Adoptive Transfer of AlloCTL for Immunotherapy of Recurrent Gliomas

AlloCTL 过继转移用于复发性胶质瘤的免疫治疗

• 批准号: 8528757
• 负责人: CAROL A KRUSE
• 金额: $ 5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528757
• 关键词: Acute; Adoptive Immunotherapy; Adoptive Transfer; Aftercare; Aliquot; Allogenic; Anaplastic astrocytoma; Antigens; Autologous; Beds; Brain; Brain Neoplasms; CD3 Antigens; CD8B1 gene; Catheters; Cells; Central Nervous System Neoplasms; Characteristics; Clinical; Clinical Research; Cytotoxic T-Lymphocytes; Data; Diagnosis; Dose; Effector Cell; Enrollment; Excision; Exposure to; Glioblastoma; Glioma; Goals; Growth Factor; HLA Antigens; Health Sciences; Histologic; Human; Immune; Immune response; Immune system; Immunotherapy; Implant; Infusion procedures; Injection of therapeutic agent; Interferons; Interleukin-2; Laboratory Study; Liquid substance; Lymphocyte; Malignant Glioma; Malignant neoplasm of brain; Maximum Tolerated Dose; Molecular; Neuraxis; Neuroglia; Neurons; Operative Surgical Procedures; Patients; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Production; Proteins; Protocols documentation; Radiation; Reaction; Recurrence; Recurrent tumor; Regulatory T-Lymphocyte; Relative (related person); Research; Research Design; Research Subjects; Resected; Safety; Surface; Surgically-Created Resection Cavity; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Toxic effect; Training; base; brain cell; brain tissue; cell killing; chemotherapy; cytokine; cytotoxic; cytotoxicity; lymphoblast; mixed gliomas; neoplastic cell; oligodendroglioma; phase 1 study; pre-clinical; prevent; public health relevance; response; standard of care; success; tumor; tumor growth

DESCRIPTION (provided by applicant): The broad, long-term objectives of our research are: i) to develop and optimize cellular immunotherapy approaches for the treatment of brain tumors; and ii) to gain a better understanding of the mechanisms of immune responses generated by cell-based strategies targeting central nervous system (CNS) neoplasms. Toward these goals, we have actively explored permutations of local adoptive immunotherapy for human malignant gliomas with autologous and allogeneic effector cells. We have achieved both pre-clinical and clinical success with adoptive transfer of intracavitary alloreactive cytotoxic T lymphocytes (aCTL), which are sensitized to the tumor host's human leukocyte antigens (HLA). HLA antigens expressed on the patient's lymphocytes are also on brain tumor cells but not on normal brain cells such as neurons and glia. Thus, the tumor-bearing host's own HLA offers a means for targeted selective glioma cell kill by CTL sensitized to them. Aim 1 of this study is to assess the safety and feasibility of intratumoral delivery of aCTL/IL-2 in recurrent glioma patients. A Phase I clinical study will involve treatment with alloreactive CTL over ten months. The immune treatment will be administered only after the patients have failed standard radiation and chemotherapy for malignant glioma. Data relative to the clinical toxicity as observed in Aim 1 will be correlated with laboratory studies conducted in parallel. Aim 2 of the laboratory studies will determine molecular/cellular and functional characteristics of the donor aCTL infusates that may influence the clinical toxicity/response. To this end we will determine the cytotoxicity of the aCTL to relevant target, perform phenotypic analyses and determine the fold-increase in the cytotoxic T cell phenotype producing IFN-? upon exposure to relevant target cells. Aim 3 of the laboratory studies will determine the reaction of the patient's endogenous immune cells to the treatment by assessing the ability of patient peripheral blood mononuclear cells pre- and post-treatment to secret Th1 and Th2 cytokines when stimulated with relevant targets. We will also assess local CNS host anti-tumor immune responses by analyzing cells and cytokines within the resection cavities at specific times after the aCTL have been infused. Thus, this is a truly bi-directional clinical project that is directly related to our long-term objectives stated above. PUBLIC HEALTH RELEVANCE: The primary objective of our research is to train immune cells from healthy donors that are manipulated outside the body with various growth factors to recognize proteins on the surfaces of brain tumor cells that are not on normal brain cells. The immune cells are termed alloreactive cytotoxic T lymphocytes (aCTL) because they are sensitized to the tumor host's human leukocyte antigens (HLA). The immune treatment will be administered only after the patients have failed standard radiation and chemotherapy. The trained immune cells will be adoptively transferred into the surgically-resected tumor beds of patients diagnosed with malignant brain tumors. Data relative to the clinical toxicity and patient response to the treatment will be correlated with laboratory studies designed to determine if the antitumor effects are due alone to the immune cells given, or whether they also activate the patient's own immune system. This immunotherapy approach will help us gain a better understanding of the mechanisms of immune responses generated by cell-based strategies targeting tumors located in the central nervous system (CNS).

描述（由申请人提供）：我们研究的广泛，长期目标是：i）开发和优化细胞免疫疗法治疗脑肿瘤的方法； ii）可以更好地了解针对中枢神经系统（CNS）肿瘤的基于细胞的策略产生的免疫反应机制。朝向这些目标，我们积极探讨了具有自体和同种异体效应细胞的人类恶性神经胶质瘤的局部收养免疫疗法的排列。我们已经实现了临床前和临床成功，并通过卫生体内同种异体反应性细胞毒性T淋巴细胞（ACTL）的继承转移对肿瘤宿主的人类白细胞抗原（HLA）敏感。在患者的淋巴细胞上表达的HLA抗原也位于脑肿瘤细胞上，而不是在正常的脑细胞上，例如神经元和神经胶质细胞。因此，肿瘤宿主自己的HLA提供了一种对靶向选择性神经胶质瘤细胞杀死的手段，CTL对其敏感。本研究的目的1是评估ACTL/IL-2在复发性神经胶质瘤患者中的肿瘤内递送的安全性和可行性。 I期临床研究将涉及十个月内同种反应性CTL的治疗。免疫治疗只有在患者的标准放射线失败和恶性神经胶质瘤的化学疗法失败之后才能进行。与AIM 1中观察到的相对于临床毒性的数据将与并行进行的实验室研究相关。实验室研究的目标2将确定可能影响临床毒性/反应的供体ACTL注入的分子/细胞和功能特征。为此，我们将确定ACTL对相关靶标的细胞毒性，进行表型分析，并确定产生IFN-的细胞毒性T细胞表型中的折叠症？暴露于相关目标细胞后。实验室研究的目标3将通过评估患者外周血单核细胞和治疗后对秘密Th1和Th2细胞因子的能力，以确定患者内源性免疫细胞对治疗的反应。我们还将通过在ACTL被注入后的特定时间内分析切除腔中的细胞和细胞因子来评估局部CNS宿主抗肿瘤免疫反应。因此，这是一个真正的双向临床项目，与上述我们的长期目标直接相关。 公共卫生相关性：我们研究的主要目的是训练来自健康供体的免疫细胞，这些供体在体外被操纵，具有各种生长因子，以识别不在正常脑细胞上的脑肿瘤细胞表面上的蛋白质。免疫细胞称为同种异体细胞毒性T淋巴细胞（ACTL），因为它们对肿瘤宿主的人类白细胞抗原（HLA）敏感。免疫治疗只有在患者的标准放射疗法和化学疗法失败之后才能进行。受过训练的免疫细胞将被顺从地转移到被诊断为恶性脑肿瘤的患者的外科手术肿瘤床中。相对于临床毒性和患者对治疗的反应的数据将与旨在确定抗肿瘤效应是否仅由于给予的免疫细胞或是否也激活患者自身的免疫系统的实验室研究相关。这种免疫疗法方法将有助于我们更好地了解靶向位于中枢神经系统（CNS）的肿瘤的基于细胞的策略产生的免疫反应机制。