Role of Bim and soluble B7-H1 in monitoring T cell responses to anti-PD-1 therapy in melanoma

 描述(申请人提供)：鉴于对新型免疫治疗药物反应的多样性，以及希望将其长期益处扩大到更多患者的愿望，越来越需要开发能够预测治疗结果的生物标记物，从而确保将这些可能具有重大毒性的昂贵的新疗法提供给更有可能受益的患者。FDA批准的抗PD1药物(pembrolizumab/MK3475)在不能预先确定的患者亚组中具有典型的戏剧性治疗反应的现象，需要在未选定的患者群体中广泛应用治疗。本应用的目的是评估和验证肿瘤反应性PD-1+T细胞中PD-1下游信号分子Bim水平以及可溶性B7-H1(PD-L1)作为监测或预测转移性黑色素瘤(MM)患者抗PD-1治疗反应的生物标志物。转移性黑色素瘤(MM)是一个很好的模型，因为PD-1/PD-L1途径正日益成为该疾病和各种其他癌症的治疗靶点，并在临床试验中获得非常有希望的结果。我们的中心假设是，肿瘤反应性CD11a高D-1+CD8+T细胞中的Bim水平可以客观地监测抗PD-1治疗的反应，肿瘤过度释放可溶性B7-H1导致黑色素瘤Bim上调和治疗抵抗。这一假设将在我们研究所接受抗PD-1单抗(Pembrolizumab)治疗的MM患者中进行验证。在强大的初步数据的指导下，我们提出了两个具体的目标来检验我们的中心假设：1)建立BIM在抗PD-1治疗中监测疾病状态的作用；2)确定抵抗抗PD-1阻断的机制。在目标1中，已经被证实的PD-1下游信号分子Bim(促凋亡的BH3-Only蛋白)，已经被确定为申请人手中PD-1参与状态的可行标记，将被用于监测和预测T细胞对抗PD-1治疗的反应，以及识别尽管放射学假性进展但可能获得晚期临床益处的患者。目的2探讨可溶性B7-H1(PD-L1)对抗PD-1治疗敏感性的影响，成为抗PD-1和抗PD-L双阻断治疗的新靶点。我们的方法是创新的，因为它利用新的标记物来评估耗尽的抗肿瘤PD-1+T细胞的可逆性和抗PD-1阻断的效率，这将直接影响抗PD-1治疗的疗效。我们提出的研究具有重要意义，因为我们的结果可以帮助识别最有可能从抗PD-1治疗中受益的黑色素瘤患者(以及可能的其他恶性肿瘤)，从而通过更个性化的癌症治疗方法提高药物疗效并降低毒性。

 DESCRIPTION (provided by applicant): Given the variability in response to the novel immunotherapeutic agents and the desire to extend their long- term benefits to more patients, there is an increased need for the development of biomarkers that can predict treatment outcomes, thereby ensure that these expensive new treatments, which may have significant toxicities, are offered to the patients who are more likely to benefit. The FDA approved anti-PD1 agent (pembrolizumab/MK3475) typifies this phenomenon of dramatic therapeutic responses in a subset of patients who cannot be pre-identified, necessitating broad treatment application in an unselected patient population. The objective in this application is to evaluate and validate Bim (a PD-1 downstream signaling molecule) levels in tumor-reactive PD-1+ T cells, as well as soluble B7-H1(PD-L1), as monitoring or predictive biomarkers for response to anti-PD-1 therapy in patients with metastatic melanoma (MM), an excellent model, as PD-1/PD-L1 pathway is an increasingly exploited therapeutic target in this disease and a variety of other cancers, with extremely promising results in clinical trials. Our central hypothesis is that Bim levels in tumor-reactive CD11a high D-1+CD8+ peripheral blood T cells can objectively monitor responses to anti-PD-1 therapy and that excessive release of soluble B7-H1 by the tumor leads to Bim upregulation and treatment resistance in melanoma. This hypothesis will be tested in MM patients undergoing treatment with an anti-PD-1 monoclonal antibody (pembrolizumab) at our Institution. Guided by strong preliminary data, we propose two Specific Aims to test our central hypothesis: 1) Establish the role of Bim for monitoring disease status during anti-PD-1 therapy; and 2) Identify the mechanisms of resistance to anti-PD-1 blockade. In aim 1, an already proven PD-1 downstream signaling molecule Bim (the pro-apoptotic BH3-only protein), which has been established as a feasible marker for the status of PD-1 engagement in the applicants' hands, will be utilized to monitor and predict the T cell responses to anti-PD-1 therapy, as well as identify patients who may achieve late clinical benefit despite radiologic pseudoprogression. Under aim 2, we will explore that soluble B7-H1 (PD-L1) could influence the sensitivity to anti-PD-1 therapy and be a new therapeutic target of dual blocker therapy (anti-PD-1 and anti-PD-L). Our approach is innovative because it utilizes novel markers to assess the reversibility of exhausted anti-tumor PD-1+ T cells and the efficiency of anti-PD-1 blockade, which would directly influence the therapeutic outcome with anti-PD-1 therapy. Our proposed research is significant, because our results could help identify patients with melanoma (and possibly other malignancies) who are most likely to benefit from anti- PD-1 therapy, therefore increasing drug efficacy and decreasing toxicity through a more personalized approach to cancer treatment.