Peptide vaccine immunotherapy for children with recurrent low-grade astrocytomas

 描述（由申请人提供）：这种新的R 01应用程序的重点是一个创新的II期临床试验的肽为基础的免疫治疗的儿童低级别星形细胞瘤，最常见的脑肿瘤的儿童。虽然手术切除对边界清楚的浅表病变是有效的，但浸润性或起源于深部结构的肿瘤，如 如视神经通路，通常无法通过手术治愈，并构成重大的管理挑战。进行性肿瘤可能对常规化疗药物和分子靶向药物有一过性反应，但此类病变经常复发，导致累积发病率，特别是在多次治疗方案失败的肿瘤中。因此，需要新的治疗方法。在这方面，我们的初步研究证明了基于胶质瘤相关抗原（GAA）的疫苗的安全性和耐受性，这些疫苗靶向一系列我们已证明在儿科胶质瘤中过表达的蛋白质，包括IL 13 R α2，EphA 2和生存素，在新诊断和复发的星形细胞瘤儿童中。这些初步研究显示了有趣的免疫学和临床反应，特别是在复发性低级别星形细胞瘤的儿童中，其中10例可评价患者中有3例在磁共振成像（MRI）上持续肿瘤消退。在这些数据的基础上，拟议的研究将系统地评估基于肽的疫苗治疗复发性低级别星形细胞瘤儿童的临床和免疫学疗效。我们将对25例患者进行皮下GAA表位疫苗接种，每3周1次，共8个疗程，联合肌肉注射聚ICLC。将通过临床、MRI和实验室评价评价受试者的方案限制性毒性（RLT）和治疗反应。显示疾病稳定或消退而无RLT的患者可接受额外的疫苗接种。这些研究利用了我们的免疫监测实验室提供的独特机构资源，这些资源被整合到临床试验中。拟议的研究将检验以下假设：基于肽的免疫疗法具有足够的临床疗效，以保证在这些肿瘤中进行更广泛的治疗检查，并且临床应答将与免疫反应性相关。为了解决这些假设，我们提出了以下目的的研究：1。使用基于MRI的肿瘤反应和无进展生存率的客观指标，确定GAA肽疫苗接种对复发性低级别星形细胞瘤儿童的疗效。2.使用IFN-γ-酶联免疫吸附斑点（ELISPOT）和四聚体试验，表征疫苗接种后外周血单核细胞对疫苗靶向抗原的免疫应答的速率和幅度，并将免疫应答与疫苗临床应答相关联。此外，拟议的研究将检查肿瘤中抗原表达与治疗反应之间的关联，以及免疫治疗后肿瘤中免疫逃逸的机制。这项研究的结果将为确定是否应该进一步检查这种方式作为这些具有挑战性的肿瘤的潜在治疗提供基础。

 DESCRIPTION (provided by applicant): This novel R01 application focuses on an innovative phase II clinical trial of peptide-based immunotherapy for children with low-grade astrocytomas, the most common brain tumors of childhood. Although surgical resection is curative for well-circumscribed superficial lesions, tumors that are infiltrative or arise from deep structures, such as the optic pathways, are often incurable with surgery and pose a major management challenge. Progressive tumors may respond transiently to conventional chemotherapy agents, and to molecularly targeted agents, but such lesions often recur, leading to cumulative morbidity, particularly in tumors that fail multiple treatment regimens. Accordingly, new treatment approaches are needed. In this regard, our preliminary studies demonstrated the safety and tolerability of glioma-associated antigen (GAA)-based vaccines targeting a series of proteins that we have shown to be overexpressed in pediatric gliomas, including IL13Rα2, EphA2, and survivin, in children with newly diagnosed and recurrent astrocytomas. These pilot studies demonstrated intriguing immunological and clinical responses, particularly in children with recurrent low-grade astrocytomas, in whom 3 of 10 evaluable patients had sustained tumor regression on magnetic resonance imaging (MRI). Building upon these data, the proposed study will systematically evaluate clinical and immunological efficacy of peptide-based vaccine therapy in children with recurrent low-grade astrocytomas. We will treat 25 patients with subcutaneous GAA epitope vaccinations every 3 weeks for 8 courses combined with intramuscular poly-ICLC. Participants will be evaluated for regimen limiting toxicity (RLT) and treatment response by clinical, MRI, and laboratory evaluations. Patients demonstrating disease stabilization or regression without RLT may receive additional vaccinations. These studies take advantage of unique institutional resources provided by our Immunologic Monitoring Laboratory, which are integrated into the clinical trial. The proposed studies will test the hypothesis that peptide-base immunotherapy has sufficient clinical efficacy to warrant broader therapeutic examination in these tumors, and that clinical response will be associated with immunological reactivity. To address these hypotheses, we propose studies with the following aims: 1. Determine the efficacy of vaccination with GAA peptides for children with recurrent low-grade astrocytomas, using objective measures of MRI-based tumor response and progression-free survival. 2. Characterize the rate and magnitude of immune response in post-vaccine peripheral blood mononuclear cells against vaccine-targeted antigens, using IFN-γ-enzyme-linked immunosorbent spot (ELISPOT) and tetramer assays, and correlate immunological response with clinical responses to the vaccine. In addition, the proposed studies will examine associations between antigen expression in the tumor and treatment response, and mechanisms of immune escape in tumors that progress after immunotherapy. The results from this study will provide a basis for determining if this modality should be examined further as a potential therapy for these challenging tumors.