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控机制 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 建立这种范式。然而，临床测试的抗CTLA-4抗体表现出次优的功效， 高毒性。我们的临床前研究表明，这种结果是通过灭活CTLA-4来预测的。 在免疫耐受中起重要作用的检查点，保护机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 免疫抑制作用（CITE）代表抗CTLA-4独特和治疗上可分离的活性 抗体的irAE可归因于CTLA-4检查点的失活，而CITE通过以下途径有效： 选择性耗竭肿瘤微环境中的调节性T细胞（Treg）。 我们假设，一种更安全、更有效的CTLA-4靶向免疫治疗应该保留，而不是保留。 而不是抑制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的溶酶体降解来保留CTLA-4免疫检查点。 新抗体ONC-392在人源化小鼠模型中具有显著降低的irAE，并且在人源化小鼠模型中具有显著升高的irAE。 在消耗肿瘤浸润性调节性T细胞方面的有效活性，导致更有效的CITE。我们有 进行IND使能研究，包括GMP级生产和非人灵长类动物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 允许我们提出一个快速通道阶段1/2 SBIR应用，以确定ONC-392的安全性和有效性， 人类癌症患者。在SBIR赠款的支持下，我们将开展一项开放标签的I/II期临床试验， 一项旨在测试ONC-392作为单药和在 在晚期实体瘤和非小细胞肺癌患者中与Pembrolizumab组合。 我们提出的研究不仅将证实ONC-392的安全性，而且还将提供临床概念验证数据， 我们的新范例CTLA-4靶向癌症免疫疗法。

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.