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

项目2：针对卵巢癌的个人新抗原靶向癌症疫苗与免疫检查点阻断相结合

• 批准号: 10469374
• 负责人: Panagiotis Konstantinopoulos
• 金额: $ 37.6万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-03 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469374
• 关键词: Address; Agonist; Antigens; Autoimmune; Autologous; Autologous Tumor Cell; Binding; Biological; Biological Markers; Biological Models; Biological Testing; Biometry; Biopsy; Blood; Blood specimen; Cancer Center; Cancer Vaccines; Cells; Clinical; Clinical Trials; Combined Vaccines; Data; Development; Disease; Disease Progression; Disease remission; Effectiveness; Epithelial ovarian cancer; Epitopes; Event; Evolution; Exhibits; Feasibility Studies; Funding; Genetic; Genomics; Glioblastoma; Grant; Human; Immune; Immune response; Immune system; Immunity; Immunize; Immunoglobulins; Immunologic Adjuvants; Immunologics; Immunotherapy; In Situ; In complete remission; Institutional Review Boards; Malignant Neoplasms; Malignant neoplasm of ovary; Monoclonal Antibodies; Mutate; Mutation; Nature; Neoadjuvant Therapy; Newly Diagnosed; Nivolumab; Organoids; Pathology; Pathway interactions; Patients; Peptides; Platinum; Poly ICLC; Proteins; Protocols documentation; Recurrence; Residual Tumors; Residual state; Residual volume; Site; Somatic Mutation; Specimen; T cell response; T-Cell Immunologic Specificity; T-Lymphocyte; TLR3 gene; Testing; Therapeutic; Time; Toxic effect; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Vaccines; anti-PD1 therapy; base; cancer therapy; cancer vaccination; central tolerance; chemotherapy; computerized tools; design; exome sequencing; genetic evolution; immune checkpoint blockade; immunogenic; improved; insight; melanoma; mouse model; neoantigen vaccine; neoantigens; neoplastic cell; novel; ovarian neoplasm; phase 1 study; prediction algorithm; pressure; programmed cell death protein 1; prospective test; response; safety and feasibility; side effect; standard of care; transcriptome; transcriptome sequencing; tumor; vaccine evaluation

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).

项目摘要 虽然上皮性卵巢癌（EOC）最初是一种化学敏感性疾病，但很少通过化疗治愈。 标准治疗（SOC）含铂化疗。鉴于大量证据表明卵巢癌 肿瘤是免疫原性的，以前已经评估了几种免疫治疗方法在这种疾病中的应用 但没有证据表明其具有有效的抗肿瘤免疫力或临床活性。免疫检查点阻断（CPB） 已经彻底改变了多种癌症治疗的治疗方法， EOC，强调迫切需要新的策略来扩大CPB在这种疾病中的受益。最近几 多年来，我们已经开发了新的计算工具，以确定免疫原性候选患者特异性突变 表位（也称为新抗原），其能够刺激肿瘤特异性T细胞应答。进展 我们的团队生成的预测算法现在为研究生成 中等突变负荷肿瘤（Abelin Immunity 2017）中的新抗原疫苗，如EOC，以及 测试疫苗如何与SOC治疗联合给药。这一前景广阔的活动 引导我们前瞻性地测试个人新肽作为癌症疫苗的靶向，我们已经证明， 免疫晚期黑素瘤患者的安全性、可行性和免疫活性（Ott，Nature 2017）和胶质母细胞瘤（凯斯金，Nature 2019），使用由多达20个突变表位组成的个人疫苗 每名患者，作为合成长肽（20- 30聚体）与强效免疫佐剂聚- ICLC，一种TLR 3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细胞应答可以识别自体肿瘤细胞。此外，持续的全面反应 当抗PD 1治疗加新抗原治疗时， 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 给予个体化新抗原靶向癌症疫苗联合CPB治疗， 体积EOC。我们假设这种方法将有效地扩增现有的肿瘤反应性T细胞， 扩大T细胞库以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，自身免疫副作用少。我们将评估Neovax在以下方面的可行性和安全性： 与纳武单抗组合治疗EOC（目标1）。通过循环血液免疫的综合表征， 肿瘤和肿瘤浸润性免疫细胞在不同时间点的原位变化 治疗过程中，包括在疾病进展的情况下，我们试图阐明候选机制， 对疫苗和CPB治疗的应答和不应答（目的2和3）。