肿瘤细胞治疗研究
英文原题：Monospecific and Bispecific Chimeric Antigen Receptor (CAR) T-cell Therapy in Multiple Myeloma: A Systematic Review, Meta-analysis and Meta-regression.
分析了 44 个队列（2 个一线队列和 42 个复发/难治性队列）的 52 篇报告，共纳入 1833 例患者。
嵌合抗原受体（CAR）T细胞疗法已革新复发/难治性多发性骨髓瘤（RRMM）的治疗。然而，不同CAR产品、靶抗原及患者亚组之间的比较疗效仍未充分明确。尤其是随着靶向G蛋白偶联受体C族5组D（GPRC5D）的策略、双特异性及双靶点策略出现，抗B细胞成熟抗原（BCMA）治疗后复发/难治患者的疗效尚未得到详细研究。研究者系统检索了5个电子数据库，检索时间为2010年1月1日至2025年12月5日。纳入报告多发性骨髓瘤CAR-T细胞治疗临床结局的研究。主要疗效终点为总缓解率（ORR）和完全缓解（CR）率；安全性终点包括血液学和免疫学毒性。采用R进行随机效应荟萃分析，并按人口学、疾病及治疗相关因素（如抗原靶点、CAR构建、既往治疗负担、髓外病变及高危细胞遗传学）开展预设亚组和荟萃回归分析。最终分析52篇报告、44个队列（2个前线队列和42个复发/难治队列），共1833例患者。所有CAR-T平台的合并ORR为88%（95%置信区间[CI]：83–91），CR率为55%（95% CI：47–62）。自体BCMA靶向CAR-T治疗的ORR为89%（95% CI：82–93），CR率为57%（95% CI：47–66）；异基因BCMA CAR-T的ORR较低，为58%（95% CI：1–100），CR率为21%（95% CI：6–51）。双特异性和双靶点策略显示出良好活性：BCMA/CD19 CAR-T的ORR为92%（95% CI：89–95），CR率为64%（95% CI：16–94）；BCMA/CD38 CAR-T的ORR为88%（95% CI：82–93），CR率为61%（95% CI：22–90）。靶向GPRC5D的CAR-T治疗ORR为89%（95% CI：84–92），CR率为50%（95% CI：32–69）。在BCMA治疗后复发/难治患者中，后续靶向GPRC5D的CAR-T治疗ORR为82%（95% CI：66–91），CR率为35%。总体可评估患者中，微小残留病（MRD）阴性率为78%（95% CI：68–86）。亚组分析显示，髓外病变比例较高的队列ORR和CR显著较低。3级血液学毒性常见：中性粒细胞减少发生率为83%（95% CI：76–89），白细胞减少为73%（95% CI：59–83），贫血为46%（95% CI：38–54），血小板减少为48%（95% CI：41–56）。3级细胞因子释放综合征发生率为8%（95% CI：6–11），3级免疫效应细胞相关神经毒性综合征发生率为3%（95% CI：2–5）。CAR-T细胞疗法可使多发性骨髓瘤患者获得较高缓解率、较深缓解及较高MRD阴性率，包括经过多线治疗的RRMM患者。抗BCMA治疗失败后转换靶点、采用GPRC5D靶向策略，显示出良好前景；双特异性和双靶点CAR-T策略也特别值得关注，其缓解率高且缓解较深。髓外病变及既往治疗负担较重仍是重要不良预后因素。但这些发现主要来自早期单臂研究，仍需前瞻性比较试验进一步指导CAR-T选择和长期疗效评估。
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for relapsed/refractory multiple myeloma (RRMM). However, comparative effectiveness across CAR products, target antigens, and patient subgroups remains incompletely characterized. Particularly, with the emergence of G protein-coupled receptor family C group 5 member D (GPRC5D)-directed, bispecific, and dual-target strategies, efficacy in patients who have relapsed/refractory disease after anti-B cell maturation antigen (BCMA) therapy has not been studied in detail. We systematically searched 5 electronic databases from January 1, 2010 to December 5, 2025. Eligible studies reported clinical outcomes of CAR T-cell therapy in MM. Primary efficacy endpoints included overall response (ORR) and complete response (CR) rate. Safety endpoints included hematologic and immunologic toxicities. Random-effects meta-analyses were performed using R, with prespecified subgroup and meta-regression analyses according to demographic, disease and treatment-related factors such as antigen target, CAR construct, prior treatment burden, extramedullary disease and high-risk cytogenetics. Of 52 reports of 44 cohorts (2 frontline and 42 relapsed/refractory cohorts) including 1833 patients were analyzed. Across all CAR T-cell platforms, the pooled ORR was 88% (95% confidence interval [CI]: 83 to 91) and CR rate was 55% (95% CI: 47 to 62). For autologous BCMA-directed CAR T-cell therapy, ORR was 89% (95% CI: 82 to 93) and CR rate was 57% (95% CI: 47 to 66), whereas allogeneic BCMA CAR-T had a lower ORR of 58% (95% CI: 1 to 100) and CR rate of 21% (95% CI: 6 to 51). Bispecific and dual-target strategies demonstrated encouraging activity with BCMA/CD19-directed CAR T-cells achieving an ORR of 92% (95% CI: 89 to 95) and CR rate of 64% (95% CI: 16 to 94), while BCMA/CD38-directed CAR T-cells achieved an ORR of 88% (95% CI: 82 to 93) and CR rate of 61% (95% CI: 22 to 90). For GPRC5D-directed CAR T-cell therapy, ORR was 89% (95% CI: 84 to 92) and CR rate was 50% (95% CI: 32 to 69). Among BCMA-relapsed/refractory patients, subsequent GPRC5D-directed CAR T-cell therapy achieved an ORR of 82% (95% CI: 66 to 91) and CR rate of 35%. MRD negativity was observed in 78% (95% CI: 68 to 86) of evaluable patients overall. Subgroup analyses demonstrated significantly lower ORR and CR in cohorts with higher extramedullary disease. Grade 3 hematologic toxicities were frequent: neutropenia occurred in 83% (95% CI: 76 to 89), leukopenia in 73% (95% CI: 59 to 83), anemia in 46% (95% CI: 38 to 54), and thrombocytopenia in 48% (95% CI: 41 to 56). Grade 3 cytokine release syndrome occurred in 8% (95% CI: 6 to 11), while grade 3 immune effector cell-associated neurotoxicity syndrome occurred in 3% (95% CI: 2 to 5). CAR T-cell therapy produces high response rates, substantial depth of remission, and frequent MRD negativity in multiple myeloma, including heavily pretreated RRMM. Antigen switching strategies after anti-BCMA failure with GPRC5D-directed strategies appear promising. Bispecific and dual-target CAR T-cell strategies appear especially promising, with high response rates and deep remissions. Extramedullary disease and high prior treatment burden remain important poor prognostic factors. However, these findings remain largely derived from early-phase, single-arm studies, and prospective comparative trials are needed to further guide optimal choice of CAR-T and long-term efficacy.
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