IMPACT OF AICD ON TCR TRANSDUCED T CELLS FOR ADOPTIVE IMMUNOTHERAPY

AICD 对用于过继免疫治疗的 TCR 转导 T 细胞的影响

• 批准号: 8744932
• 负责人: MICHAEL I. NISHIMURA
• 金额: $ 29.72万
• 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/8744932
• 关键词: Address; Adoptive Cell Transfers; Adoptive Immunotherapy; Affect; Affinity; Antigens; Antioxidants; Autologous; Avidity; Back; Biology; Blood; Cell Death; Cell Death Signaling Process; Cells; Clinical Trials; Cytotoxic T-Lymphocytes; Data; Development; Effector Cell; Evaluation; Frequencies; Gene-Modified; Generations; Genes; Human; Immune; Immunotherapy; In Vitro; Lead; Link; MAPK8 gene; MEL Gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Memory; Modeling; Mus; Outcome; Oxidation-Reduction; Oxidative Stress; Patients; Population; Process; Proteins; Protocols documentation; RNA Interference; Regulation; Resistance; Retroviral Vector; Signal Transduction; Signal Transduction Pathway; Solid Neoplasm; T cell therapy; T-Cell Activation; T-Cell Development; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Thioredoxin; Transgenic Model; Transgenic Organisms; Tumor Antigens; Tumor-Infiltrating Lymphocytes; cancer therapy; catalase; cellular transduction; fighting; genetically modified cells; human AMID protein; immunogenic; improved; in vivo; inhibitor/antagonist; meetings; melanoma; neoplastic cell; prevent; research study; response; success; tool; translational approach; tumor; vector

Adoptive T cell therapy (ACT) can lead to impressive results but the frequency of success is low. Generally success correlates with persistence ofthe adoptively transferred T cells. Our results indicate that repetitive TCR stimulation, which occurs during ACT leads to activation induced cell death (AICD) of CDS effector cells. Thus AICD may contribute to poor persistence of adoptively transferred T cells. Recently, it has become possible to genetically modify autologous T cells by transduction with a tumor-specific TCR such as the high affinity TIL13S3i TCR central to this application. While little is known about the biology of these genetically modified cells, we show that they also undergo AICD, Thus a feasible translational approach to enhance persistence of genetically modified T cells will be to insert an additional protective gene into the vector expressing the TlL1383i TCR. Therefore, it will be necessary to understand the signal transduction pathways leading to AICD. Our preliminary data identify JNK, p53, and AIF as mediators of AICD in T cells expressing a native TCR. However, similarities and differences between T cells expressing a native vs. a transduced TCR as well as downstream mediators and remain to be elucidated. We will therefore compare AICD and anti-tumor efficacy between T cells natively expressing the TlL1383i (derived from the h3T transgenic model) and T cells that have been transduced with the TlL31S3i TCR. We observed that ROS generation is a common phenomenon associated with AICD and that pharmacological inhibition with ROS scavenger results in protection from cell death without interfering with T cell activation, which places redox regulation at a central point for therapeutic intervention. It is our hypothesis is that genetically enhancing the antioxidant capacity of TIL1383i TCR transduced T cells will lead to specific and sustained protection from AICD thereby increasing persistence, memory pool development and anti-tumor efficacy following adoptive T cell transfer Our aims are: Specific Aim 1. To dissect the mechanism of AICD in TCR transduced T cells after repetitive TCR stimulation. Specific Aim 2. To determine how increasing the antioxidant capacity of TCR transduced T cells impacts, survival, function, and memory development in vitro. Specific Aim 3. To evaluate how increased antioxidant capacity of adoptively transferred TCR transduced T cells affects their persistence and memory development as well as tumor regression in vivo. Our approach could directly impact ongoing clinical trials, in which genetically modified T cells are used for immunotherapy of melanoma.

连续性T细胞疗法（ACT）可以产生令人印象深刻的结果，但成功的频率很低。一般来说，成功与过继转移的T细胞的持久性相关。我们的结果表明，在ACT期间发生的重复TCR刺激导致CDS效应细胞的活化诱导细胞死亡（AICD）。因此，AICD可能导致过继转移的T细胞的持久性差。最近，已经可以通过用肿瘤特异性TCR（例如对该应用至关重要的高亲和力TIL 13S3i TCR）转导来遗传修饰自体T细胞。虽然对这些遗传修饰的细胞的生物学知之甚少，但我们表明它们也经历AICD。因此，增强遗传修饰的T细胞的持久性的可行的翻译方法将是将另外的保护性基因插入表达T1L1383i TCR的载体中。因此，有必要了解导致AICD的信号转导途径。我们的初步数据确定JNK，p53，和AIF作为介导的AICD在T细胞表达天然TCR。然而，表达天然与转导的TCR以及下游介体的T细胞之间的相似性和差异仍有待阐明。因此，我们将比较天然表达T1L1383i的T细胞（来源于h3T转基因模型）和已经用T1L31S3i TCR转导的T细胞之间的AICD和抗肿瘤功效。我们观察到ROS产生是与AICD相关的常见现象，并且用ROS清除剂的药理学抑制导致保护免于细胞死亡而不干扰T细胞活化，这将氧化还原调节置于治疗干预的中心点。我们的假设是，在遗传上增强TIL 1383 i TCR转导的T细胞的抗氧化能力将导致特异性和持续的抗AICD保护，从而增加过继性T细胞转移后的持久性、记忆池发展和抗肿瘤功效。我们的目标是：探讨TCR转导的T细胞在反复TCR刺激后发生AICD的机制。具体目标2。确定增加TCR转导的T细胞的抗氧化能力如何影响体外存活、功能和记忆发育。具体目标3。评估过继转移的TCR转导的T细胞的抗氧化能力增加如何影响它们的持久性和记忆发展以及体内肿瘤消退。我们的方法可以直接影响正在进行的临床试验，其中遗传修饰的T细胞用于黑色素瘤的免疫治疗。