Enhancing Adoptive Immunotherapy Targeting Pediatric High-Grade Gliomas

 描述(申请人提供)：恶性脑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，儿童脑肿瘤的标准治疗几乎总是会给幸存的儿童留下严重的终身神经缺陷。开发高效和特定的治疗方法，能够在不增加毒性的情况下提高当前治疗方式的疗效，是未来非常重要的优先事项。 儿童侵袭性脑瘤的治疗。过继细胞治疗是治疗难治性转移性黑色素瘤的一种非常有效的治疗方法，它包括肿瘤特异性淋巴细胞的体外扩增和非清髓性(NMA)和清髓性(MA)预适应方案后的回输。这种专门的细胞治疗策略已经在大约50%接受NMA调理的患者和高达75%的在过继细胞治疗之前接受MA治疗的患者中取得了客观的临床反应。这些反应还包括对中枢神经系统内转移灶的持久和完全应答率超过40%，表明大脑对细胞免疫疗法的有效治疗并不是难治性的。与最近开发和FDA批准的使用通路抑制剂的治疗策略相比，过继细胞疗法在晚期癌症患者中具有显著的治疗潜力。这项提议推进了儿童胶质瘤过继细胞治疗的平台方法，克服了迄今为止在很大程度上限制了过继细胞治疗在黑色素瘤体验中的应用的许多挑战。扩增的肿瘤RNA负载的树突状细胞在癌症的免疫治疗中的应用提供了一种可再生的肿瘤抗原来源，可以从有限的手术活检标本中获得，甚至可以从脑脊液细胞浆中获得。我们采用了装载RNA的树突状细胞作为从外周血中扩增肿瘤特异性T细胞的呈递平台，进一步消除了从有限的肿瘤标本中分离和扩增足够的肿瘤浸润性淋巴细胞的需要。此外，我们在原位、耐辐射和抗替莫唑胺的恶性胶质瘤模型中显示，在MA和NMA条件下的造血干细胞(HSCs)在极大地促进过继转移的淋巴细胞在肿瘤内的运输以及介导免疫排斥反应和已建立的高侵袭性肿瘤的治愈方面发挥了新的作用。这项建议将促进我们对HSCs在浸润性恶性胶质瘤免疫排斥反应中的新作用的机制的理解，并将这一知识应用于I/II期临床试验背景下的儿童恶性胶质瘤的过继细胞治疗。

 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.