Adjuvant immunotherapy for non-small cell lung cancer

描述（由申请方提供）：临床分期为IB、IIA/B和IIIA的非小细胞肺癌（NSCLC）患者的5年生存率较差，范围为15- 40%。一项国际合作研究的初步结果表明，通过术后化疗和/或放疗治疗患者可能会改善生存率（约5%），尽管高比例的患者（23%）发生了严重的4级毒性。需要更多的肿瘤特异性和毒性较小的辅助治疗。我们提出，树突状细胞（DC）加载离体抗原从病人自己的放射性自体肿瘤，并与干扰素-γ（IFN-γ）和灭活/甲醛固定（BCG）的组合成熟，可用于安全地诱导抗肿瘤免疫的状态，并延长无肿瘤生存的佐剂设置。将进行I期临床试验，以评估将这种形式的DC疫苗给予选定的临床阶段IB、IIA/B或IIIA NSCLC的术后患者的安全性和耐受性。肿瘤细胞产生免疫抑制因子，可以抑制宿主免疫力并提高肿瘤存活率。切除原发性肿瘤可以减少这些因素，并暂时恢复免疫反应。肿瘤切除术还降低了肿瘤负荷，降低了肿瘤变异体逃避免疫检测的风险。因此，在术后期间治疗患者为采用抗肿瘤疫苗提供了最佳窗口。DC前体将通过白细胞去除术收获，并用GM-CSF和IL-4离体分化。自体肿瘤将在患者的原发性肿瘤切除术期间收获，并使用新的免疫耗竭方案纯化。使用患者自身的肿瘤，DC将负载有能够诱导CD 4和CD 8 T细胞应答的肿瘤抗原的全部库。在抗原加载后，DC将用BCG和IFN-γ处理以增强IL-12产生、共刺激活性和T细胞活化能力。DC疫苗将在术后恢复后连续三个月每月皮内注射一次。总共12-15名患者将在两个组群中接受治疗，一个组群每次免疫接种接受2 X IO 6个DC，第二个组群每次免疫接种接受6 X IO 6个DC。除了标准的毒性、耐受性和临床结果外，（IL-10、VEGF、TGF-β）和细胞亚群（DC 1、DC 2、T抑制因子）将用于监测肿瘤相关免疫抑制的变化; PPD皮试反应、BCG特异性T细胞增殖和细胞内细胞因子对负载BCG的DC的反应将用于监测对疫苗的反应; T细胞增殖和细胞内细胞因子对肿瘤负载DC的反应将用于监测肿瘤特异性免疫的发展。患者将接受总计1年的随访。疫苗安全性的证据、可行的生产工艺文件以及疫苗特异性免疫应答的证据将提供支持后续临床试验所需的信息，这些临床试验的重点是临床结局和生存率。

DESCRIPTION (provided by applicant): Patients with clinical stage IB, IIA/B and IIIA non-small cell lung cancer (NSCLC) have poor 5-year survival rates that range from 15-40%. Preliminary results from an international cooperative study suggest that survival might be improved (approximately 5%) by treating patients with post-operative chemotherapy and/or radiation, although a high percentage of patients (23%) experienced serious Grade 4 toxicity. Adjuvant therapies that are more tumor-specific and less toxic are needed. We propose that dendritic cells (DC) loaded ex vivo with antigens from the patient's own irradiated autologous tumor, and matured with a combination of interferon-gamma (IFN-gamma) and inactivated/formaldehyde-fixed (BCG), can be used to safely induce a state of anti-tumor immunity and prolong tumor-free survival in the adjuvant setting. A Phase I clinical trial will be carried out to evaluate the safety and tolerability of administering this form of DC vaccine to postoperative patients with selected clinical stage IB, IIA/B or IIIA NSCLC. Tumor cells produce immunosuppressive factors that can suppress host immunity and enhance tumor survival. Resection of the primary tumor reduces these factors and temporarily restores immune responsiveness. Tumor resection also reduces tumor burden, reducing the risk that tumor variants will escape immune detection. As such, treating patients in the postoperative period provides an optimal window for employing anti-tumor vaccines. DC precursors will be harvested by leukapheresis and differentiated ex vivo with GM-CSF and IL-4. Autologous tumor will be harvested during the patient's primary tumor resection and purified using a novel immunodepletion protocol. Using the patient's own tumor, DC will be loaded with a full repertoire of tumor antigens capable of inducing both CD4 and CD8 T cell responses. After antigen loading, DC will be treated with BCG and IFN-gamma to enhance IL-12 production, co-stimulatory activity and capacity for T cell activation. The DC vaccine will then be administered as a monthly intradermal injection for three consecutive months following recovery from surgery. A total of 12-15 patients will be treated in two cohorts, one receiving 2 x 106 DC per immunization and the second receiving 6 x 106 DC per immunization. In addition to standard toxicity, tolerability and clinical outcomes, changes in serum cytokines (IL-10, VEGF, TGF-beta) and cell subsets (DC1, DC2, T suppressor) will be used to monitor changes in tumor-related immunosuppression; skin-test reactions to PPD, BCG-specific T cell proliferation and intracellular cytokine responses to DC loaded with BCG will be used to monitor responses to the vaccine; and T cell proliferation and intracellular cytokine responses to tumor-loaded DC will be used to monitor the development of tumor-specific immunity. Patients will be followed for a total of 1 year. Evidence that the vaccine is safe, documentation of a feasible manufacturing process, and evidence of vaccine-specific immune responses will provide the information required to support subsequent clinical trials focused on clinical outcomes and survival.