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: 8819181
• 负责人: CAROL A KRUSE
• 金额: $ 1.47万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8819181
• 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; 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; 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.

描述（由申请人提供）：我们研究的广泛、长期目标是： i) 开发和优化治疗脑肿瘤的细胞免疫治疗方法； ii) 更好地了解针对中枢神经系统 (CNS) 肿瘤的细胞策略产生的免疫反应机制。为了实现这些目标，我们积极探索使用自体和同种异体效应细胞治疗人类恶性胶质瘤的局部过继免疫疗法的排列。我们通过腔内同种异体反应性细胞毒性 T 淋巴细胞 (aCTL) 的过继转移，取得了临床前和临床的成功，这些细胞对肿瘤宿主的人类白细胞抗原 (HLA) 敏感。患者淋巴细胞上表达的 HLA 抗原也在脑肿瘤细胞上表达，但在正常脑细胞（如神经元和神经胶质细胞）上不表达。因此，携带肿瘤的宿主自身的 HLA 提供了一种通过对其敏感的 CTL 选择性选择性杀死神经胶质瘤细胞的方法。本研究的目的 1 是评估在复发性神经胶质瘤患者中瘤内递送 aCTL/IL-2 的安全性和可行性。 I 期临床研究将涉及十个月的同种反应性 CTL 治疗。只有在恶性胶质瘤的标准放疗和化疗失败后才会进行免疫治疗。与目标 1 中观察到的临床毒性相关的数据将与并行进行的实验室研究相关联。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 输注物的分子/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-α的细胞毒性T细胞表型的倍数增加。暴露于相关靶细胞后。实验室研究的目标 3 将通过评估治疗前和治疗后患者外周血单核细胞在受到相关靶点刺激时分泌 Th1 和 Th2 细胞因子的能力，确定患者内源性免疫细胞对治疗的反应。我们还将通过在输注 aCTL 后特定时间分析切除腔内的细胞和细胞因子来评估局部中枢神经系统宿主的抗肿瘤免疫反应。因此，这是一个真正的双向临床项目，与我们上述的长期目标直接相关。

项目成果

Fascin-1 knock-down of human glioma cells reduces their microvilli/filopodia while improving their susceptibility to lymphocyte-mediated cytotoxicity.

Fascin-1 敲低人神经胶质瘤细胞可减少其微绒毛/丝状伪足，同时提高其对淋巴细胞介导的细胞毒性的易感性。

• 发表时间: 2015
• 作者: Hoa, Neil T;Ge, Lisheng;Erickson, Kate L;Kruse, Carol A;Cornforth, Andrew N;Kuznetsov, Yurii;McPherson, Ale;Martini, Filippo;Jadus, Martin R
• 通讯作者: Jadus, Martin R

Exploring the Therapeutic Efficacy of Glioma Vaccines Based on Allo- and Syngeneic Antigens and Distinct Immunological Costimulation Activators.

探索基于同种异体和同基因抗原以及不同免疫共刺激激活剂的胶质瘤疫苗的治疗效果。

• 发表时间: 2012
• 作者: Stathopoulos, Apostolos;Pretto, Chrystel;Devillers, Laurent;Pierre, Denis;Hofman, Florence M;Epstein, Alan L;Farghadani, Hooman;Kruse, Carol A;Jadus, Martin R;Chen, Thomas C;Schijns, Virgil E J C
• 通讯作者: Schijns, Virgil E J C

The potential for genetically altered microglia to influence glioma treatment.

基因改变的小胶质细胞影响神经胶质瘤治疗的潜力。

• 发表时间: 2013-09
• 作者: Li, W;Holsinger, R M D;Kruse, C A;Flügel, A;Graeber, M B
• 通讯作者: Graeber, M B

Small cell lung cancer cells express the late stage gBK tumor antigen: a possible immunotarget for the terminal disease.

小细胞肺癌细胞表达晚期 gBK 肿瘤抗原：晚期疾病的可能免疫靶点。

• 发表时间: 2014-05-15
• 期刊: American journal of translational research
• 作者: N. Hoa;Lisheng Ge;R. Tajhya;C. Beeton;A. Cornforth;A. Abolhoda;N. Lambrecht;M. Dacosta;Ouyang Yi;Anthony Mai;E. Hong;Judy Shon;M. Hickey;K. L. Erickson;C. Kruse;M. Jadus
• 通讯作者: M. Jadus

Evidence for the involvement of gamma delta T cells in the immune response in Rasmussen encephalitis.

γδT 细胞参与拉斯穆森脑炎免疫反应的证据。

• 发表时间: 2015-07-19
• 作者: Owens, Geoffrey C;Erickson, Kate L;Malone, Colin C;Pan, Calvin;Huynh, My N;Chang, Julia W;Chirwa, Thabiso;Vinters, Harry V;Mathern, Gary W;Kruse, Carol A
• 通讯作者: Kruse, Carol A