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

 描述（由申请人提供）：考虑到对新型免疫抑制剂的反应的可变性以及将其长期益处扩展至更多患者的期望，对开发可以预测治疗结果的生物标志物的需求增加，从而确保将这些可能具有显著毒性的昂贵的新治疗提供给更有可能受益的患者。FDA批准的抗PD 1药物（pembrolizumab/MK 3475）代表了这种在无法预先识别的患者亚组中发生显著治疗反应的现象，需要在COPD患者人群中广泛应用治疗。本应用程序的目的是评估和验证Bim肿瘤反应性PD-1+ T细胞中的PD-1（PD-1下游信号传导分子）水平以及可溶性B7-H1（PD-L1），作为转移性黑色素瘤（MM）患者对抗PD-1治疗反应的监测或预测生物标志物，因为PD-1/PD-L1通路是这种疾病和各种其他癌症中越来越多地利用的治疗靶点，在临床试验中具有非常有希望的结果。我们的中心假设是，肿瘤反应性CD 11 a高D-1+ CD 8+外周血T细胞中的Bim水平可以客观地监测对抗PD-1治疗的反应，并且肿瘤过度释放可溶性B7-H1导致黑色素瘤中Bim上调和治疗抗性。该假设将在我们机构接受抗PD-1单克隆抗体（派姆单抗）治疗的MM患者中进行检验。在强有力的初步数据的指导下，我们提出了两个具体目标来检验我们的中心假设：1）确定Bim在抗PD-1治疗期间监测疾病状态的作用; 2）确定抗PD-1阻断剂耐药的机制。在目标1中，已经证实的PD-1下游信号传导分子Bim（促凋亡BH 3-only蛋白），其已经被确定为申请人手中PD-1参与状态的可行标志物，将用于监测和预测对抗PD-1疗法的T细胞应答，以及鉴定尽管放射学假进展但可能实现晚期临床益处的患者。在目标2下，我们将探索可溶性B7-H1（PD-L1）是否可以影响抗PD-1治疗的敏感性，并成为双重阻断剂（抗PD-1和抗PD-L）治疗的新靶点。我们的方法是创新的，因为它利用新的标志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治疗的治疗结果。我们提出的研究是重要的，因为我们的结果可以帮助确定最有可能从抗PD-1治疗中受益的黑色素瘤（以及可能的其他恶性肿瘤）患者，因此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.