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：
8673758
负责人：
PATRICK HWU
金额：
$ 35.58万
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/8673758
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 Data Disease Dose Drug Targeting Fingerprint Frequencies Gene Expression Profile Genetic Goals 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 Medicine Metastatic Melanoma Modality Modeling Molecular Nature Neoplasm Metastasis Pathway interactions Patient Selection Patients Pharmaceutical Preparations Phase II Clinical Trials Phenotype Process Proteins Regimen Relapse Research Resistance Resistance development Role Salvage Therapy Screening procedure Site 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 cancer care cancer immunotherapy cancer therapy improved in vivo inflammatory marker melanoma novel programs public health relevance resistance mechanism response response marker 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）：鉴定生物标志物以跟踪药物的临床活动和作为患者选择的预测工具，对于我们寻求发展至关重要个性化癌症疗法。这在癌症免疫疗法领域尤其重要，在癌症的领域，复杂的相互作用因子最终控制治疗效果以及在旷日持久的时间内可以发生反应的地方。使用扩展的自体肿瘤浸润淋巴细胞（TIL）以及IL-2一起使用的过养细胞疗法已成为一种强大的转移性黑色素瘤的救助疗法。多次TIL治疗临床试验，包括我们中心的临床试验，一直在大约50％的先前疗法（包括靶向疗法（BRAF和MEK抑制））和较新的免疫治疗措施（例如CTLA-4和PD-1封锁）中，始终产生客观肿瘤消退率并长期生存。 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知道肿瘤内对直到疗法无反应的耐药机制，尤其是在初次反应后的继发进展（复发）期间。在这个项目中，我们建议对黑色素瘤患者进行直到治疗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，以及全身性炎症介质和肿瘤进展因素调节TIL表型，并可以区分对TIL治疗的反应以及在治疗过程中发展抗药性（肿瘤）的患者。在这里，我们将首次结合多种不同的协同方法，以鉴定扩展的TIL，肿瘤和血液中可预测临床反应的生物标志物。在AIM＃1中，我们将分析肿瘤中的黑色素瘤和体内扩张后的黑色素瘤及其与临床反应和体内持续性的关联。在AIM＃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，作为对TIL治疗反应的预测标志物。在AIM＃3中，通过从患者初次输注后从患者那里获取其他肿瘤和血液样本，我们将探索最初不反应的肿瘤中的耐药机制，或者在手术中去除的转移的新部位中。这些研究不仅将确定可以针对进一步改善直到治疗的新因素，而且对所有形式的免疫疗法具有影响，这些免疫疗法最终会融合TIL在肿瘤微环境中的功能以及促进或抑制T细胞浸润的因素的相互作用和在肿瘤部位的功能。