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疗法具有精确靶向浸润性脑肿瘤的潜力，对周围脑组织的损害有限。包括我们在内的四个独立实验室最近的发现和证实，人类巨细胞病毒（CMV）在GBMs中传播的比例很高，而不会感染周围的正常大脑，这为指导脑肿瘤免疫治疗针对特征明确、免疫原性高的病毒靶点提供了无与伦比的机会。我们最近完成了一项评估CMV pp65 rna负载树突状细胞（DC）疫苗在新诊断的GBM患者中的临床试验，该试验显示出有希望的免疫和临床反应。虽然DC疫苗接种增加了cmv特异性细胞应答，但这些应答的强度并没有接近急性病毒感染期间通常诱导的应答，也没有反映出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，体外扩增CMV特异性T细胞，使用RNA脉冲dc可在GBM患者中产生显著的多功能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免疫并可能根除CMV相关星形细胞瘤的潜在策略。在本研究中，我们旨在评估针对CMV pp65的过继细胞治疗在新诊断的GBM患者从tmz诱导的淋巴细胞减少中恢复造血功能的安全性和有效性。使用pp65 rna脉冲DC疫苗延长过继性转移T细胞在体内持续和扩增的能力将在I/II期临床试验的背景下进行探索。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，可能适用于其他恶性肿瘤的免疫治疗。

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.