Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Transplant Cell Ther. 2023 Sep;29(9):574.e1-574.e10. doi: 10.1016/j.jtct.2023.06.019. Epub 2023 Jun 30.
Outcomes for post-chimeric antigen receptor (CAR) T cell therapy (CART) relapse are poor. The utilization of a unique CAR T cell construct for post-CART failure is increasing, but this approach is not well described. In this study, with CART-A the first unique CAR T cell construct received and CART-B the second, the primary objective was to characterize outcomes following CART-B. Secondary objectives included evaluating safety and toxicity with sequential CART infusions; investigating the impact of potential factors, such as antigen modulation and interval therapy, on CART-B response; and characterizing long-term outcomes in patients receiving multiple CARTs. This was a retrospective review (NCT03827343) of children and young adults with B cell acute lymphoblastic leukemia (B-ALL) undergoing CART therapy who received at least 2 unique CART constructs, excluding interim CART reinfusions of the same product. Of 135 patients, 61 (45.1%) received 2 unique CART constructs, including 13 who received >2 CARTs over time. Patients included in this analysis received 14 distinct CARTs targeting CD19 and/or CD22. The median age at CART-A was 12.6 years (range, 3.3 to 30.4 years). The median time from CART-A to CART-B was 302 days (range, 53 to 1183 days). CART-B targeted a different antigen than CART-A in 48 patients (78.7%), owing primarily to loss of CART-A antigen target. The rate of complete remission (CR) was lower with CART-B (65.5%; 40 of 61) than with CART-A (88.5%; 54 of 61; P = .0043); 35 of 40 (87.5%) CART-B responders had CART-B targeting a different antigen than CART-A. Among the 21 patients with a partial response or nonresponse to CART-B, 8 (38.1%) received CART-B with the same antigen target as CART-A. Of 40 patients with CART-B complete response (CR), 29 (72.5%) relapsed. For the 21 patients with evaluable data, the relapse immunophenotype was antigen in 3 (14.3%), antigen in 7 (33.3%), antigen in 10 (47.6%), and lineage switch in 1 (4.8%). The median relapse-free survival following CART-B CR was 9.4 months (95% confidence interval [CI], 6.1 to 13.2 months), and overall survival was 15.0 months (95% CI, 13.0 to 22.7 months). Given the limited salvage options for post-CART relapse, identifying optimizing strategies for CART-B is critical. We raise awareness about the emerging use of CART for post-CART failure and highlight clinical implications accompanying this paradigm shift.
嵌合抗原受体 (CAR) T 细胞治疗 (CART) 后复发的结果较差。越来越多地使用独特的 CAR T 细胞构建物来治疗 CART 后失败，但这种方法尚未得到很好的描述。在这项研究中，CART-A 是第一个接受的独特 CAR T 细胞构建物，CART-B 是第二个，主要目的是描述 CART-B 后的结果。次要目标包括评估连续 CART 输注的安全性和毒性；研究潜在因素（如抗原调节和间隔治疗）对 CART-B 反应的影响；并描述接受多次 CART 的患者的长期结果。这是一项对接受 CAR T 治疗的 B 细胞急性淋巴细胞白血病 (B-ALL) 儿童和青少年进行的回顾性研究（NCT03827343），他们至少接受了 2 种独特的 CAR T 构建物，不包括同一产品的中期 CART 再输注。在 135 名患者中，61 名（45.1%）接受了 2 种独特的 CAR T 构建物，其中 13 名患者随着时间的推移接受了 >2 种 CAR T。接受分析的患者接受了 14 种针对 CD19 和/或 CD22 的不同 CAR T。CART-A 的中位年龄为 12.6 岁（范围，3.3 至 30.4 岁）。从 CART-A 到 CART-B 的中位时间为 302 天（范围，53 至 1183 天）。CART-B 的抗原靶点与 CART-A 不同，在 48 名患者（78.7%）中，主要是由于 CART-A 抗原靶点的丢失。CART-B 的完全缓解（CR）率（65.5%；61 名中的 40 名）低于 CART-A（88.5%；61 名中的 54 名；P =.0043）；40 名 CART-B 反应者中的 35 名（87.5%）的 CART-B 靶向抗原与 CART-A 不同。在对 CART-B 有部分反应或无反应的 21 名患者中，8 名（38.1%）接受了与 CART-A 相同抗原靶点的 CART-B。在 40 名 CART-B 完全缓解（CR）的患者中，29 名（72.5%）复发。对于 21 名可评估数据的患者，复发免疫表型为抗原阳性 3 例（14.3%），抗原阳性 7 例（33.3%），抗原阳性 10 例（47.6%），谱系转换 1 例（4.8%）。CART-B CR 后无复发生存期的中位数为 9.4 个月（95%置信区间 [CI]，6.1 至 13.2 个月），总生存期为 15.0 个月（95%CI，13.0 至 22.7 个月）。鉴于 CART 后复发的挽救选择有限，确定优化 CART-B 的策略至关重要。我们提高了对 CART 用于 CART 后失败的认识，并强调了伴随这一范式转变的临床意义。
