DNA去甲基化药物地西他滨抑制肿瘤血管生成改善肿瘤免疫微环境以提高PD-1抗体临床反应性调控机制研究

Anti-PD-1 antibodies have been approved in treatment with various tumor types, although patients with relapsed/refractory classical Hodgkin’s lymphoma (r/r cHL) having the highest clinical response, anti-PD-1 monotherapy can induce complete remission only in less than 25% patients. It is of vital importance to identify prognosis biomarkers and novel efficient combination strategy with PD-1 inhibitor. Based on the observation that DNA demethylating agent could enhance T cell activity, our team firstly registered in China and performed clinical trials of low-dose decitabine combined anti-PD-1 antibody in relapsed or refractory malignancies. These preliminary data has shown that decitabine-primed anti-PD-1 could induce prominent complete response in patients with r/r cHL, and outcome the resistance to anti-PD-1 monotherapy. The serum cytokine level detection indicated that the baseline and alteration of EGF, VEGF levels might be associated with the clinical response of decitabine-plus-anti-PD-1 combination therapy. Thus, we proposed hypothesis that the regulation of tumor angiogenesis and tumor microenvironment would be beneficial to PD-1 blockade in r/r cHL. In this program, we will first analyze the relationship between serum cytokine levels and therapeutic benefit of decitabine-plus-anti-PD-1 combination treatment, and detect the function of EGF, VEGF signaling in PD-1 blockade as well as combination therapy from various aspects, to explore the association of tumor angiogenesis/immune microenvironment/immune checkpoint blockade, and finally establish the prognosis system and optimal clinical strategy.

PD-1抗体已批准用于多种肿瘤，治疗霍奇金淋巴瘤（cHL）疗效最好，但仅不足25%患者可完全缓解。疗效预测生物标志物及新型联合治疗抗肿瘤机理的探索成为研究重点。鉴于DNA去甲基化药物地西他滨对T细胞活性调控作用，本团队国内首先注册开展低剂量地西他滨联合PD-1抗体治疗复发难治性恶性肿瘤临床试验。前期结果表明联合治疗显著提高cHL患者完全缓解率，并可克服PD-1抗体抵抗。血清学检测提示EGF、VEGF本底水平及其变化趋势与联合治疗反应性相关，因而提出肿瘤血管发生及免疫微环境调控可能参与PD-1抑制剂抗瘤作用的假说。本项目从血清细胞因子水平深入分析地西他滨与PD-1抗体联合治疗敏感性相关指标，从细胞、小鼠及临床样本多层面检测EGF、VEGF及其信号通路在PD-1抗体及联合治疗中的调控作用，解析肿瘤血管生成、免疫微环境与免疫治疗反应性之间的关联，建立PD-1抗体联合治疗评估体系及最优临床方案。

PD-1抗体已批准用于多种肿瘤临床治疗，霍奇金淋巴瘤中总反应率最高，但单药治疗完全缓解率不超过30%，且PD-1抗体复发耐药现象日益凸显。探索新型免疫治疗联合策略及其抗肿瘤机理具有重要研究及临床价值。基于低剂量表观遗传药物对T细胞活性的直接调控及其抑制T细胞耗竭作用，本团队开创性设计并开展了“低剂量地西他滨与PD-1抗体联合方案在实体瘤及淋巴瘤中的临床试验”。此疗法在复发难治霍奇金淋巴瘤中取得临床突破，显著提高了肿瘤完全清除率及无进展生存期，而且约一半的PD-1抗体抵抗患者接受联合治疗后可再次临床获益，且获得较长期无进展生存期。为探讨表观免疫疗法抗肿瘤作用机制，本项目分别在荷瘤小鼠模型和霍奇金淋巴瘤患者肿瘤组织样本中，探讨治疗后对肿瘤微环境的调控效应，通过质谱流式及单细胞转录组测序的检测，观察到瘤内浸润CD8+ T细胞、CD4+ T细胞、NK细胞数量的增加，巨噬细胞数量的减少，并鉴定到多种表型免疫细胞亚群的变化，明确了表观免疫联合疗法对肿瘤微环境的重塑作用。本项目基于团队原创性表观免疫联合治疗抗肿瘤临床方案，在复发难治霍奇金淋巴瘤不同治疗史患者中开展了系列临床研究，完成临床疗效评估，并在小鼠模型、临床样本层面探索了表观药物联合PD-1抗体对肿瘤微环境重塑作用，为深入解析免疫治疗抗肿瘤作用机理奠定基础。

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