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

• 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
• 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

 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，儿科脑肿瘤的标准治疗几乎总是会使幸存的儿童留下深刻的终身神经缺陷。开发高效和特异性的治疗方法，可以提高目前治疗方式的疗效，而不会产生额外的毒性，这是未来的一个非常高的优先事项 侵袭性小儿脑肿瘤的管理。连续性细胞治疗，包括肿瘤特异性淋巴细胞的离体扩增和在非清髓性（NMA）和清髓性（MA）预处理方案后再输注到患者体内，已成为难治性转移性黑色素瘤的一种非常有效的治疗方式。这种专门的细胞治疗策略已在接受NMA预处理的患者中实现了约50%的客观临床应答，在过继细胞治疗之前接受MA治疗的患者中达到了高达75%的客观临床应答。这些缓解还包括CNS内转移性病灶的持久和完全缓解率超过40%，表明脑对细胞免疫疗法的有效治疗并非难治性。与最近开发的和FDA批准的采用通路抑制剂的治疗策略相反，过继细胞疗法在晚期癌症患者中具有显著的治疗潜力。该提案提出了一种用于儿童胶质瘤过继细胞治疗的平台方法，该方法克服了迄今为止在很大程度上限制过继细胞治疗应用于黑色素瘤经验的许多挑战。扩增的肿瘤RNA负载的树突状细胞在癌症的免疫治疗中的使用提供了来自有限的手术活检标本或甚至脑脊髓液细胞离心涂片的肿瘤抗原的可再生资源。我们已经将加载RNA的树突状细胞作为用于从外周血扩增肿瘤特异性T细胞的呈递平台，进一步否定了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的需要。此外，我们已经在原位、耐辐射和耐替莫唑胺的恶性胶质瘤模型中表明，MA和NMA条件下的造血干细胞（HSC）在极大地促进过继转移淋巴细胞的瘤内运输和介导免疫排斥和治愈已建立的高度侵袭性肿瘤方面发挥了新的作用。这一建议将促进我们对HSC在浸润性恶性胶质瘤免疫排斥中的新作用的机制理解，并将这些知识应用于I/II期临床试验中对恶性胶质瘤儿童的过继细胞治疗。