Clinical Trials using TCR Transduced T Cells for Adoptive Immunotherapy

使用 TCR 转导 T 细胞进行过继免疫治疗的临床试验

• 批准号: 8555361
• 负责人: DAVID J COLE
• 金额: $ 69.33万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555361
• 关键词: Adoptive Immunotherapy; Adoptive Transfer; Affinity; Antigens; Area; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cell Culture Techniques; Cell physiology; Cells; Clinical; Clinical Trials; Cohort Studies; Dendritic Cells; Disease; Dose; Engineering; Enrollment; Excision; Frequencies; Gene Transfer; Gene-Modified; Genes; HLA-A2 Antigen; Human; Immunodominant Epitopes; Immunologics; Infusion procedures; Lead; Lesion; Leukocytes; MHC Class I Genes; MLANA gene; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Melanoma; Monophenol Monooxygenase; Mus; Patients; Peptides; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Physiology; Process; Property; Randomized; Relative (related person); Reporting; Retroviral Vector; Safety; Source; Specificity; Staging; T-Lymphocyte; Therapeutic; Transgenic Organisms; Treatment Efficacy; Unresectable; Virus; cancer therapy; cellular transduction; chemotherapy; improved; in vivo; melanoma; neoplastic cell; patient population; pre-clinical; programs; response; tumor

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.

越来越多的早期临床试验证据表明，过继免疫治疗可以介导已建立的肿瘤消退，其中许多消退可以持久。到目前为止，具有最大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，这对于所有恶性肿瘤都是不可行的，甚至对于黑色素瘤患者，许多患者患有不可切除的疾病。为了规避这一障碍，我们证明了正常PBL衍生的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。所得到的TIL 5 TCR转导的T细胞培养物可以特异性识别负载MART-I肽的T2细胞和HLA-A2、MART-I黑素瘤细胞。随后，TIL 5 TCR是第一个用于治疗具有TCR基因修饰的T细胞的黑素瘤患者的TCR。虽然客观临床应答的数量较低，但该I期试验和其他试验证明了产生TCR转导的T细胞用于患者治疗的可行性，并且可以安全地施用TCR转导的T细胞。 在过去的十年中，已经克隆了数十个TCR基因，并表征了它们改造T细胞以识别病毒感染细胞和肿瘤细胞的能力。深入研究的一个领域是TCR亲和力对抗原识别的影响。我们报道了一个独特的T细胞克隆（TIL 13 S3 I），一个MHC I类限制性CD 4 T细胞，它识别HLA-A2呈递的酪氨酸酶的免疫显性表位。随后克隆了TIL 13831 TCR，并在小鼠和人T细胞中显示能够将不依赖于⑶ S的抗肿瘤活性转移至其他效应物。该TIL 13831 TCR具有与高亲和力TCR一致的所有性质。表达TIL 13831 TCR（h3 T）和TIL 13 S31 TCR转导的小鼠T细胞的转基因T细胞的连续转移可介导已建立的人和小鼠黑素瘤的消退。这些临床前小鼠结果和使用高亲和力TCR的临床试验支持了以下假设：对于TCR基因转移研究，高亲和力TCR上级具有低亲和力的TCR。 在这个项目中，我们的假设是：1）TCR转导的T细胞携带高亲和力TCR，其靶向 酪氨酸酶可以安全地施用于用非清髓性化疗预处理的黑素瘤患者，和2）导致TCR转导的T细胞的持续性改善的因素将导致癌症患者中治疗功效的改善。为了评估这些假设，我们将首先进行TIL 13 S31 TCR转导的T细胞的I期剂量递增试验，然后进行II期试验，将患者随机分配到TIL 13831 TCR转导的CD 8 +/-CD 4 + T细胞之间，以确定CD 4 T细胞如何影响体内TCR转导的CD 8 T细胞的持久性和功能。