First in Human Phase I/II clinical trial of ONC-392: Preserving CTLA-4 immune tolerance checkpoint for safer and more effective cancer immunotherapy

ONC-392首个人体I/II期临床试验：保留CTLA-4免疫耐受检查点，实现更安全、更有效的癌症免疫治疗

• 批准号: 10010179
• 负责人: Christian Diego Rolfo
• 金额: $ 40万
• 依托单位: ONCOIMMUNE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-03 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010179
• 关键词: Adverse event; Aftercare; Antibodies; Autoimmune Diseases; Biological; Biopsy; CTLA4 gene; Cancer Patient; Cells; Clinical; Clinical Research; Data; Disease Resistance; Dose; Drug Kinetics; Enrollment; Exhibits; Feedback; Generations; Goals; Grant; Histology; Human; Immune Targeting; Immune Tolerance; Immune checkpoint inhibitor; Immunotherapeutic agent; Immunotherapy; Infrastructure; Leukocytes; Malignant neoplasm of lung; Non-Small-Cell Lung Carcinoma; Outcome; Patients; Peripheral; Phase; Phase I/II Clinical Trial; Phase I/II Trial; Play; Preparation; Refractory; Regulatory T-Lymphocyte; Resistance; Role; Safety; Sampling; Small Business Innovation Research Grant; Solid Neoplasm; Suspensions; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Titrations; Toxic effect; advanced disease; anti-CTLA4; anti-CTLA4 antibodies; arm; cancer immunotherapeutics; cancer immunotherapy; cohort; efficacy testing; first-in-human; humanized mouse; immune checkpoint; meetings; mouse model; next generation; nonhuman primate; open label; phase I trial; phase II trial; pre-clinical; preclinical study; preservation; recruit; research clinical testing; safety testing; single-cell RNA sequencing; tumor; tumor microenvironment

Summary 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.

总结