Use of Genetically Engineered T cells Targeting Tumor Stroma to Treat Lung Cancer

描述（由申请人提供）：免疫治疗的一个特别有前途的领域是过继性转移基因编程，患者来源的血液淋巴细胞转染嵌合抗原受体基因（CARs），结合T淋巴细胞的效应功能和抗体的能力，以非mhc限制的方式识别高特异性预先定义的表面抗原。CAR-T细胞疗法的成功依赖于靶向一种抗原，这种抗原在肿瘤中高度表达，但在正常组织中表达水平极低。迄今为止，仅针对癌细胞，然而，已经确定的是，超过最小尺寸，癌症的进展依赖于包含血管，炎症细胞和成纤维细胞的基质。这个提议的基本假设是破坏

DESCRIPTION (provided by applicant): One especially promising area of immunotherapy has been adoptive transfer of genetically programmed, patient-derived blood lymphocytes transfected with chimeric antigen receptor genes (CARs) to combine the effector functions of T lymphocytes with the ability of antibodies to recognize pre-defined surface antigens with high specificity in a non-MHC restricted manner. The success of CAR-T cell therapy depends on targeting an antigen that is highly expressed in tumors, but at minimal levels in normal tissues. To date, only cancer cells have been targeted, however, it is well established that beyond a minimal size, cancer progression is dependent on a stroma that contains blood vessels, inflammatory cells, and fibroblasts. The underlying hypothesis of this proposal is that destruction of stromal cells using CAR-T cells will alter the tumor microenvironment leading to inhibition of tumor growth in lung cancer. Because stromal cells are diploid and genetically stable, this could reduce the incidence of immune evasion. To test this hypothesis, we will target fibroblast activation protein (FAP), a stromal cell-surface protein highly expressed on cancer-associated fibroblasts in most human epithelial cancers, including lung cancers, but present at very low levels on normal adult tissues, except healing wounds and in some chronic inflammatory conditions. We propose the following specific aims: Aim 1. Evaluate the efficacy of retrovirally-transduced murine FAP-CAR T cells to inhibit the growth of lung cancers (using three mouse lung cancer models). Aim 2. Evaluate the mechanisms by which retrovirally-transduced murine FAP-CAR T cells inhibit the growth of tumors. Aim 3. Evaluate the combination of FAP-CAR T cells with chemotherapy (Aim 3A) and with a tumor-cell targeted CAR (mesothelin-CAR) (Aim 3B). Aim 4. Evaluate the efficacy and mechanisms of lentivirally-transduced human FAP-CAR T cells to inhibit the growth of human lung cancers in immunodeficient mice. In addition to obtaining answers to the scientific questions described above, completion of these aims will provide the preclinical data needed to implement a clinical trial for lung cancer. Funding for a potential FAP-CAR clinical trial is not requested in this proposal, but will be obtained through other support. If our strategy proves effective, this project will likely have additional significace beyond lung cancer, since FAP could be targeted in many tumors.