Project 2: Combined personal neoantigen-targeting cancer vaccines with immune checkpoint blockade for ovarian cancer

项目概要 尽管上皮性卵巢癌（EOC）最初是一种化学敏感性疾病，但很少能通过以下方法治愈： 标准护理（SOC）铂类化疗。鉴于大量证据表明卵巢 肿瘤具有免疫原性，之前已经在这种疾病中评估了几种免疫治疗方法 但没有有效的抗肿瘤免疫或临床活性的证据。免疫检查点封锁（CPB） 这种疗法彻底改变了多种癌症的治疗方法，但在以下方面仅表现出有限的效果： EOC，强调迫切需要新的策略来扩大 CPB 在这种疾病中的益处。最近过去 多年来，我们开发了新的计算工具来识别免疫原性候选患者特异性突变 表位（也称为新抗原）能够刺激肿瘤特异性 T 细胞反应。进展 我们团队生成的预测算法现在为研究生成的可行性提供了机会 用于具有中等突变负荷的肿瘤的新抗原疫苗（Abelin Immunity 2017），例如 EOC，以及 测试如何将疫苗与 SOC 疗法结合使用。这项充满希望的活动 引导我们前瞻性地测试个人新肽作为癌症疫苗的靶向性，并且我们已经证明 对晚期黑色素瘤患者进行免疫接种的安全性、可行性和免疫活性（Ott，Nature 2017）和胶质母细胞瘤（Keskin，Nature 2019），其个人疫苗包含多达 20 个突变表位 每名患者以合成长肽（20-30mers）的形式与强效免疫佐剂多聚体混合交付 ICLC，一种 TLR3 激动剂（称为“Neovax”）。在这些概念验证研究中，一些诱导的新抗原 特异性 T 细胞反应可以识别自体肿瘤细胞。此外，持续的完整反应 当除新抗原外还给予抗 PD1 治疗时，患者观察到病情缓解 疫苗。基于这些有希望的结果，我们现在建议在一项新的临床试验中评估联合疗法 个人新抗原靶向癌症疫苗联合 CPB 治疗可实现低残留 体积 EOC。我们假设这种方法将有效地扩大现有的肿瘤反应性 T 细胞， 扩大 T 细胞库，包括新的肿瘤特异性 T 细胞，从而产生高度特异性的抗 肿瘤免疫，自身免疫副作用较少。我们将评估 Neovax 的可行性和安全性 与纳武单抗联合治疗 EOC（目标 1）。通过循环血液免疫的综合表征 整个时间点上肿瘤和肿瘤浸润免疫细胞的原位变化的反应 治疗过程中，包括在疾病进展的情况下，我们寻求阐明候选机制 对疫苗和 CPB 治疗有反应和无反应（目标 2 和 3）。

Project Summary Although epithelial ovarian cancer (EOC) is initially a chemosensitive disease, it is infrequently cured by standard-of-care (SOC) platinum-based chemotherapy. Given the abundant evidence indicating that ovarian tumors are immunogenic, several immunotherapy approaches have been previously evaluated in this disease but without evidence of potent anti-tumor immunity or clinical activity. Immune checkpoint blockade (CPB) therapy, which has revolutionized treatment of multiple cancers, has demonstrated only modest effectiveness in EOC, highlighting the urgent need of new strategies to extend the benefit of CPB in this disease. Over recent years, we have developed new computational tools to identify immunogenic candidate patient-specific mutated epitopes (also called neoantigens) that are capable of stimulating tumor-specific T cell responses. Advances in prediction algorithms generated by our team now provide opportunities for studying the feasibility of generating neoantigen vaccines in tumors with intermediate mutation load (Abelin Immunity 2017), such as EOC, and for the testing of how the vaccine can be administered in conjunction with SOC therapy. This promising activity has led us to prospectively test the targeting of personal neopeptides as cancer vaccines, and we have demonstrated the safety, feasibility and immunologic activity of immunizing patients with advanced melanoma (Ott, Nature 2017) and glioblastoma (Keskin, Nature 2019) with personal vaccines consisting of up to 20 mutated epitopes per patient, delivered as synthetic long peptides (20-30mers) admixed with the potent immune adjuvant poly- ICLC, a TLR3 agonist (called ‘Neovax’). In these proof-of-concept studies, some of the induced neoantigen- specific T cell responses could recognize autologous tumor cells. Moreover, complete responses with sustained remissions were observed in patients when anti-PD1 therapy was administered in addition to neoantigen vaccine. Based on these promising results, we now propose to evaluate, in a new clinical trial, the combined administration of personal neoantigen-targeted cancer vaccines together with CPB therapy for low residual volume EOC. We hypothesize that this approach will effectively expand existing tumor-reactive T-cells and broaden the T-cell repertoire to include new tumor-specific T-cells and thereby generating highly specific anti- tumor immunity with fewer autoimmune side effects. We will evaluate the feasibility and safety of Neovax in combination with nivolumab in EOC (Aim 1). Through integrated characterization of circulating blood immune responses with in situ changes in the tumor and tumor-infiltrating immune cells at serial time points across the course of therapy, including in the event of disease progression, we seek to elucidate candidate mechanisms of response and non-response to vaccine and CPB therapy (Aims 2 and 3).