Enhancing Adoptive Immunotherapy Targeting Pediatric High-Grade Gliomas

加强针对儿童高级别胶质瘤的过继免疫治疗

基本信息

批准号：
9316587
负责人：
DUANE A. MITCHELL
金额：
$ 63.39万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9316587
关键词：
Adjuvant Adoptive Immunotherapy Adoptive Transfer Adult Advanced Malignant Neoplasm Affinity Animals Antigen Receptors Antigen Targeting Area Autologous Avidity Biopsy Specimen Brain CD8B1 gene Cancer Etiology Cerebrospinal Fluid Cessation of life Child Childhood Childhood Brain Neoplasm Childhood Glioma Childhood Malignant Brain Tumor Clinical Clinical Protocols Clinical Trials Complex Coupled Cytotoxic T-Lymphocyte-Associated Protein 4 Dendritic Cells Development Diagnosis Disease Dissection Engineering Evaluation Excision FDA approved Future Genetic Engineering Glioma Hematologic Neoplasms Hematopoietic stem cells High Dose Chemotherapy Human Immunocompetent Immunologics Immunotherapeutic agent Immunotherapy In complete remission Infusion procedures Intracranial Neoplasms Intravenous Knowledge Lead Lesion Lymphocyte Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Mediating Metastatic Melanoma Modality Modeling Mus Myeloablative Chemotherapy Nature Neoplasm Metastasis Neuraxis Neurologic Deficit Newly Diagnosed Normal tissue morphology Operative Surgical Procedures Pathway interactions Patients Phase Physiologic pulse Play Population RNA Radiation Refractory Regimen Research Resistance Resources Role Solid Solid Neoplasm Specimen Spinal System T-Cell Receptor T-Lymphocyte Therapeutic Time Toxic effect Translations Treatment Efficacy Treatment Protocols Tumor Antigens Tumor Escape Tumor Expansion Tumor Immunity Tumor-Infiltrating Lymphocytes Vaccination cancer therapy childhood cancer mortality chimeric antigen receptor combinatorial conditioning effective therapy experience improved in vivo inhibitor/antagonist irradiation melanoma mouse model neoplastic cell novel novel therapeutics pediatric patients peripheral blood public health relevance radioresistant receptor reconstitution response standard care success targeted treatment temozolomide therapy outcome therapy resistant trafficking treatment strategy tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Malignant brain tumors are the second most common cause of cancer-related deaths in children. Furthermore, due to the sensitive nature of the developing central nervous system, standard treatments for pediatric brain tumors almost invariably leave surviving children with profound and lifelong neurologic deficits. The development of highly effective and specific therapies that can increase the efficacy of current treatment modalities without additional toxicity is an extraordinarily high priority for the future management of invasive pediatric brain tumors. Adoptive cellular therapy, involving the ex vivo expansion of tumor-specific lymphocytes and re-infusion into patients following non-myeloablative (NMA) and myeloablative (MA) conditioning regimens has emerged as a remarkably effective treatment modality for refractory metastatic melanoma. This specialized cellular treatment strategy has achieved objective clinical responses in approximately 50% of patients receiving NMA conditioning and up to 75% of patients receiving MA treatment prior to adoptive cellular therapy. These responses have also included a greater than 40% durable and complete response rate of metastatic lesions within the CNS, demonstrating that the brain is not refractory to effective treatment by cellular immunotherapy. In contrast to recently developed and FDA-approved treatment strategies employing pathway inhibitors, adoptive cellular therapy has significant curative potential in patients with advanced cancer. This proposal advances a platform approach to adoptive cellular therapy for pediatric gliomas that overcomes many of the challenges that, to date, have largely limited the application of adoptive cellular therapy to the melanoma experience. The use of amplified tumor RNA-loaded dendritic cells in immunotherapeutic treatment of cancers provides a renewable resource of tumor antigen from limited surgical biopsy specimens or even cerebral spinal fluid cytospins. We have adapted RNA-loaded dendritic cells as a presentation platform for expanding tumor-specific T cells from the peripheral blood, furthermore negating the need to isolate and expand sufficient tumor-infiltrating lymphocytes from limited tumor specimens. Additionally, we have shown in an orthotopic, radiation-resistant, and temozolomide-resistant, malignant glioma model that hematopoietic stem cells (HSCs) under both MA and NMA conditioning play a novel role in greatly facilitating the intratumoral trafficking of adoptively transferred lymphocytes and mediating the immunologic rejection and cure of established and highly-invasive tumors. This proposal will advance our mechanistic understanding of the novel role for HSCs in the immunologic rejection of infiltrative malignant gliomas and apply that knowledge to advance adoptive cellular therapy for children with malignant gliomas in the context of a phase I/II clinicl trial.

描述（由适用提供）：恶性脑肿瘤是儿童与癌症相关死亡的第二大最常见原因。此外，由于发展中枢神经系统的敏感性，针对小儿脑肿瘤的标准治疗方法几乎总是使生存儿童患有深远而终生的神经系统缺陷。发展高效和特定的疗法，可以提高当前治疗方式而没有其他毒性的有效性侵入性小儿脑肿瘤的管理。涉及非乳阻动剂（NMA）和骨髓性（MA）调节治疗方案后，涉及肿瘤特异性淋巴细胞的离体扩张并重新输注患者的过继细胞疗法已成为一种非常有效的治疗方法，用于冷冻转移性梅兰瘤。这种专门的细胞治疗策略已在接受NMA调节的患者中达到了客观的临床反应，并且在收养细胞治疗之前接受MA治疗的患者中最多可以接受75％。这些反应还包括中枢神经系统内转移性病变的耐用性和完全反应率，这表明大脑对通过细胞免疫疗法有效治疗不耐受。与最近开发和FDA批准的治疗策略相反，使用途径抑制剂，自适应细胞疗法在晚期癌症患者中具有显着的治疗潜力。该建议推进了一种适应性细胞疗法针对小儿神经胶质瘤的平台方法，该方法克服了许多挑战，迄今为止，这些挑战在很大程度上限制了适应性细胞疗法在黑色素瘤体验中的应用。在癌症的免疫治疗治疗中使用扩增的肿瘤RNA的树突状细胞提供了可再生的肿瘤抗原资源，这些资源来自有限的手术活检标本，甚至是脑脊髓液体细胞植物。我们已经适应了RNA负载的树突状细胞，作为一种呈现平台，用于从外周血扩展肿瘤特异性T细胞，此外，否定了从有限肿瘤标本中分离和扩展足够的肿瘤浸润淋巴细胞的需求。此外，我们在直齿，抗辐射抗性和抗苯乙酰胺的恶性神经瘤模型中表明，在MA和NMA条件下，造血干细胞（HSCS）在自适应转移的淋巴细胞内的肿瘤内肿瘤和非疾病中的肿瘤和contrandiation均具有较大的作用，并高度地支持淋巴细胞的肿瘤和co虫，并高度地均被指示，并高度地均被指示，并高度均被统治。该提案将提高我们对HSC在浸润性恶性神经胶质瘤免疫排斥中的新作用的机械理解，并在I/II期临床试验的背景下应用这些知识来推进恶性神经胶质瘤儿童的过继细胞疗法。