Autologous Dendritic Cell Vaccines in NSCLC

描述(申请人提供)：不能切除的III期非小细胞肺癌的临床结果普遍较差。放化疗联合治疗的生存期为11-18个月。有必要对其他疗法进行研究。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冲击的自体树突状细胞可以在非小细胞肺癌患者中诱导可测量的免疫反应。无论阶段或先前的治疗，都可以看到反应，频谱包括有反应者和无反应者。宿主环境似乎在调节T细胞对疫苗的反应方面起着重要作用。我们推测，生理的(诱导的)和病理的(NSCLC肿瘤细胞的结构性表达)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，具有许多直接和间接的作用，使免疫反应极化为抑制或耐受。PGE2诱导的PGE-2和单核细胞来源的IL-10可显著抑制NSCLC特异性T细胞的抗原提呈和增殖，并导致DC的过早死亡。用COX-2抑制剂改变宿主环境是可行的，也是增强T细胞对DC疫苗反应的合理策略。文献和初步数据支持这些戒律。因此，研究旨在测试DC疫苗在不能切除的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效果。假设COX-2活性与疫苗免疫应答之间存在负相关关系，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。标记物还将用于追踪COX-2抑制剂Celebrex在非小细胞肺癌中的生物效应。

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.