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在我们寻求开发的过程中至关重要 个人化癌症治疗。这在癌症免疫治疗领域尤为关键，在癌症免疫治疗领域，复杂的相互作用因素最终控制着治疗效果，而且反应可能会在很长一段时间内发生。用扩增的自体肿瘤浸润性淋巴细胞(TIL)联合IL-2进行过继细胞治疗已成为治疗转移性黑色素瘤的一种有效的挽救方法。多项TIL治疗临床试验，包括我们中心的临床试验，一致地在经过多种先前治疗(包括靶向治疗(BRAF和MEK抑制)和较新的免疫疗法，如CTLA-4和PD-1阻断)后进展的约50%的患者中，获得了客观的肿瘤消退率和延长的生存时间。然而，知识上的三大空白限制了我们将TIL疗法进一步发展为主流疗法的能力：1)我们仍然对介导TIL疗法的肿瘤消退及其水平在体内如何变化与肿瘤消退和复发的变化相平行的T细胞类型知之甚少；2)目前还没有关于TIL疗法中宿主肿瘤和血液因素的深入生物标志物研究，以及它们与临床疗效的关系；3)对于TIL疗法无效的肿瘤内耐药的机制，尤其是在初始应答后的继发进展(复发)期间，我们尚不清楚。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一项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与全身炎症介质和肿瘤进展因子一起调节TIL的表型，并可以区分对TIL治疗有效的患者和在治疗过程中产生抵抗(肿瘤逃逸)的患者。在这里，我们将第一次结合一些不同的协同方法来识别扩大的TIL、肿瘤和血液中预测临床反应的生物标记物。在第一个目标中，我们将分析黑色素瘤肿瘤内和体外扩张后的TIL及其与临床反应和体内TIL持久性的关系。在目标2中，我们将测量肿瘤组织和血液中炎症、免疫抑制和肿瘤进展的标记物，作为TIL治疗反应的预测标记物。在第三个目标中，通过采集患者在初次注射TIL后的额外肿瘤和血液样本，我们将探索最初无反应的肿瘤或手术切除的新转移部位的耐药机制。这些研究不仅将确定可作为进一步改进TIL治疗的靶点的新因素，而且对最终集中于TIL在肿瘤微环境中的功能以及促进或抑制T细胞渗透的因素的相互作用的所有形式的免疫治疗都有意义 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.