Clinical Trials using TCR Transduced T Cells for Adoptive Immunotherapy

来自早期临床试验的越来越多的证据表明，过继性免疫治疗可以介导已建立的肿瘤的消退，并且许多这些消退可以持久。迄今为止，最有治疗潜力的肿瘤反应性T细胞的来源是TIL。不幸的是，TIL需要切除肿瘤病变，这对所有恶性肿瘤甚至黑色素瘤患者都是不可行的，许多患者都有不可切除的疾病。为了克服这一障碍，我们证明了正常pbl来源的T细胞的特异性可以使用编码来自MART-1反应性T细胞克隆TIL 5的TCR α和β基因的逆转录病毒载体进行重定向。由此产生的TIL 5 TCR转导的T细胞培养物可以特异性识别装载MART-1肽的T2细胞和HLA-A2， MART-1黑色素瘤细胞。随后，TIL 5 TCR成为第一个用于治疗黑色素瘤患者的TCR基因修饰T细胞。虽然客观临床反应的数量很低，但这个I期试验和其他试验证明了产生TCR转导T细胞用于患者治疗的可行性，并且TCR转导T细胞可以安全使用。

There is mounting evidence from early stage clinical trials that indicate adoptive immunotherapy can mediate regression of established tumors and many of these regressions can be durable. So far, the source of tumor reactive T cells with the greatest therapeutic potential has been TIL. Unfortunately, TIL requires resection of tumor lesions which is not feasible for all malignancies and even for melanoma patients, many have unresectable disease. To circumvent this obstacle, we demonstrated that the specificity of normal PBL-derived T cells can be redirected using retroviral vectors encoding the TCR alpha and beta genes from the MART-1 reactive T cell clone TIL 5. The resulting TIL 5 TCR transduced T cell cultures could specifically recognize MART-1 peptide loaded T2 cells and HLA-A2, MART-1 melanoma cells. Subsequently, the TIL 5 TCR was the first TCR used to treat melanoma patients with TCR gene modified T ceils. While the number of objective clinical responses were low, this phase I trial and others demonstrated the feasibility of generating TCR transduced T cells for patient treatment and that TCR transduced T cells could be administered safely. Over the past decade, dozens of TCR genes have been cloned and characterized for their ability to engineer T cells to recognize virus infected cells and tumor cells. One area of intense study has been the impact of TCR affinity on antigen recognition. We reported a unique T cell clone (TIL 13S3I), an MHC class I restricted CD4 T cell which recognized the immunodominant epitope from tyrosinase presented by HLA-A2. The TIL 13831 TCR was subsequently cloned and was shown in mouse and human T cells to be able to transfer CDS-independent anti-tumor activity to other effectors. This TIL 13831 TCR had all of the properties consistent with a high affinity TCR. Adoptive transfer of transgenic T cells expressing the TIL 13831 TCR (h3T) and TIL 13S3I TCR transduced mouse T cells can mediate regression of established human and mouse melanoma. These preclinical mouse results and clinical trials using high affinity TCRs support the hypothesis that high affinity TCRs are superior to TCRs with low affinity for TCR gene transfer studies. In this project, our hypotheses are 1) TCR transduced T cells bearing a high affinity TCR that targets tyrosinase can be administered safely to melanoma patients pretreated with non-myeloablative chemotherapy, and 2) factors that lead to improved persistence of TCR transduced T cells will lead to improved therapeutic efficacy in cancer patients. To evaluate these hypotheses, we will first conduct a phase I dose escalation trial of TIL 13S3I TCR transduced T cells followed by phase II trial randomizing patients between TIL 13831 TCR transduced CD8 +/- CD4+ T cells to determine how CD4 T cells impact the persistence and function of TCR transduced CD8 T cells in vivo.