TCR Gene Modified T Cells for Adoptive Immunotherapy

最近在美国国家癌症研究所（NCI）外科分部进行的临床试验发现，将自体肿瘤反应性T细胞过继转移到预先接受非清髓性化疗的患者体内，可产生显著的持久的客观临床反应。这些研究中使用的T细胞是从黑色素瘤病变处采集的TIL。有两个关键问题限制了它在NCI之外的使用。首先，许多患者没有合适的肿瘤。其次，对大多数患者来说，很难分离和扩增肿瘤反应性T细胞到治疗数量。如果这种方法要超越实验阶段，就需要新的过继性T细胞转移方法。

Recent clinical trials conducted at the Surgery Branch of the National Cancer Institute (NCI) has have found that adoptive transfer of autologous tumor reactive T cells into patients preconditioned with nonmyeloablative chemotherapy leads to significant durable objective clinical responses. T cells used in these studies were TIL harvested from melanoma lesions. There are two key problems that have limited its use outside the NCI. First, many patients don't have suitable tumors TIL harvest. Second, it is difficult to isolate and expand tumor reactive T cells to therapeutic numbers for most patients. New approaches for adoptive T cell transfer are needed if this approach will make it beyond the experimental stage. We published the first report demonstrating that it was feasible to redirect the reactivity of normal PBL-derived T cells using retroviral vectors encoding TCR genes isolated from a MART-1 reactive T cell clone. This opened the possibility of providing any patient with a source of autologous tumor-reactive T cells capable of recognizing any antigen so long as a TCR was available which could recognize that antigen. This MART-1 reactive TCR was the first used to treat patients with TCR gene modified T cells demonstrating the feasibility and safety of using TCR gene modified T cells in humans. However, this trial and three others had fewer objective clinical response compared to TIL suggesting TCR gene modified T cells are less effective that TIL. Based on these trials, it is clear there are critical differences between these two cells types. Over the years, the field of TCR gene transfer has focused on TCR affinity, TCR pairing, and TCR expression. The biology of T cells engineered with viral vectors has largely been unexplored. We therefore hypothesize that TCR gene modified T cells are fundamentally different than "normal" T cells in how they respond to environmental factors. We further hypothesize that a better understanding of how TCR transduced T cells are impacted by lymphopenia, T cell help, activation-induced cell death (AICD), costimulation, and immune suppression will lead to better TCR transduced T cells for patient treatment. Based on these hypotheses, we developed this Program to improve the function of TCR gene modified T cells through a series of laboratory comparing TCR transduced T cells to normal T cells bearing the same TCR. When complimented with clinical trials, our highly integrated Program will advance the field of TCR gene transfer leading to their improved therapeutic efficacy not only for patients with melanoma but for patients with other malignancies and chronic viral infections.