Autologous Dendritic Cell Vaccines in NSCLC

非小细胞肺癌自体树突状细胞疫苗

• 批准号: 6793868
• 负责人: Edward A. Hirschowitz
• 金额: $ 30.19万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-19 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6793868
• 关键词: T lymphocyte; biomarker; clinical research; combination cancer therapy; dendritic cells; enzyme activity; enzyme linked immunosorbent assay; human subject; human therapy evaluation; immune response; immunomodulators; interferon gamma; interleukin 10; interleukin 4; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; neoplastic process; nonsmall cell lung cancer; oxidoreductase inhibitor; patient oriented research; prognosis; prostaglandin endoperoxide synthase; tumor antigens; tumor infiltrating lymphocyte

DESCRIPTION (provided by applicant): Clinical outcomes of unresectable stage III NSCLC are universally poor. Survival with combination chemo-radiotherapy is 11-18 months. Investigation of additional therapies is warranted. Immunotherapies, specifically cancer vaccines, have therapeutic potential. Preliminary data indicate that autologous dendritic cells, pulsed with allogeneic tumor antigens can induce measurable immune responses in individuals with NSCLC. Responses have been seen irrespective of stage or prior therapy, and the spectrum includes responders and nonresponders. The host environment appears to play a significant role in regulating T cell responses to vaccines. We postulate that physiologic (inducible) and pathologic (constitutive expression by NSCLC tumor cells) COX-2 activity can mediate immune regulation. COX-2 is the enzyme responsible for PGE-2 production, a prominent immunosuppressive cytokine with numerous direct and indirect effects that polarize the immune response towards suppression or tolerance. Specifically, PGE-2 and monocyte-derived IL 10 induced by PGE2 may significantly suppress antigen presentation and proliferation of NSCLC specific T cells, as well as lead to premature death of DCs. Modifying the host environment with COX-2 inhibitors is feasible and a rational strategy to enhance T cell responses to DC vaccines. Literature and preliminary data support these precepts. Thus, studies are designed to test the routine effectiveness of DC vaccines in unresectable stage III NSCLC and further evaluate the immune modulating effects of COX-2 inhibitors used in concert with tumor vaccines. Postulating an inverse relationship between COX-2 activity and immunologic response to vaccines, biomarkers of COX-2 activity will be evaluated as correlative markers of immune reactivity. Markers will also be used to track biologic effects of the COX-2 inhibitor Celebrex in NSCLC.

描述（由申请人提供）：不可切除的 III 期 NSCLC 的临床结果普遍较差。联合放化疗的生存期为 11-18 个月。有必要研究其他疗法。免疫疗法，特别是癌症疫苗，具有治疗潜力。初步数据表明，用同种异体肿瘤抗原脉冲的自体树突状细胞可以在 NSCLC 个体中诱导可测量的免疫反应。无论阶段或先前的治疗如何，都可以看到缓解，并且范围包括缓解者和无缓解者。宿主环境似乎在调节 T 细胞对疫苗的反应中发挥着重要作用。我们假设生理（诱导）和病理（NSCLC 肿瘤细胞组成型表达）COX-2 活性可以介导免疫调节。 COX-2 是负责产生 PGE-2 的酶，PGE-2 是一种重要的免疫抑制细胞因子，具有多种直接和间接作用，使免疫反应极化为抑制或耐受。具体而言，PGE-2和PGE2诱导的单核细胞源性IL 10可能显着抑制NSCLC特异性T细胞的抗原呈递和增殖，并导致DC过早死亡。用 COX-2 抑制剂改变宿主环境是增强 T 细胞对 DC 疫苗反应的可行且合理的策略。文献和初步数据支持这些规则。因此，研究旨在测试 DC 疫苗在不可切除的 III 期 NSCLC 中的常规有效性，并进一步评估 COX-2 抑制剂与肿瘤疫苗联合使用的免疫调节作用。假设COX-2活性和对疫苗的免疫反应之间存在反比关系，COX-2活性的生物标志物将被评估为免疫反应性的相关标志物。标记物还将用于追踪 COX-2 抑制剂 Celebrex 在 NSCLC 中的生物效应。