Biomarkers and Resistance Mechanisms in Melanoma T-cell Therapy

黑色素瘤 T 细胞治疗中的生物标志物和耐药机制

基本信息

批准号：
9143058
负责人：
PATRICK HWU
金额：
$ 33.77万
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：
2014
资助国家：
美国
起止时间：
2014-09-26 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9143058
关键词：
Affect Appearance Arts Autologous Autologous Tumor-Infiltrating Lymphocyte BRAF gene Biological Markers Blood Blood specimen CD8B1 gene Cancer Patient Caring Cell Therapy Cells Clinical Complex Cytotoxic T-Lymphocyte-Associated Protein 4 Data Disease Dose Drug Targeting Fingerprint Frequencies Gene Expression Profile Genetic Goals Health Immune Immune system Immunohistochemistry Immunosuppression Immunosuppressive Agents Immunotherapy Infiltration Inflammation Mediators Inflammatory Infusion procedures Interleukin-2 Intervention Knowledge MEK inhibition Mainstreaming Malignant Neoplasms Measures Mediating Metastatic Melanoma Modality Modeling Molecular Nature Neoplasm Metastasis Pathway interactions Patient Selection Patients Pharmaceutical Preparations Phenotype Process Proteins Regimen Relapse Research Resistance Resistance development Role Salvage Therapy Screening procedure Site Surrogate Markers Survival Rate T cell therapy T-Lymphocyte T-Lymphocyte Subsets Technology Therapeutic Therapy Clinical Trials Time Treatment Efficacy Tumor Escape Tumor Immunity Tumor Tissue Tumor-Infiltrating Lymphocytes University of Texas M D Anderson Cancer Center Work biomarker identification cancer immunotherapy cancer therapy improved in vivo inflammatory marker melanoma novel personalized cancer care personalized cancer therapy personalized medicine phase II trial predicting response predictive marker predictive tools programs resistance mechanism responders and non-responders response response biomarker specific biomarkers targeted treatment therapy resistant tool tumor tumor infiltrating lymphocyte therapy tumor microenvironment tumor progression

项目摘要

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.

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至关重要个性化癌症治疗。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治疗效果，并且反应可能会持续很长时间。使用扩增的自体肿瘤浸润淋巴细胞 (TIL) 与 IL-2 结合的过继细胞疗法已成为转移性黑色素瘤的有效挽救疗法。多项 TIL 疗法临床试验（包括我们中心的试验）始终取得了客观的肿瘤消退率，并在经过多种先前疗法（包括靶向疗法（BRAF 和 MEK 抑制）和较新的免疫疗法，例如如 CTLA-4 和 PD-1 阻断。然而，我们知识上的 3 个主要差距限制了我们进一步开发 TIL 疗法作为主流疗法的能力：1）我们对 TIL 介导肿瘤消退的 T 细胞类型以及它们的水平如何在体内随肿瘤变化而变化知之甚少。消退和复发，2) 尚未对 TIL 治疗中的宿主肿瘤和血液因子以及它们与临床反应的关系进行深入的生物标志物研究，3) 对于无反应的肿瘤内的耐药机制一无所知至 TIL治疗，尤其是在初始缓解后的继发性进展（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许多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 表型，并可以区分对 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，我们将首次结合多种不同的协同方法来识别扩展的 TIL、肿瘤和血液中可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，及其与临床反应和体内 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炎症、免疫抑制和肿瘤进展的标志物，作为 TIL 治疗反应的预测标志物。在目标 3 中，通过在初次 TIL 输注后从患者身上获取额外的肿瘤和血液样本，我们将探索最初没有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进一步改善 TIL 治疗的新因素，而且对所有形式的免疫治疗都有影响，这些免疫治疗最终集中于 TIL 在肿瘤微环境中的功能以及促进或抑制 T 细胞的因素的相互作用浸润并在肿瘤部位发挥作用。