Adoptive Immunotherapy for GBM During Hematopoietic Recovery from Temozolomide

描述（由申请人提供）：胶质母细胞瘤（GBM）是普遍致命的，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具有精确靶向浸润性脑肿瘤的潜力，对周围功能脑的损伤有限。包括我们在内的四个独立实验室最近的发现和确认，即人巨细胞病毒（CMV）在高比例的GBM中传播，而不感染周围的正常大脑，这为指导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的招募，该试验评估了新诊断的GBM患者中CMV pp 65 RNA负载的树突状细胞（DC）疫苗，该疫苗显示出有希望的免疫学和临床反应。虽然DC疫苗接种增加了CMV特异性细胞应答，但这些应答的幅度没有接近急性病毒感染期间通常诱导的应答，并且没有反映与针对慢性病毒的保护性免疫相关的多功能效应子表型。然而，我们已经表明，使用RNA脉冲的DC在体外扩增CMV特异性T细胞产生了来自GBM患者的显著的多功能CMV特异性T细胞应答，突出了过继性细胞疗法作为在这些患者中恢复有效的多功能CMV免疫并潜在地根除CMV相关星形细胞瘤的潜在策略。 在这项提案中，我们的目的是评估安全性和评估过继细胞治疗靶向CMV pp 65在造血恢复TMZ诱导的淋巴细胞减少症的新诊断GBM患者的疗效。将在I/II期临床试验的背景下探索用并行pp 65 RNA脉冲的DC疫苗延长过继转移的T细胞的体内持久性和扩增的能力。这项研究有可能显著改善GBM患者目前可用的治疗方法，并为过继细胞治疗提供一个平台策略，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，它可能会推进恶性脑肿瘤的新疗法，并提供可应用于许多其他癌症的治疗策略。改进的癌症治疗具有显著的潜力，可以改善受恶性疾病影响的患者的公共健康和生活质量。

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.