficacy of conventional treatments, such as radiation therapy, with the goal of providing a path for rapid translation to the clinic.
2:50 OX40: Is Timing Everything?
Brendan Curti, MD, Robert W. Franz Chair for Clinical Research, Earle A. Chiles Research Institute, Providence Cancer Institute
We now have FDA-approved checkpoint immunotherapy for many stage III and IV cancers, but administration of immunotherapy before surgery has not been as extensively investigated. A clinical trial of the neoadjuvant administration of an agonist antibody to OX40, a T cell co-stimulatory agent, will be discussed, along with changes in tumor infiltrating CD39+CD103+ T cells that we hypothesize are relevant to achieving effective anti-tumor immunity.
3:20 Sponsored Presentation (Opportunity Available)
3:50 Networking Refreshment Break
4:20 Agonist Bispecific Antibodies Delivering the Next Immuno-Oncology Breakthrough
Mihriban Tuna, PhD, Vice President, Drug Discovery, F-star Biotechnology, Ltd.
Targeting T cell costimulatory pathways can strongly activate the immune system due to the broad expression of receptors such as OX40 and CD137 across multiple immune cell types. However, Fcg receptor (FcgR)-mediated crosslinking is often required for the activity of monoclonal antibodies, and we hypothesise that this likely limits clinical activity due to the inherently low affinity of Fc:FcgR interactions, as well as the potential for FcgR-mediated depletion of T cells through ADCC. Here we will present novel bispecific antibody programmes that do not rely on FcgR binding, but instead crosslink using their two target binding sites.
4:50 Development of SIRPa-Fc-CD40L for Cancer Immunotherapy
Taylor Schreiber, PhD, CSO, Research & Development, Shattuck Labs, Inc.
The CD47/SIRPa axis functions to enhance antigen cross-presentation within the context of anti-tumor immunity, which holds promise for the treatment of immune-neglected tumors. The subset of dendritic cells which are the most potent antigen cross-presenters express CD40, and stimulation of CD40 enhances activation of CD8+ lymphocytes by these cells. SIRPa-Fc-CD40L has demonstrated superiority to CD47/SIRPa blocking antibodies, CD40 agonist antibodies, and antibody combinations in both rodent and non-human primate studies, which position this compound to provide unique benefits to human cancer patients.
5:20 End of Day
5:20 Registration for Dinner Short Courses
*Separate registration required.
Day 1 | Day 2
FRIDAY, APRIL 12
8:00 am Morning Coffee
TNF AND 4-1BB AGONIST TARGETS
8:30 Chairperson’s Remarks
Christopher Thanos, PhD, CEO, Actym Therapeutics
8:35 The Appeal of The TNFR2 Target for Immunotherapy: Tregs and Tumor Oncogenes
Denise L. Faustman, MD, PhD, Director of Immunobiology, Massachusetts General Hospital, Associate Professor of Medicine, Harvard Medical School
Immune checkpoint inhibitors have revolutionized cancer therapy but can exhibit variable efficacy. TNFR2 is a signaling molecule found on a subset of potent Treg cells that activates the proliferation of these cells. TNFR2 is also abundantly expressed on the surface of many human tumors as an oncogene. We propose blocking TNFR2 might target abundant TNFR2+ tumor-infiltrating Tregs and directly kill TNFR2-expressing tumors. TNFR2 inhibitors might also potentially constitute safer and more targeted immunotherapy.
9:05 Development of TNF Superfamily Agonists
Andreas Raue, PhD, Associate Director, Research, Merrimack Pharmaceuticals
Members of the TNF superfamily of costimulatory receptors have emerged as promising immuno-oncology targets, and agonistic antibodies are currently being evaluated clinically. Here, we describe our STIMULI platform, which consists of novel multispecific and multivalent TNF receptor agonists, engineered to provide more precise activation of immune cell subsets.
9:35 Sponsored Presentation (Opportunity Available)
10:05 Networking Coffee Break
10:35 IGM Antibodies with Very Potent Agonism to DR-5 Induced Apoptosis and as Anti-Tumor Agents
Bruce Keyt, PhD, CSO, IGM Biosciences
IGM Biosciences has anti-DR5 antibodies prepared as IgG and IgM. Anti-DR5 as IgM exhibits very potent and robust tumor cell killing in vitro and in vivo. IgM has broad anti-cancer bioactivity against various epithelial and hematologic tumors, both as established tumor cell lines as well as PDX cells in vitro. In vivo studies show very strong positive results in single agent treatment or in combinations with chemotherapy. Primate models show very low to no evidence of toxicity. We are scaling these antibodies for IND enabling studies and FIH human trials.
11:05 ATOR-1017, A 4-1BB Antibody Developed for Tumor Directed Immunotherapy of Cancer
Karin Enell Smith, PhD., Senior Scientist, Immuno-oncology, Alligator Bioscience
ATOR-1017 is a 4-1BB agonistic IgG4 antibody designed for optimal efficacy and safety. The agonistic activity of ATOR-1017 depends on engagement with certain FcγRs, and it will thereby induce a tumor directed immune activation in patients with tumors co-expressing these FcγRs and 4-1BB. The preclinical data package supports a favorable safety/efficacy profile. Clinical studies with ATOR-1017 are planned for 2019.
11:35 Structure of the 4-1BB/4-1BBL Complex and Distinct Binding and Functional Properties of Utomilumab and Urelumab
Christopher Kimberlin, PhD, Senior Scientist, Biotherapeutic Design and Discovery, Pfizer
4-1BB is an inducible costimulatory receptor expressed on activated T cells. Two agonist antibodies, utomilumab (PF-05082566) and urelumab (BMS-663513), demonstrate distinct activities in the clinic. To understand these differences, we solved structures of the human 4-1BB/4-1BBL complex, the 4-1BBL trimer alone, and 4-1BB bound to utomilumab or urelumab. Additionally, cell-based assays demonstrate utomilumab is a milder agonist than urelumab. Collectively, our data provide a deeper understanding of the 4-1BB signaling complex, providing a template for future development of next generation 4-1BB targeted biologics.
12:05 pm CB307, A Novel T-Cell Agonist Humabody Therapeutic for PSMA-Positive Tumours
James Legg, PhD, Vice President, Research and Development, Crescendo Biologics
Crescendo Biologics has initiated pre-clinical development of CB307 a novel bispecific Humabody VH targeting CD137 (4-1BB) and prostate specific membrane antigen (PSMA). The talk will describe the identification, mechanism of action and preclinical characterisation of the CB307 drug candidate. The benefits of using the modular Humabody VH platform, rather than an IgG format to develop this molecule will be discussed, including optimal (monovalent) engagement of both targets with small VH domains and the avoidance of Fc receptor interactions. The unique design of CB307 enables highly potent and tumour selective T-cell co-stimulation.
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:05 Networking Refreshment Break
4-1BB, TLR AND STING AGONIST TARGETS
1:35 Chairperson’s Remarks
Christopher Thanos, PhD, CEO, Actym Therapeutics
1:40 CTX-471 Eradicates Very Large Tumors without Causing Hepatic Toxicity
Ugur Eskiocak, PhD, Associate Director, Translational Immunology & Immunopharmacology, Compass Therapeutics
CTX-471 is a fully human IgG4 agonistic antibody targeting a unique CD137 (4-1BB) epitope and displays differentiated pharmacology and toxicology profile. In vitro, CTX-471 increased IFN-γ production by human T cells in an FcγR-dependent manner, displaying an intermediate level of activity between two clinical-stage anti-CD137 antibodies. In mice, CTX-471 exhibited curative monotherapy activity in various syngeneic tumor models and showed a unique ability to cure very large (~500 mm3) tumors compared to validated antibodies against checkpoints and TNFR superfamily members. In mice and monkeys, extremely high doses of CTX-471 (up to 100 mg/kg weekly for 4 weeks) were well-tolerated, with no signs of hepatic toxicity. Phase 1 trial for CTX-471 is planned for 2019.
2:10 TLR Agonists Mimic a Life-Threatening Infection in Culture, Triggering Emergence of Tumor-Ag Driven, Genetically Unmodified CD4+ and CD8+ T-Cells from Unfractionated PBMC
Peter A. Cohen, MD, Professor, Medicine and Immunology, Mayo Clinic
Metastatic melanoma is sometimes curable by adoptively transferring autologous T-cells after culture-expansion from tumor-infiltrating lymphocytes (TIL). Such cultures are nonspecifically (anti-CD3) driven, and TIL from malignancies besides melanoma are seldom therapeutic. Paradoxically, although PBMC are abundant in T-cells and DC, they are normally unreliable for therapy, including melanoma. Nonetheless, by respecting principles of natural Ag-driven immunity, PBMC from advanced cancer patients can be specifically driven by tumor-associated Ag in culture.
2:40 A Novel Systemically Delivered STING Pathway Agonist Therapy Demonstrates Robust Anti-Tumor Efficacy in Multiple Murine Cancer Models
Christopher Thanos, PhD, CEO, Actym Therapeutics
Delivery of immunotherapy to directly activate tumor-resident immune cells is required to elicit durable anti-tumor immunity. To this end, we have generated an immunotherapy platform that allows for tumor-specific delivery of engineered RNAi towards any tumor/immune target of interest (alone or in combination). For our initial RNAi target selection, a therapy targeting TREX1 was designed. TREX1 is a 3′ exonuclease immune checkpoint that degrades cytosolic DNA, thereby preventing it from binding cGAS and activating the STING pathway.
3:10 Beyond PD1: Targeting STING and Other Novel Pathways
Anthony Desbien, PhD., Senior Scientist, Translation Immunology, Aduro Biotech
3:40 End of Conference