Adoptive Immunotherapy for GBM During Hematopoietic Recovery from Temozolomide

描述(由申请人提供)：胶质母细胞瘤(GBM)是一种普遍致命的疾病，有效的治疗受到正常组织附带损伤的限制。针对肿瘤特异性抗原的免疫治疗有可能精确地靶向浸润性脑肿瘤，而对周围口才的损害有限。包括我们在内的四个独立实验室最近的发现和确认，人类巨细胞病毒(CMV)在高比例的基底膜内传播，而不会感染周围的正常大脑，这为针对具有良好特性和高度免疫原性的病毒靶点进行脑肿瘤免疫治疗提供了一个无与伦比的机会。我们最近完成了一项临床试验，评估CMV pp65 RNA负载的树突状细胞(DC)疫苗在新诊断的GBM患者中的应用，该疫苗显示出良好的免疫学和临床反应。虽然DC疫苗增加了CMV特异性细胞反应，但这些反应的大小没有达到急性病毒感染时通常诱导的水平，也没有反映与慢性病毒保护性免疫相关的多功能效应表型。然而，我们已经证明，在体外扩增CMV特异性T细胞，使用RNA冲击的DC可以产生来自GBM患者的显著的多功能CMV特异性T细胞反应，强调过继细胞治疗是恢复这些患者有效的多功能CMV免疫和潜在根除CMV相关星形细胞瘤的潜在策略。在这项建议中，我们旨在评估针对巨细胞病毒pp65的过继细胞疗法在新诊GBM患者TMZ诱导的淋巴细胞减少症的造血恢复过程中的安全性和有效性。我们将在一项I/II期临床试验的背景下，探讨同时使用pp65 RNA脉冲DC疫苗来延长过继转移的T细胞体内持久性和扩张性的能力。这项研究有可能显著改进目前对GBM患者的现有治疗方法，并为过继细胞疗法提供一种平台策略，该策略可能适用于其他恶性肿瘤的免疫治疗。 公共卫生相关性：这项研究的意义在于，它可能会推进一种治疗恶性脑瘤的新方法，并提供一种可以应用于许多其他癌症的治疗策略。癌症治疗的改进在改善公共健康和受恶性疾病影响的患者的生活质量方面具有重大潜力。

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is universally fatal, and effective therapy is limited by collateral damage to normal tissue. Immunotherapy directed against tumor-specific antigens holds the potential to precisely target infiltrative brain tumors with limited damage to surrounding eloquent brain. The recent finding and confirmation by four independent laboratories, including ours, that human cytomegalovirus (CMV) propagates within a high proportion of GBMs, without infecting surrounding normal brain, provides an unparalleled opportunity to direct brain tumor immunotherapy against well-characterized and highly immunogenic viral targets. We have recently completed enrollment on a clinical trial evaluating CMV pp65 RNA-loaded dendritic cell (DC) vaccines in patients with newly diagnosed GBM that has shown promising immunologic and clinical responses. While DC vaccination increased CMV-specific cellular responses, the magnitude of these responses did not approach that typically induced during acute viral infections, and did not reflect the polyfunctional effector phenotype that has been associated with protective immunity against chronic viruses. We have shown that expansion of CMV- specific T cells in vitro however, using RNA pulsed DCs produced marked polyfunctional CMV- specific T cells responses from patients with GBM, highlighting adoptive cellular therapy as a potential strategy to restore effective polyfunctional CMV immunity in these patients and potentially eradicate CMV-associated astrocytomas. In this proposal, we aim to evaluate the safety and estimate the efficacy of adoptive cellular therapy targeting CMV pp65 during hematopoietic recovery from TMZ-induced lymphopenia in patients with newly-diagnosed GBM. The capacity to prolong the in vivo persistence and expansion of adoptively transferred T cells with concurrent pp65 RNA-pulsed DC vaccines will be explored in the context of a Phase I/II clinical trial. This research has the potential to significantly improve currently available treatments for patients with GBM, as well as provide a platform strategy for adoptive cellular therapy that may be applicable to the immunologic treatment of other malignancies. PUBLIC HEALTH RELEVANCE: The significance of this research is that it may advance a new therapy for malignant brain tumors as well as provide a strategy for treatment that can be applied to many other cancers. Improved therapy for cancer has significant potential to improve public health and quality of life for patients affected by malignant disease.