Project 3 Immunotherapeutic Targeting of SLC45A2 for Treatment of Uveal Melanoma

项目3 SLC45A2的免疫治疗靶向治疗葡萄膜黑色素瘤

基本信息

批准号：
10208810
负责人：
Cassian Yee
金额：
$ 38.89万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-16 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208810
关键词：
Adoptive Cell Transfers Adoptive Transfer Adult Affinity Alleles Antigens Autologous Automobile Driving Binding Bolus Infusion CD28 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CTLA4 blockade CTLA4 gene Carrier Proteins Cell Line Cell Surface Proteins Cells Cellular Immunity Cessation of life Clinical Clinical Research Clinical Trials Cutaneous Melanoma Cytotoxic T-Lymphocytes Development Differentiation Antigens Disease Disease regression Distant Dose Epitope spreading Epitopes Eye Fostering Future Genetic Goals Helper-Inducer T-Lymphocyte Hepatic Immune response Immunotherapeutic agent Immunotherapy In Vitro Infusion procedures Intercept Interleukin-2 Liver Liver Failure Lung Malignant Neoplasms Measures Mediating Melanoma Cell Memory Metastatic Melanoma Modification Mutation Neoplasm Metastasis Patients Peptides Phase Population Process Proteins Refractory Regimen SILV gene Safety Signal Transduction Site Source Specificity Surface Survival Rate T cell response T cell therapy T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Time Toxic effect Tumor Antigens Tumor-Infiltrating Lymphocytes University of Texas M D Anderson Cancer Center Uveal Melanoma anti-CTLA4 anti-tumor immune response antigen-specific T cells base cell type checkpoint therapy chimeric antigen receptor clinical development clinical efficacy cohort conventional therapy cytotoxic effective therapy first-in-human immune checkpoint blockade immunogenic improved improved outcome in vivo intrahepatic ipilimumab kinase inhibitor melanocyte melanoma neoplastic cell novel novel therapeutics patient population peripheral blood phase 1 study phase II trial receptor response standard care targeted treatment tumor

项目摘要

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.

项目3：项目摘要/摘要新型免疫疗法方案在治疗皮肤黑色素瘤方面表现出希望晚期紫菜叶黑色素瘤在现场对高度治疗的疾病仍然是明显的未满足需求难治性并导致患者的生存率惨淡。收养细胞疗法（ACT）是免疫疗法的一种形式具有强大的潜力来改善紫veal黑色素瘤患者的预后。 ACT涉及离体隔离并扩展抗原特异性的肿瘤反应性T细胞，这些细胞被注入患者的目的介导疾病回归并保持持久的反应。我们的小组证明了更长的皮肤黑色素瘤患者的过养细胞毒性T淋巴细胞（CTL）的持久性与改善的临床反应相关，因此我们使用IL-21开发了体外过程为了产生长寿命的中央记忆型T细胞，其体内生存率从输液。遵循我们对黑色素瘤相关转运蛋白的表位的关键鉴定 SLC45A2在紫美黑色素瘤细胞中高度表达，但在正常黑色素细胞中不表达引起针对紫美黑色素瘤细胞系有效的细胞毒性反应，我们将评估该表位和在同一蛋白质中搜索可以介导的CTL驱动的卵子黑色素瘤的其他蛋白质中的其他蛋白质疾病回归。具体而言，我们提出了I阶段研究，我们将确定安全性和临床靶向SLC45A2的ACT的功效对转移性卵巢黑色素瘤患者。这项研究将包括剂量 - 由IL-21启动的SLC45A2特异性CTL的升级队列，以富集中央记忆样CD8 T细胞，然后在剂量下进行相同CTL的膨胀队列，而无需限制毒性与 CTLA4封锁（ipilimumab）。我们以前已经证明了这种组合实现的能力完整的，耐用的响应，具有强大的T细胞持久性和抗原转移性的抗原黑色素瘤。为了评估研究，我们将测量转移的SLC45A2特异性T细胞的体内持久性每周间隔并与临床反应相关，并评估多价T细胞的诱导通过抗原散布的响应。最后，为了扩大符合条件的黑色素瘤患者数量对于SLC45A2靶向免疫疗法，我们将1）从该蛋白质中确定其他表位由其他普遍的HLA类同种型提出，2）从 SLC45A2可增强抗肿瘤免疫反应的助手T细胞介导的扩增。这些研究代表使用靶向免疫疗法的紫美黑色素瘤治疗的关键新途径，该疗法持有在这种挑战性的恶性肿瘤方面提高患者生存的潜力。