TCR Gene Modified T Cells for Adoptive Immunotherapy

美国国家癌症研究所(NCI)外科分部最近进行的临床试验发现，将自体肿瘤反应性T细胞过继转移到接受非清髓性化疗预适应的患者体内，可以产生显著的持久客观临床反应。这些研究中使用的T细胞是从黑色素瘤病变中获取的TIL。有两个关键问题限制了它在NCI之外的使用。首先，许多患者在收获之前没有合适的肿瘤。其次，对于大多数患者来说，分离和扩增肿瘤反应性T细胞到治疗数量是困难的。如果这种方法能够超过实验阶段，就需要采用新的方法进行T细胞移植。 我们发表了第一份报告，证明了使用从Mart-1反应性T细胞克隆中分离出的编码TCR基因的逆转录病毒载体来重定向正常PBL来源的T细胞的反应性是可行的。这为任何患者提供能够识别任何抗原的自体肿瘤反应性T细胞来源打开了可能性，只要有TCR可以识别该抗原。这种MART-1反应性TCR首次用于治疗TCR基因修饰的T细胞患者，证明了在人类中使用TCR基因修饰的T细胞的可行性和安全性。然而，与TIL相比，这项试验和其他三项试验的客观临床反应较少，这表明TCR基因修饰的T细胞的疗效不如TIL。根据这些试验，很明显，这两种细胞类型之间存在着关键的差异。 多年来，TCR基因转移的研究领域主要集中在TCR亲和力、TCR配对和TCR表达。用病毒载体设计的T细胞的生物学在很大程度上还没有被探索。因此，我们假设TCR基因修饰的T细胞在对环境因素的反应方面与“正常”T细胞有根本的不同。我们进一步假设，更好地了解TCR转导的T细胞如何受到淋巴细胞减少、T细胞帮助、激活诱导细胞死亡(AICD)、共刺激和免疫抑制的影响，将导致更好的TCR转导的T细胞用于患者治疗。在这些假设的基础上，我们开发了这一程序，通过一系列实验室比较转导TCR的T细胞和携带相同TCR的正常T细胞来改善TCR基因修饰的T细胞的功能。与临床试验相结合，我们高度集成的计划将推进TCR基因转移领域，从而不仅对黑色素瘤患者，而且对其他恶性肿瘤和慢性病毒感染患者提高治疗效果。

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.