Project 3 Immunotherapeutic Targeting of SLC45A2 for Treatment of Uveal Melanoma

项目3：项目概要/摘要 虽然新的免疫治疗方案在治疗皮肤黑色素瘤方面显示出希望，但有效的治疗方法， 晚期葡萄膜黑色素瘤仍然是该领域对高度治疗性疾病的明显未满足的需求 难治性的，并导致令人沮丧的患者存活率。免疫细胞疗法（ACT）是一种免疫疗法 具有改善葡萄膜黑色素瘤患者预后的强大潜力。ACT涉及离体分离 和扩增抗原特异性肿瘤反应性T细胞，其被输注到患者中，目的是 介导疾病消退并维持持久的反应。我们的团队已经证明， 皮肤黑色素瘤患者过继转移的细胞毒性T淋巴细胞（CTL）的持续性 与改善的临床反应相关，因此我们开发了一种使用IL-21的体外方法， 以产生长寿命的中央记忆型T细胞，其体内存活期从移植时起可长达数年。 输液在我们确定了黑色素瘤相关转运蛋白的一个重要表位后， SLC 45 A2在葡萄膜黑色素瘤细胞中高度表达，但在正常黑色素细胞中不表达， 诱导针对葡萄膜黑色素瘤细胞系的有效细胞毒性应答，我们将评估该表位， 在同一蛋白质中寻找其他可以介导过继转移的CTL驱动的葡萄膜黑色素瘤 疾病回归具体来说，我们提出了一项I期研究，我们将确定安全性和临床 靶向SLC 45 A2的ACT在转移性葡萄膜黑色素瘤患者中的疗效。这项研究将包括一个剂量- 由IL-21引发以富集中央记忆样CD 8 T细胞的SLC 45 A2特异性CTL的递增队列， 随后是相同CTL的扩展组群，其剂量不限制毒性，与 CTLA 4阻断（伊匹单抗）。我们之前已经证明了这种组合的能力， 在难治性转移性淋巴瘤中具有完整、持久的反应，具有强T细胞持久性和抗原扩散性 黑素瘤为了评估该研究，我们将测量转移的SLC 45 A2特异性T细胞的体内持久性， 每周一次，并与临床反应相关，并额外评估多价T细胞的诱导 通过抗原扩散的反应。最后，为了扩大符合条件的黑色素瘤患者的数量， 对于SLC 45 A2靶向免疫治疗，我们将：1）从该蛋白质中鉴定可能与SLC 45 A2结合的其他表位。 由其他流行的HLA类同种异型呈递，和2）从 SLC 45 A2增强辅助性T细胞介导的抗肿瘤免疫应答的扩增。这些研究 代表了使用靶向免疫疗法治疗葡萄膜黑色素瘤的关键新途径， 提高这种具有挑战性的恶性肿瘤患者生存率的潜力。

Project 3: Project Summary/Abstract While novel immunotherapy regimens show promise in treating cutaneous melanoma, effective therapies for advanced uveal melanoma remain a clear unmet need in the field for a disease that is highly treatment refractory and leads to dismal patient survival rates. Adoptive cell therapy (ACT) is a form of immunotherapy with strong potential to improve the outcome for uveal melanoma patients. ACT involves the ex vivo isolation and expansion of antigen-specific, tumor-reactive T cells that are infused into the patient with the aim of mediating disease regression and maintaining a durable response. Our group has demonstrated that longer persistence of adoptively transferred cytotoxic T lymphocytes (CTL) in patients with cutaneous melanoma correlates with improved clinical response, and we have accordingly developed an in vitro process using IL-21 to generate long-lived central memory-type T cells whose in vivo survival extends up to years from the time of infusion. Following our crucial identification of an epitope of the melanoma-associated transporter protein SLC45A2 that is highly expressed in uveal melanoma cells but not in normal melanocytes and capable of eliciting a potent cytotoxic response against uveal melanoma cell lines, we will evaluate this epitope and search for others within the same protein that can mediate adoptively transferred CTL-driven uveal melanoma disease regression. Specifically, we propose a Phase I study in which we will determine the safety and clinical efficacy of ACT targeting SLC45A2 in patients with metastatic uveal melanoma. This study will include a dose- escalation cohort of SLC45A2-specific CTL primed by IL-21 to enrich for central-memory-like CD8 T cells, followed by an expansion cohort of the same CTL at a dose without limiting toxicities in combination with CTLA4 blockade (ipilimumab). We have previously demonstrated the ability of this combination to achieve complete, durable responses with strong T cell persistence and antigen-spreading in refractory metastatic melanoma. To evaluate the study, we will measure in vivo persistence of transferred SLC45A2-specific T cells at weekly intervals and correlate with clinical response, and additionally assess induction of a multivalent T cell response through antigen-spreading. Finally, in an effort to expand the number of melanoma patients eligible for SLC45A2-targeted immunotherapy, we will, 1) identify additional epitopes from this protein that may be presented by other prevalent HLA class allotypes, and 2) search for HLA class II-restricted peptides from SLC45A2 to boost helper T cell-mediated amplification of the anti-tumor immune response. These studies represent a critical new avenue for uveal melanoma treatment using targeted immunotherapy, which holds the potential to improve patient survival for this challenging malignancy.