Division of Hematology/Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Cancer Discov. 2022 Oct 5;12(10):2372-2391. doi: 10.1158/2159-8290.CD-21-1026.
Chimeric antigen receptor T-cell (CART) immunotherapy led to unprecedented responses in patients with refractory/relapsed B-cell non-Hodgkin lymphoma (NHL); nevertheless, two thirds of patients experience treatment failure. Resistance to apoptosis is a key feature of cancer cells, and it is associated with treatment failure. In 87 patients with NHL treated with anti-CD19 CART, we found that chromosomal alteration of B-cell lymphoma 2 (BCL-2), a critical antiapoptotic regulator, in lymphoma cells was associated with reduced survival. Therefore, we combined CART19 with the FDA-approved BCL-2 inhibitor venetoclax and demonstrated in vivo synergy in venetoclax-sensitive NHL. However, higher venetoclax doses needed for venetoclax-resistant lymphomas resulted in CART toxicity. To overcome this limitation, we developed venetoclax-resistant CART by overexpressing mutated BCL-2(F104L), which is not recognized by venetoclax. Notably, BCL-2(F104L)-CART19 synergized with venetoclax in multiple lymphoma xenograft models. Furthermore, we uncovered that BCL-2 overexpression in T cells intrinsically enhanced CART antitumor activity in preclinical models and in patients by prolonging CART persistence.
This study highlights the role of BCL-2 in resistance to CART immunotherapy for cancer and introduces a novel concept for combination therapies-the engineering of CART cells to make them resistant to proapoptotic small molecules, thereby enhancing the therapeutic index of these combination therapies. This article is highlighted in the In This Issue feature, p. 2221.
嵌合抗原受体 T 细胞（CART）免疫疗法在难治/复发 B 细胞非霍奇金淋巴瘤（NHL）患者中引起了前所未有的反应；然而，三分之二的患者治疗失败。细胞凋亡抵抗是癌细胞的一个关键特征，与治疗失败有关。在 87 例接受抗 CD19 CART 治疗的 NHL 患者中，我们发现淋巴瘤细胞中 B 细胞淋巴瘤 2（BCL-2）的染色体改变，这是一种关键的抗凋亡调节剂，与存活率降低有关。因此，我们将 CART19 与 FDA 批准的 BCL-2 抑制剂 venetoclax 联合使用，并在 venetoclax 敏感的 NHL 中证明了体内协同作用。然而，venetoclax 耐药淋巴瘤需要更高的 venetoclax 剂量，导致 CART 毒性。为了克服这一限制，我们通过过表达突变的 BCL-2（F104L）来开发 venetoclax 耐药的 CART，这种突变的 BCL-2 不被 venetoclax 识别。值得注意的是，BCL-2（F104L）-CART19 与 venetoclax 在多种淋巴瘤异种移植模型中协同作用。此外，我们发现 T 细胞中 BCL-2 的过表达通过延长 CART 持续时间，在临床前模型和患者中内在增强了 CART 的抗肿瘤活性。
这项研究强调了 BCL-2 在癌症对 CART 免疫疗法的抵抗中的作用，并提出了联合治疗的新概念——工程化 CART 细胞使其对促凋亡小分子产生耐药性，从而提高这些联合治疗的治疗指数。本文在本期的特色文章中进行了重点介绍，第 2221 页。
