Augmenting Chimeric Antibody Receptor Directed T cell Therapy for Cancer

描述（由申请人提供）：该项目描述了一个为期5年的培训计划，作为一个医生，科学家的职业生涯，建立一个研究计划内的胸部和胸膜肿瘤学领域的长期目标。申请人已经完成了在宾夕法尼亚大学的肺，过敏和重症监护医学奖学金。他目前正在进行恶性胸膜间皮瘤（MPM）的过继性T细胞免疫疗法的研究，这是一种致命的石棉相关胸膜恶性肿瘤，治疗选择仍然有限。该提案的研究重点是增强基于嵌合抗体受体（CAR）的T细胞免疫疗法的抗肿瘤效果。该提案的中心假设是，MPM的CAR T细胞疗法可以通过改善T细胞运输、抑制肿瘤微环境免疫抑制以及使T细胞对肿瘤诱导的功能抑制更具弹性来显著增强。在特定目标1中，CAR T细胞将被遗传修饰以表达适合于由MPM肿瘤分泌的趋化因子的趋化因子受体，以试图增加T细胞向肿瘤的运输。在特定目标2中，已知抑制T细胞活化的T细胞信号传导分子/结构域将被遗传失活，以增加T细胞对肿瘤诱导的失活的恢复力。在特定目标3中，使用两种互补的CAR T细胞免疫疗法小鼠模型，分泌到肿瘤微环境中的允许逃避免疫的已建立的抑制性介质将被抑制，以试图增强T细胞抗肿瘤功效。该提案的培训部分包括正式的课程，参与胸/胸膜肿瘤学博士后讲座和研讨会的丰富环境，获得先进的实验室技术和个人指导。该项目将在宾夕法尼亚大学肺部研究和胸部肿瘤实验室主任Steven Albelda博士和宾夕法尼亚大学Abramson癌症中心转化研究主任Carl June博士的监督下进行。Albelda博士和June博士指导了100多名学员。此外，一个由杰出科学家组成的咨询委员会将在整个颁奖期间提供实验援助，智力指导和职业建议。

DESCRIPTION (provided by applicant): This project describes a 5 year training program for a career as a Physician-Scientist with the long term goal of establishing a research program within the field of thoracic and pleural oncology. The applicant has finished a fellowship in Pulmonary, Allergy, and Critical Care Medicine at the University of Pennsylvania. He is currently conducting research in adoptive T cell immunotherapy for malignant pleural mesothelioma (MPM), a deadly asbestos-related pleural malignancy for which treatment options remain limited. The research focus of this proposal is to enhance the anti-tumor effect of chimeric antibody receptor (CAR)-based T cell immunotherapy. The central hypothesis of the proposal is that CAR T cell therapy for MPM can be significantly enhanced by improving T cell trafficking, inhibiting tumor microenvironment immunosuppression, and making T cells more resilient to tumor induced functional inhibition. In Specific Aim 1, CAR T cells will be genetically modified to express chemokine receptors appropriate for the chemokines secreted by MPM tumor in attempt to augment T cell trafficking to tumor. In Specific Aim 2, T cell signaling molecules/domains known to inhibit T cell activation will be genetically inactivated in order to increase T cell resilience to tumor-induced inactivation. In Specific Aim 3, using two complementary mouse models of CAR T cell immunotherapy, established inhibitory mediators secreted into the tumor microenvironment that allow evasion of immunity will be inhibited in attempts to augment T cell anti-tumor efficacy. The training component of this proposal includes formal coursework, participation in a rich environment of post-doctoral lectures and seminars in thoracic/pleural oncology, acquisition of advanced laboratory techniques, and individual mentoring. This project will take place under the supervision of Dr. Steven Albelda who is the Director of Lung Research and the Thoracic Oncology Laboratory at the University of Pennsylvania; and Dr. Carl June who is the Director of Translational Research at the Abramson Cancer Center at Penn. Dr. Albelda and Dr. June have mentored over 100 trainees. In addition, an advisory committee of distinguished scientists will provide experimental assistance, intellectual guidance, and career advice throughout the duration of this award.