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：
10683953
负责人：
Cassian Yee
金额：
$ 41.42万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683953
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 Eligibility Determination 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 MHC binding peptide Malignant Neoplasms Measures Mediating Melanoma Cell Melanosomes Memory Metastatic Melanoma Modification Mutation Neoplasm Metastasis Patients Peptides Peripheral Blood Lymphocyte 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-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 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 interleukin-21 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：项目总结/摘要虽然新型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疾病的明显未满足的需求难治性并导致患者生存率低下。过继细胞疗法（ACT）是免疫疗法的一种形式具有改善葡萄膜黑色素瘤患者预后的强大潜力。 ACT 涉及离体隔离以及扩增抗原特异性、肿瘤反应性 T 细胞，将其输注到患者体内，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，更长的时间皮肤黑色素瘤患者过继转移的细胞毒性 T 淋巴细胞 (CTL) 的持续存在与临床反应的改善相关，因此我们开发了一种使用 IL-21 的体外工艺产生长寿命的中央记忆型 T 细胞，其体内存活期可长达数年输液。在我们对黑色素瘤相关转运蛋白的表位进行重要鉴定之后 SLC45A2 在葡萄膜黑色素瘤细胞中高表达，但在正常黑色素细胞中不表达，并且能够引发针对葡萄膜黑色素瘤细胞系的有效细胞毒性反应，我们将评估该表位并寻找同一蛋白质中可以介导过继转移的 CTL 驱动的葡萄膜黑色素瘤的其他蛋白质疾病消退。具体来说，我们提出了一项 I 期研究，其中我们将确定安全性和临床效果靶向 SLC45A2 的 ACT 对转移性葡萄膜黑色素瘤患者的疗效。这项研究将包括剂量- 由IL-21引发的SLC45A2特异性CTL的升级队列，以富集中央记忆样CD8 T细胞，随后以不限制毒性的剂量对相同的 CTL 进行扩展队列，并与 CTLA4 阻断（伊匹单抗）。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产生完整、持久的反应，具有强大的 T 细胞持久性和抗原扩散能力黑色素瘤。为了评估这项研究，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扩散产生反应。最后，为了扩大符合资格的黑色素瘤患者数量对于 SLC45A2 靶向免疫疗法，我们将，1) 从该蛋白质中识别出可能是的其他表位由其他流行的 HLA 类同种异型呈现，以及 2) 搜索 HLA II 类限制性肽 SLC45A2 可增强辅助 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重要新途径，该疗法拥有提高这种具有挑战性的恶性肿瘤患者生存率的潜力。