DNA去甲基化药物地西他滨提高PD-1抑制剂治疗霍奇金淋巴瘤临床反应性并逆转抵抗的作用机制及临床研究

PD-1 inhibitor has revealed outstanding clinical benefit in Hodgkin’s lymphoma, but the complete response rate of anti-PD-1 monotherapy was less than 25%, and drug resistance is becoming a major challenge. Decitabine, a demethylating agent, was documented to directly boost T cell function and also possibly delay/reverse PD-1-blocked T cell exhaustion. Bio-therapeutic department of Chinese PLA General Hospital has firstly registered in China clinical trials with low-dose decitabine-primed anti-PD-1 treatment in relapsed/refractory classical Hodgkin lymphoma (r/r cHL). The preliminary result has confirmed the safety of decitabine combined anti-PD-1 therapy, which induces complete remission in over 50% r/r cHL patients. In cHL patients with anti-PD-1 history, about 20% patients could acquire complete response after this combination treatment. Moreover, the proliferation and activity of peripheral T cells, especially CD4+ T cells, were significantly enhanced following this combination therapy. In this study, we aim to carry out clinical trials and take advantage of clinical species, to systematically analyze the dynamic alteration of peripheral immunocytes, and investigate the distribution, activity of tumor infiltrating immune cells with single-cell sequencing technology, also identify the clinical responding indexes. In addition, we will investigate the roles of CD4+ T cells during epigenetic and immunotherapy from in vivo and ex vivo studies, and reveal the essential effector cells and mechanisms of resistance to anti-PD-1 inhibitor and decitabine-mediated anti-tumor response enhancement of PD-1 inhibitor.

PD-1抑制剂治疗霍奇金淋巴瘤临床疗效较好，但单药治疗完全缓解率不超过25%，且PD-1抑制剂复发耐药现象越发凸显。DNA去甲基化药物地西他滨已报道能够增强效应T细胞活性，且可能延缓或逆转T细胞耗竭。解放军总医院生物治疗病区在国内首先注册开展地西他滨联合PD-1抑制剂治疗复发难治性霍奇金淋巴瘤临床试验。前期研究显示，地西他滨与PD-1抑制剂联合方案具有安全性，完全缓解率超过50%；PD-1抑制剂抵抗患者，依然有20%可实现肿瘤完全清除；而且治疗后患者外周T细胞，尤其是CD4+T细胞，其增殖及活性显著增强。本项目将开展并利用临床研究样本，系统分析联合治疗后外周免疫细胞动态变化，单细胞测序等技术研究肿瘤浸润免疫细胞分布、活性及临床疗效相关免疫指标，体内外实验深入探讨CD4+T细胞在表观免疫治疗中的作用，进而解析PD-1抗体抵抗发生以及地西他滨增强PD-1抑制剂抗瘤活性的核心效应细胞及作用机理。

PD-1抑制剂治疗实体瘤疗效有限，在霍奇金淋巴瘤中总反应率较高，但单药治疗完全缓解率（CR）不超过30%，且PD-1抑制剂复发耐药现象越发凸显。鉴于低剂量DNA去甲基化药物地西他滨对T淋巴细胞的直接调控作用及延缓T细胞耗竭潜能，本团队自主设计“低剂量地西他滨与PD-1抗体联合治疗方案”，国际上率先开展了“表观免疫”抗肿瘤临床试验，在复发难治性霍奇金淋巴瘤中取得疗效突破，CR率达到70%以上，中位无进展生存期达到35个月，获得CR的患者中，即使在停药后2年仍然有2/3以上处于CR状态，证实表观干预途径抗肿瘤的免疫增效作用与表观免疫联合方案在霍奇金淋巴瘤中的可治愈潜能。此外，PD-1抗体抵抗患者中50%以上在接受联合治疗后临床产生抗瘤疗效，且可获得较长期无进展生存期。针对地西他滨与PD-1抗体联合方案治疗无效或者复发/进展的cHL 患者，本团队进而开展了地西他滨和HDAC抑制剂双表观药物联合PD-1抗体的临床研究，最新临床数据显示超过90%患者接受双表观免疫治疗后能够临床获益，CR率仍可以达到45%，提示不同表观遗传途径干预对PD-1抗体增敏及逆转抵抗的协同作用。通过在荷瘤小鼠模型中研究，明确表观药物干预对PD-1抗体免疫治疗的增敏效应及调控机制。本项目围绕团队自主设计的表观免疫治疗原创性临床方案，霍奇金淋巴瘤中完成系列临床研究，探讨临床疗效相关性指标，并在小鼠模型及临床样本层面初步探索表观药物免疫治疗增敏作用机制，为其他瘤种中探索合适的PD-1抗体联合方案提供借鉴。