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（由申请人提供）：恶性脑肿瘤是儿童癌症相关死亡的第二大常见原因。此外，由于发育中的中枢神经系统的敏感性，小儿脑肿瘤的标准治疗几乎总是让幸存的儿童罹患癌症。开发高效且特异性的疗法，可以提高当前治疗方式的疗效，而不产生额外的毒性，是未来的当务之急。侵袭性儿童脑肿瘤的治疗，包括离体扩增肿瘤特异性淋巴细胞并在非清髓性（NMA）和清髓性（MA）调理方案后重新输注到患者体内，已成为一种显着有效的治疗方式。这种专门的细胞治疗策略在接受 NMA 调理的患者和在过继性细胞治疗之前接受 MA 治疗的患者中达到了客观的临床反应。缓解率还包括中枢神经系统内转移性病变的持久和完全缓解率超过 40%，这表明大脑对于细胞免疫疗法的有效治疗并不难治，与最近开发和 FDA 批准的采用途径抑制剂的治疗策略相比，过继细胞疗法对晚期癌症患者具有显着的治疗潜力，该提案提出了一种用于儿童神经胶质瘤过继细胞疗法的平台方法，克服了迄今为止在很大程度上限制过继细胞疗法在黑色素瘤中的应用的许多挑战。在癌症的免疫治疗中使用扩增的肿瘤RNA负载树突状细胞，可以从有限的手术活检标本甚至脑脊髓液细胞离心涂片中获得肿瘤抗原的可再生资源，我们已经将负载RNA的树突状细胞用作扩展的展示平台。外周血中的肿瘤特异性 T 细胞，此外，无需从有限的肿瘤标本中分离和扩增足够的肿瘤浸润淋巴细胞。抗辐射、抗替莫唑胺的恶性神经胶质瘤模型表明，造血干细胞 (HSC) 在 MA 和 NMA 条件下发挥着新的作用，极大地促进过继转移淋巴细胞的瘤内运输，并介导已建立和高度复发的免疫排斥和治愈。 -侵袭性肿瘤。该提案将增进我们对 HSC 在浸润性恶性神经胶质瘤免疫排斥中的新作用的机制理解，并应用该知识来推进在 I/II 期临床试验中对患有恶性胶质瘤的儿童进行过继细胞疗法。