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

项目摘要 虽然上皮性卵巢癌(EOC)最初是一种化疗敏感型疾病，但很少通过 标准护理(SOC)铂为基础的化疗。鉴于大量证据表明卵巢 肿瘤是免疫原性的，几种免疫治疗方法已经在这种疾病中被评估过。 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) 这种疗法使多种癌症的治疗发生了革命性的变化，但在以下方面仅显示出不大的疗效 EoC，强调迫切需要新的战略来扩大CPB在这种疾病中的益处。在最近 多年来，我们已经开发出新的计算工具来识别免疫原性候选患者特异性突变 能够刺激肿瘤特异性T细胞反应的表位(也称为新抗原)。最新进展 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 中等突变负荷的肿瘤中的新抗原疫苗(Abelin免疫2017)，如EOC，以及 测试疫苗如何与SOC疗法结合使用。这一前景看好的活动具有 引导我们前瞻性地测试个人新肽作为癌症疫苗的靶向性，我们已经证明 晚期黑色素瘤患者免疫的安全性、可行性和免疫学活性 和胶质母细胞瘤(凯斯金，自然，2019)，由多达20个突变表位组成的个人疫苗 每名患者，以合成长肽(20-30mer)的形式提供，其中混合了有效的免疫佐剂Poly- 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，完整的回应和持续的 在新抗原的基础上加用抗PD1治疗的患者观察到缓解。 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 个人新抗原靶向肿瘤疫苗联合体外循环治疗低残留 音量EoC。我们假设，这种方法将有效地扩大现有的肿瘤反应性T细胞和 扩大T细胞谱系，包括新的肿瘤特异性T细胞，从而产生高度特异的抗- 肿瘤免疫，自身免疫副作用较少。我们将在#年评估Neovax的可行性和安全性 与nivolumab联合应用于EoC(目标1)。通过循环血液免疫的综合表征 在连续的时间点上肿瘤和肿瘤浸润性免疫细胞的原位变化 治疗过程中，包括在疾病进展的情况下，我们试图阐明候选的机制 对疫苗和体外循环治疗的应答和无应答(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).