Project 3 Immunotherapeutic Targeting of SLC45A2 for Treatment of Uveal Melanoma

项目3：项目摘要/摘要 虽然新的免疫疗法在治疗皮肤黑色素瘤方面前景看好，但有效的治疗方法 晚期葡萄膜黑色素瘤在这种高度治疗的疾病领域仍然是一个明显的未得到满足的需求 难治性，导致患者存活率低。过继细胞疗法(ACT)是一种免疫疗法。 有很强的潜力改善葡萄膜黑色素瘤患者的预后。ACT涉及到体外分离 和扩增抗原特异性的肿瘤反应性T细胞，这些T细胞被注入患者体内，目的是 调解疾病的消退并维持持久的反应。我们的团队已经证明了这一点 过继转移的细胞毒性T淋巴细胞在皮肤黑色素瘤患者中的持久性 与改善的临床反应相关，因此我们开发了一种使用IL-21的体外过程 为了产生长寿的中央记忆型T细胞，这种T细胞在体内的存活时间从 输液。在我们鉴定了黑色素瘤相关转运蛋白的一个表位之后 SLC45A2在葡萄膜黑色素瘤细胞中高表达，但在正常黑素细胞中不表达，并能够 诱导对葡萄膜黑色素瘤细胞系产生有效的细胞毒反应，我们将评估该表位并 在同一蛋白中寻找可介导过继转移的CTL驱动的葡萄膜黑色素瘤的其他蛋白 疾病消退。具体地说，我们提出了一项I期研究，在该研究中，我们将确定 靶向SLC45A2的ACT治疗转移性葡萄膜黑色素瘤的疗效这项研究将包括一种剂量- IL-21激活的SLC45A2特异性CTL的升级队列，以丰富中央记忆样CD8 T细胞， 随后是相同CTL的扩展队列，剂量不限制毒性，联合 CTLA4阻断(Ipilimumab)。我们之前已经展示了这种组合实现的能力 在难治性转移瘤中具有强大的T细胞持久性和抗原扩散的完整、持久的应答 黑色素瘤。为了评估这项研究，我们将测量被转移的SLC45A2特异性T细胞在体内的持久性 每周一次，并与临床反应相关，并另外评估多价T细胞的诱导 通过抗原传播作出反应。最后，为了扩大符合条件的黑色素瘤患者的数量 对于SLC45A2靶向免疫治疗，我们将：1)从这种蛋白中识别可能是 由其他流行的HLA类同种异型提出，以及2)从 SLC45A2能增强辅助性T细胞介导的抗肿瘤免疫反应的放大。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，该疗法持有 有可能改善这种具有挑战性的恶性肿瘤患者的存活率。

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.