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 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.