Biomarkers and Resistance Mechanisms in Melanoma T-cell Therapy

描述（由申请人提供）：识别生物标志物以跟踪药物的临床活性并作为患者选择的预测工具，对于我们寻求开发 个性化癌症治疗这在癌症免疫治疗领域尤其重要，因为复杂的相互作用因素最终控制着治疗效果，并且反应可能会持续很长一段时间。使用扩增的自体肿瘤浸润淋巴细胞（TIL）与IL-2一起的诱导细胞疗法已成为转移性黑色素瘤的有力挽救疗法。多项TIL治疗临床试验，包括我们中心的临床试验，一直在约50%的患者中产生客观的肿瘤消退率和延长的生存期，这些患者在多次既往治疗后进展，包括靶向治疗（BRAF和MEK抑制）和较新的免疫治疗，如CTLA-4和PD-1阻断。然而，我们知识中的3个主要差距限制了我们进一步发展TIL疗法作为主流治疗的能力：1）我们仍然对介导肿瘤消退的TIL中的T细胞的类型以及它们的水平如何在体内与肿瘤消退和复发的变化平行地变化知之甚少，2）尚未对TIL治疗中的宿主肿瘤和血液因子以及它们如何与临床应答相关进行深入的生物标志物研究，和3）对TIL治疗无反应的肿瘤内的抗性机制一无所知，特别是在初始反应后的继发性进展（复发）期间。在这个项目中，我们建议对接受TIL治疗的黑色素瘤患者进行全面的生物标志物研究。我们假设肿瘤微环境中的一些相互作用的免疫调节因子，连同全身炎症介质和肿瘤进展因子一起调节TIL表型，并且可以区分对TIL治疗有反应的患者和在治疗期间产生耐药性（肿瘤逃逸）的患者。在这里，我们将首次联合收割机结合许多不同的协同方法来鉴定扩增的TIL、肿瘤和血液中预测临床反应的生物标志物。在目标#1中，我们将分析肿瘤中和离体扩增后的黑色素瘤TIL及其与临床应答和体内TIL持久性的关联。在目标#2中，我们将测量肿瘤组织和血液中的炎症、免疫抑制和肿瘤进展的标志物，作为对TIL疗法的响应的预测标志物。在目标#3中，通过在患者的初始TIL输注之后从患者获取额外的肿瘤和血液样品，我们将探索最初不响应的肿瘤中或手术切除的新转移部位中的抗性机制。这些研究不仅将确定可靶向以进一步改善TIL治疗的新因子，而且对所有形式的免疫治疗都有意义，这些免疫治疗最终集中在肿瘤微环境中TIL的功能以及促进或抑制T细胞浸润的因子的相互作用上。 并在肿瘤部位发挥作用

DESCRIPTION (provided by applicant): The identification of biomarkers to track clinical activity of drugs and as predictive tools for patient selection is critical in our quest to develop personalized cancer therapies. This is especially critical in the field of cancer immunotherapy, where complex interacting factors ultimately control treatment efficacy and where responses can occur over a protracted period of time. Adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes (TIL) together with IL-2 has emerged as a powerful salvage therapy for metastatic melanoma. Multiple TIL therapy clinical trials, including those at our center, have consistently yielded objective tumor regression rates and prolonged survival in about 50% of patients that have progressed after multiple previous therapies, including targeted therapies (BRAF and MEK inhibition) and newer immunotherapies, such as CTLA-4 and PD-1 blockade. However, 3 major gaps in our knowledge limit our ability to further develop TIL therapy as a mainstream therapeutic: 1) We still know relatively little about the types of T cells n TIL mediating tumor regression and how their levels change in vivo paralleling changes in tumor regression and relapse, 2) There have been no in-depth biomarker studies on host tumor and blood factors in TIL therapy and how they are related to clinical response, and 3) Nothing is known about the mechanisms of resistance within tumors that do not respond to TIL therapy, especially during secondary progression (relapse) after an initial response. In this project, we propose to perform a comprehensive biomarker study on melanoma patients getting TIL therapy. We hypothesize that a number of interacting immunoregulatory factors within the tumor microenvironment, together with systemic inflammatory mediators and tumor progression factors regulate TIL phenotype and can distinguish patients responding to TIL therapy and those who develop resistance (tumor escape) during therapy. Here for the first time, we will combine a number of different synergistic approaches to identify biomarkers in the expanded TIL, tumor, and blood that are predictive of clinical response. In Aim #1, we will analyze melanoma TIL in tumors and after ex vivo expansion and their association with clinical response and TIL persistence in vivo. In Aim #2, we will measure markers of inflammation, immune suppression, and tumor progression in tumor tissue and blood as predictive markers of response to TIL therapy. In Aim #3, by acquiring additional tumor and blood samples from patients following their initial TIL infusion, we will explore the mechanisms of resistance in tumors that initially d not respond, or in new sites of metastases that are surgically removed. These studies will not only identify novel factors that can be targeted to further improve TIL therapy, but have implications for all forms of immunotherapy that ultimately converge on the function of TIL in the tumor microenvironment and the interplay of factors that facilitate or suppress T-cell infiltration and function at the tumor site.