Isshiki Yusuke, Chen Xi, Teater Matt, Karagiannidis Ioannis, Nam Henna, Cai Winson, Meydan Cem, Xia Min, Shen Hao, Gutierrez Johana, Easwar Kumar Vigneshwari, Carrasco Sebastián E, Ouseph Madhu M, Yamshon Samuel, Martin Peter, Griess Ofir, Shema Efrat, Porazzi Patrizia, Ruella Marco, Brentjens Renier J, Inghirami Giorgio, Zappasodi Roberta, Chadburn Amy, Melnick Ari M, Béguelin Wendy
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
Cancer Cell. 2025 Jan 13;43(1):49-68.e9. doi: 10.1016/j.ccell.2024.11.006. Epub 2024 Dec 5.
T cell-based immunotherapies have demonstrated effectiveness in treating diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) but predicting response and understanding resistance remains a challenge. To address this, we developed syngeneic models reflecting the genetics, epigenetics, and immunology of human FL and DLBCL. We show that EZH2 inhibitors reprogram these models to re-express T cell engagement genes and render them highly immunogenic. EZH2 inhibitors do not harm tumor-controlling T cells or CAR-T cells. Instead, they reduce regulatory T cells, promote memory chimeric antigen receptor (CAR) CD8 phenotypes, and reduce exhaustion, resulting in a decreased tumor burden. Intravital 2-photon imaging shows increased CAR-T recruitment and interaction within the tumor microenvironment, improving lymphoma cell killing. Therefore, EZH2 inhibition enhances CAR-T cell efficacy through direct effects on CAR-T cells, in addition to rendering lymphoma B cells immunogenic. This approach is currently being evaluated in two clinical trials, NCT05934838 and NCT05994235, to improve immunotherapy outcomes in B cell lymphoma patients.
基于T细胞的免疫疗法已在治疗弥漫性大B细胞淋巴瘤（DLBCL）和滤泡性淋巴瘤（FL）方面显示出有效性，但预测反应和理解耐药性仍然是一项挑战。为了解决这一问题，我们开发了反映人类FL和DLBCL遗传学、表观遗传学和免疫学的同基因模型。我们表明，EZH2抑制剂可对这些模型进行重编程，使其重新表达T细胞结合基因，并使其具有高度免疫原性。EZH2抑制剂不会损害控制肿瘤的T细胞或嵌合抗原受体T细胞（CAR-T细胞）。相反，它们会减少调节性T细胞，促进记忆性嵌合抗原受体（CAR）CD8表型，并减少耗竭，从而减轻肿瘤负担。活体双光子成像显示，肿瘤微环境中CAR-T细胞的募集和相互作用增加，从而改善了淋巴瘤细胞的杀伤效果。因此，EZH2抑制除了使淋巴瘤B细胞具有免疫原性外，还通过对CAR-T细胞的直接作用增强了CAR-T细胞的疗效。目前，这一方法正在两项临床试验（NCT05934838和NCT05994235）中进行评估，以改善B细胞淋巴瘤患者的免疫治疗效果。
