Autologous Dendritic Cell Vaccines in NSCLC

描述（由申请人提供）：不可切除的III期NSCLC的临床结局普遍较差。联合放化疗的生存期为11-18个月。需要研究其他疗法。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应答。无论分期或既往治疗如何，均观察到缓解，范围包括缓解者和无缓解者。宿主环境似乎在调节T细胞对疫苗的应答中起重要作用。我们推测生理性（诱导型）和病理性（非小细胞肺癌肿瘤细胞的组成型表达）考克斯-2活性可以介导免疫调节。考克斯-2是负责产生PGE-2的酶，PGE-2是一种显著的免疫抑制细胞因子，具有许多直接和间接作用，使免疫应答朝向抑制或耐受。PGE-2和PGE-2诱导的单核细胞来源的IL-10可显著抑制NSCLC特异性T细胞的抗原呈递和增殖，并导致DC过早死亡。用考克斯-2抑制剂修饰宿主环境是可行的，并且是增强T细胞对DC疫苗的应答的合理策略。文献和初步数据支持这些观点。因此，设计研究以测试DC疫苗在不可切除的III期NSCLC中的常规有效性，并进一步评估与肿瘤疫苗一起使用的考克斯-2抑制剂的免疫调节作用。假定考克斯-2活性与对疫苗的免疫应答之间存在反比关系，将评价考克斯-2活性的生物标志物作为免疫反应性的相关标志物。标记物也将用于跟踪考克斯-2抑制剂西乐葆在NSCLC中的生物学效应。

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.