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

总结 癌症免疫治疗的一个主要范例是使用检查点抑制剂来打破调节机制 保护宿主免受自身免疫性疾病的侵害。 CTLA-4靶向免疫疗法是第一个例子 建立这个范式。然而，临床测试的抗 CTLA-4 抗体表现出次优疗效，但 高毒性。我们的临床前研究表明，这一结果是通过灭活 CTLA-4 来预测的 检查点在免疫耐受中发挥重要作用，保护身体免受自身免疫性疾病的侵害。 重要的是，我们的研究表明，免疫治疗相关的不良事件 (irAE) 和癌症 免疫治疗效果 (CITE) 代表抗 CTLA-4 的独特且治疗上可分离的活性 抗体。 irAE 归因于 CTLA-4 检查点失活，而 CITE 则通过以下方式有效： 选择性耗竭肿瘤微环境中的调节性 T 细胞 (Treg)。 我们假设更安全、更有效的 CTLA-4 靶向免疫疗法应该保留 比抑制 CTLA-4 检查点同时增强 Treg 耗竭的功效和选择性 肿瘤微环境。 为了准备在临床上测试这一突破性的假设，我们已经产生了新一代的抗 CTLA-4 抗体通过避免 CTLA-4 的溶酶体降解来保护 CTLA-4 免疫检查点。 新抗体 ONC-392 在人源化小鼠模型中具有显着较低的 irAE，并且显着较高 有效消耗肿瘤浸润调节性 T 细胞，从而产生更有效的 CITE。我们有 进行了 IND 支持研究，包括 GMP 级生产和非人类灵长类动物中的 GLP 毒性。 我们还通过 IND 前会议寻求 FDA 对我们临床计划的反馈。这些进展 使我们能够提出快速通道 1/2 期 SBIR 申请，以确定 ONC-392 的安全性和有效性 人类癌症患者。在SBIR资助的支持下，我们将开展开放标签的I/II期临床 研究测试 ONC-392 作为单一药物的安全性、药代动力学 (PK) 和功效 与 Pembrolizumab 联合治疗晚期实体瘤和非小细胞肺癌患者。 我们提出的研究不仅将证实 ONC-392 的安全性，还将提供临床概念验证数据 我们的 CTLA-4 靶向癌症免疫疗法的新范例。

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.