Cell Therapy Core

最近的研究表明，过继T细胞转移(ACT)是治疗转移性癌症的有效方法。ACT最常见的抗原反应性T细胞来源是体外扩增的肿瘤浸润性淋巴细胞(TIL)或抗原刺激的PBL来源的T细胞。治疗ACT患者的主要限制之一是大量抗原反应性自体T细胞的可用性。为了绕过这一限制，我们首先证明了使用从肿瘤反应性T细胞克隆中分离出的编码TCRα和β基因的逆转录病毒载体来重定向T细胞的特异性是可能的。随后，我们和其他人证明了分离识别多种肿瘤和病毒抗原的TCR是可能的。由此产生的TCR转导的T细胞可以像抗原特异性T细胞一样有效地分泌细胞因子和杀伤靶标。第一个高亲和力的人类TCR的鉴定进一步推进了这一领域，这种TCR可以同时设计CD4+和CD8+T细胞来识别肿瘤细胞表达的抗原的生理水平。这些研究和其他研究开启了向大量患者提供ACT的可能性，无论他们产生抗肿瘤免疫的天然能力如何。 2006年，首次报道了TCR转导的T细胞在人类中的应用。本研究的结论是，TCR基因修饰的T细胞可以安全地应用于患者，并且有证据表明它们在体内具有抗肿瘤活性。随后，还发表了另外三项研究，支持在癌症患者中使用TCR转导的T细胞的安全性。在这些研究中，当使用高亲和力TCR时，客观的临床反应被观察到更高的频率。然而，TCR转导的T细胞治疗的临床应答率(12-30%)明显低于TIL治疗的患者(~50%)。因此，TCR转导的T细胞和TIL的生物学特性可能存在根本性差异，从而解释了临床应答率的差异。 这个程序需要一个一致的和可重现的老鼠和人类来源，直到13831 TCR转导的T细胞在整个项目中使用。因此，核心C的目标是为项目1-4提供高质量的TIL 13831 TCR转导的小鼠和人T细胞，用于其体外和体内研究，并为项目5的临床试验提供临床级别的TIL 13831 TCR转导的T细胞。

Recent studies have shown that adoptive T cell transfer (ACT) can be an effective treatment for patients with metastatic cancer. The most common source of antigen reactive T cells for ACT is ex vivo expanded tumor infiltrating lymphocytes (TIL) or antigen stimulated PBL-derived T cells. One of the main limitations to treating patients with ACT is the availability of large numbers of antigen reactive autologous T cells. To circumvent this limitation, we first demonstrated that it was possible to redirect the specificity of T cells using retroviral vectors encoding the TCR alpha and beta genes isolated from a tumor-reactive T cell clone. Subsequently, we and others have shown that it is possible to isolate TCR's that recognize a wide variety of tumor and viral antigens. The resulting TCR transduced T cells can secrete cytokines and lyse targets as efficiently as antigen specific T cells. The field was further advanced by the identification of the first high affinity human TCR that could engineer both CD4+ and CD8+ T cells to recognize the physiologic levels of antigen expressed by tumor cells. These studies and others have open the possibility of providing ACT to a large number of patients regardless of their natural ability to generate anti-tumor immunity. In 2006, the first use of TCR transduced T cells was reported in humans. The conclusions from this study were that TCR gene modified T cells can be safely administered to patients and there was evidence of their anti-tumor activity in vivo. Subsequently, three other studies have been published which support the safety of using TCR transduced T cells in cancer patients. In these studies, objective clinical responses were observed at higher frequencies when high affinity TCRs were used. However, the frequency of the clinical responses in patients treated with TCR transduced T cells (12-30%) was substantially less than in patient treated with TIL (~50%). Therefore, there may be fundamental differences between the biology of TCR transduced T cells and TIL which account for the differences in the clinical response rates. What is needed for this Program is a consistent and reproducible source of mouse and human TIL 13831 TCR transduced T cells for use throughout the Program. Therefore, the goal of Core C is to provide Projects 1-4 with high quality TIL 13831 TCR transduced mouse and human T cells for their in vitro and in vivo studies and to generate clinical grade TIL 13831 TCR transduced T cells for the clinical trials in Project 5.