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

摘要 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袭。CTLA-4靶向免疫疗法是第一个 建立这一范式。然而，临床测试的抗CTLA-4抗体的疗效并不理想，但 高毒性。我们的临床前研究表明，这种结果是通过使CTLA-4失活来预测的 在免疫耐受中发挥重要作用的检查点，保护身体免受自身免疫性疾病的侵袭。 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 免疫治疗效应(CITE)代表了抗CTLA-4独特的和治疗上可分离的活性 抗体。IRAE是由于CTLA-4检查站失活，而CITE通过以下方式有效 肿瘤微环境中调节性T细胞(Treg)的选择性去除 我们假设，一种更安全、更有效的CTLA-4靶向免疫疗法应该保留 抑制CTLA-4检查点，同时增强Treg耗竭的有效性和选择性 肿瘤微环境。 为了准备在临床上测试这一开创性的假设，我们已经产生了新一代反 通过避免CTLA-4的溶酶体降解来保护CTLA-4免疫检查点的CTLA-4抗体。 新抗体ONC-392在人源化小鼠模型中具有显著降低的irAEs和显著高于人源化小鼠模型的irAEs 在消耗肿瘤浸润性调节性T细胞方面具有强大的活性，从而导致更有效的CITE。我们有 进行了支持IND的研究，包括GMP级制造和GLP对非人类灵长类动物的毒性。 我们还通过IND前会议征求了FDA对我们临床计划的反馈。这些进展 允许我们提出Fast Track阶段1/2 SBIR应用，以确定ONC-392在 人类癌症患者。在SBIR赠款的支持下，我们将进行开放式标签I/II期临床 ONC-392单药和单药的安全性、药代动力学和疗效研究 培溴利珠单抗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，而且还将为临床提供概念验证数据 我们的CTLA-4靶向肿瘤免疫治疗的新范例。

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.