CLINICAL TRIALS USING TCR TRANSDUCED T CELL 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: 8744936
• 负责人: MICHAEL I. NISHIMURA
• 金额: $ 73.5万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-04 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8744936
• 关键词: Adoptive Immunotherapy; Adoptive Transfer; Affinity; Antigens; Area; CD4 Positive T Lymphocytes; 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 a and p 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 CDS +/- CD4+ T cells to determine how CD4 T cells impact the persistence and function of TCR transduced CDS T cells in vivo.

早期临床试验中有越来越多的证据表明，收养免疫疗法可以介导已建立的肿瘤的回归，其中许多回归可能是持久的。到目前为止，肿瘤反应性T细胞具有最大的治疗潜力。不幸的是，TIL需要切除肿瘤病变，这对于所有恶性肿瘤，甚至对于黑色素瘤患者都不可行，许多患者都有无法切除的疾病。 To circumvent this obstacle, we demonstrated that the specificity of normal PBL derived T cells can be redirected using retroviral vectors encoding the TCR a and p 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.随后，TIL 5 TCR是第一个用于治疗TCR基因改性TCEIL的TCR。虽然客观的临床反应数量很少，但该阶段I试验以及其他试验表明，产生TCR转导的T细胞进行患者治疗的可行性，并且可以安全地管理TCR转导的T细胞。在过去的十年中，数十个TCR基因的克隆和特征是它们具有识别病毒感染细胞和肿瘤细胞的能力。强烈研究的一个领域是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 13S3I），这是一种MHC I类限制的CD4 T细胞，它从HLA-A2呈现的酪氨酸酶识别出免疫主流表位。随后将TIL 13831 TCR克隆，并在小鼠和人T细胞中显示，以便能够将无关CD的抗肿瘤活性转移到其他效应子中。直到13831 TCR具有与高亲和力TCR一致的所有属性。表达TIL 13831 TCR（H3T）和TIL 13S3I TCR转导的小鼠T细胞的转基因T细胞的产物转移可以介导已建立的人类和小鼠黑色素瘤的回归。这些临床前小鼠的结果和使用高亲和力TCR的临床试验支持了以下假设：高亲和力TCR优于TCR，对TCR基因转移研究的亲和力低。在这个项目中，我们的假设是1）具有高亲和力TCR的TCR转导的TCR细胞，该TCR可以安全地施用酪氨酸酶的酪氨酸酶，以安全地施用对通过非毛层性化学疗法预处理的黑色素瘤患者，而2）导致TCR转移T细胞持久性的因素会导致改善癌症患者的治疗效果。为了评估这些假设，我们将首先进行TIL 13S3I TCR转导的T细胞的I期剂量升级试验，然后进行II阶段试验，然后在TIL 13831 TCR TCR之间随机对患者进行随机转导的CDS +/- CD4 + T细胞，以确定CD4 T细胞如何影响TCR转移CDS T细胞在VIV中的持久性和功能。