Department of Biochemistry and Genetics, Universidad de Navarra, Pamplona, Spain.
Hemato-Oncology Program, Center for Applied Medical Research (CIMA), Pamplona, Spain.
J Immunother Cancer. 2023 Feb;11(2). doi: 10.1136/jitc-2022-006113.
Approximately one-third of diffuse large B cell lymphoma (DLBCL) patients exhibit co-expression of MYC and BCL2 (double-expressor lymphoma, DEL) and have a dismal prognosis. Targeted inhibition of the anti-apoptotic protein BCL2 with venetoclax (ABT-199) has been approved in multiple B-cell malignancies and is currently being investigated in clinical trials for DLBCL. Whether BCL2 anti-apoptotic function represents a multifaceted vulnerability for DEL-DLBCL, affecting both lymphoma B cells and T cells within the tumor microenvironment, remains to be elucidated.
Here, we present novel genetically engineered mice that preclinically recapitulate DEL-DLBCL lymphomagenesis, and evaluate their sensitivity ex vivo and in vivo to the promising combination of venetoclax with anti-CD20-based standard immunotherapy.
Venetoclax treatment demonstrated specific killing of MYC/BCL2 lymphoma cells by licensing their intrinsically primed apoptosis, and showed previously unrecognized immunomodulatory activity by specifically enriching antigen-activated effector CD8 T cells infiltrating the tumors. Whereas DEL-DLBCL mice were refractory to venetoclax alone, inhibition of BCL2 significantly extended overall survival of mice that were simultaneously treated with a murine surrogate for anti-CD20 rituximab.
These results suggest that the combination of anti-CD20-based immunotherapy and BCL2 inhibition leads to cooperative immunomodulatory effects and improved preclinical responses, which may offer promising therapeutic opportunities for DEL-DLBCL patients.
大约三分之一的弥漫性大 B 细胞淋巴瘤 (DLBCL) 患者表现出 MYC 和 BCL2 的共表达（双表达淋巴瘤，DEL），预后不良。抗凋亡蛋白 BCL2 的靶向抑制物维奈托克（ABT-199）已在多种 B 细胞恶性肿瘤中获得批准，目前正在临床试验中研究用于 DLBCL。BCL2 抗凋亡功能是否代表 DEL-DLBCL 的多方面脆弱性，影响肿瘤微环境中的淋巴瘤 B 细胞和 T 细胞，仍有待阐明。
在这里，我们提出了一种新的基因工程小鼠，该小鼠可在临床前重现 DEL-DLBCL 的淋巴瘤发生，并评估它们对 venetoclax 与基于抗 CD20 的标准免疫疗法联合治疗的体外和体内敏感性。
venetoclax 治疗通过许可其内在引发的凋亡来特异性杀死 MYC/BCL2 淋巴瘤细胞，并通过特异性富集浸润肿瘤的抗原激活效应 CD8 T 细胞显示出以前未被认识到的免疫调节活性。虽然 DEL-DLBCL 小鼠对 venetoclax 单独治疗无反应，但 BCL2 的抑制显著延长了同时接受抗 CD20 利妥昔单抗替代物治疗的小鼠的总生存期。
这些结果表明，基于抗 CD20 的免疫疗法和 BCL2 抑制的联合治疗导致协同的免疫调节作用和改善的临床前反应，这可能为 DEL-DLBCL 患者提供有希望的治疗机会。
