A major paradigm in cancer immunotherapy is to use checkpoint inhibitors to break regulatory mechanisms that guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example to establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Our preclinical study demonstrate that this outcome is predicated by inactivating the CTLA-4 checkpoint that plays important role in immune tolerance protecting body against autoimmune diseases. Importantly, our studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4 antibodies. The irAE is attributable to inactivation of CTLA-4 checkpoint, while the CITE is effective through selective depletion of regulatory T cells (Treg) in tumor microenvironment. We hypothesize that a safer and more effective CTLA-4-targeting immunotherapy should preserve rather than inhibit the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg-depletion in tumor microenvironment. In preparation to test this ground-breaking hypothesis clinically, we have generated a new generation of anti- CTLA-4 antibodies that preserving CTLA-4 immune checkpoint by avoiding lysosomal degradation of CTLA-4. The new antibody, ONC-392, has dramatically lower irAEs in humanized mouse model and significantly higher potent activity in depleting tumor-infiltrating regulatory T cells, resulting in more effective CITE. We have conducted IND-enabling studies, including GMP-grade manufacturing and GLP toxicity in non-human primate. We have also sought FDA feedback on our clinical plan through a pre-IND meeting. These progresses allowed us to propose a Fast Track Phase 1/2 SBIR application to determine safety and efficacy of ONC-392 in human cancer patients. With the support of the SBIR grant, we will carry out an open label Phase I/II clinical study to test the safety, pharmacokinetics (PK), and efficacy of ONC-392 as a single agent and in combination with Pembrolizumab in advanced solid tumors and non-small cell lung cancer patients. Our proposed study will not only confirm safety of ONC-392, but also provide clinical proof-of-concept data for our new paradigm of CTLA-4 targeting cancer immunotherapy.
Public Health Relevance Statement: Project Narrative A major paradigm in cancer immunotherapy is to use checkpoint inhibitors to break regulatory mechanisms that guard the host against autoimmune diseases. Here we presented our preclinical data to support a ground- breaking hypothesis that a safer and more effective CTLA-4-targeting immunotherapy should preserve rather than inhibit the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg-depletion in tumor microenvironment. This Fast Track SBIR grant will support an open label Phase I/II clinical study to test the safety, pharmacokinetics (PK), and efficacy of a next generation anti-CTLA 4 antibody, ONC-392, as a single agent and in combination with Pembrolizumab in advanced solid tumors and non-small cell lung cancer patients.
Project Terms: advanced disease; Adverse event; Aftercare; anti-CTLA4; anti-CTLA4 antibodies; Antibodies; arm; Autoimmune Diseases; Biological; Biopsy; cancer immunotherapeutics; cancer immunotherapy; Cancer Patient; Cells; Clinical; Clinical Research; cohort; CTLA4 gene; Data; Disease Resistance; Dose; Drug Kinetics; efficacy testing; Enrollment; Exhibits; Feedback; first-in-human; Generations; Goals; Grant; Histology; Human; humanized mouse; immune checkpoint; Immune checkpoint inhibitor; Immune Targeting; Immune Tolerance; Immunotherapeutic agent; Immunotherapy; Infrastructure; Leukocytes; Malignant neoplasm of lung; meetings; mouse model; next generation; Non-Small-Cell Lung Carcinoma; nonhuman primate; open label; Outcome; Patients; Peripheral; Phase; phase I trial; Phase I/II Clinical Trial; Phase I/II Trial; phase II trial; Play; pre-clinical; preclinical study; Preparation; preservation; recruit; Refractory; Regulatory T-Lymphocyte; research clinical testing; Resistance; Role; Safety; safety testing; Sampling; single-cell RNA sequencing; Small Business Innovation Research Grant; Solid Neoplasm; Suspensions; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Titrations; Toxic effect; tumor; tumor microenvironment