CD38 和 BCMA 双特异性 CAR-T 在复发或难治性多发性骨髓瘤中的高效和安全性。

BACKGROUND: B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy has obtained promising results in relapsed or refractory multiple myeloma (R/R MM), while some patients do not response, or relapse in short term after treatment. Combining with anti-CD38 might solve the problem of targeting BCMA alone. We aimed to assess the efficacy and safety of BCMA and CD38 (BCMA-CD38) bispecific CAR-T cells in R/R MM patients. METHODS: We did a single-center, single-arm clinical study at the Second Affiliated Hospital of Yangtze University in China. Patients meeting with the inclusion criteria were administered with fludarabine and cyclophosphamide before CAR-T cells infusion. Response and adverse events were assessed after infusion. This study was registered with the Chinese Clinical Trial Registration Center (ChiCTR1900026286). RESULTS: First, we found BCMA-CD38 CAR-T cells exhibited enhanced killing effect on BCMA+CD38+ cells in vitro, compared to BCMA CAR-T and CD38 CAR-T cells. We further demonstrated its anti-tumor activity in vivo. Then, we enrolled 16 R/R MM patients for safety and efficacy analyses. Of the 16 evaluable patients, 14 (87.5%) respond to the treatment, including 13 stringent complete response (sCR) and one partial response (PR), while two patients did not respond. At a median follow-up of 11.5 months, of the 13 patients who achieved sCR, 76.9% (10/13) did not relapse or progress during follow-up. Relapse occurred in 3 patients (Patient 2, 3 and 4) after achieving sCR. In sum, four patients died, of which one died of hemophagocytic lymphohistiocytosis syndrome secondary to severe cytokine release syndrome (CRS) and three died of disease progression or relapse. The 1-year progression-free survival rates was 68.8%. The 1-year overall survival rate was 75.0%. Extramedullary lesions were eliminated in 62.5% (5/8) patients. The most common symptoms after CAR-T infusion were cytopenia (16, 100%), fever (10, 62.5%), fatigue (8, 50.0%) and myalgias (8, 50.0%). Twelve patients (75.0%) were observed with various grades of CRS, of which five patients (31.3%) got serious CRS (Grade ≥ 3). The CAR+ cell expansion levels were associated with the severity of CRS. Transient clonal isotype switch was observed after CAR-T infusion. CONCLUSION: Our results confirm that BCMA-CD38 CAR-T cells therapy is feasible in treating R/R MM patients, with high response rate, low recurrence rate and manageable CRS, which will be a promising treatment option for R/R MM. TRIAL REGISTRATION: ChiCTR1900026286, registered on September 29, 2019, retrospectively registered, URL: https://www.chictr.org.cn/showproj.aspx?proj=43805.

背景：B 细胞成熟抗原（BCMA）嵌合抗原受体 T（CAR-T）细胞疗法在复发性或难治性多发性骨髓瘤（R/R MM）中取得了令人瞩目的效果，但有些患者在治疗后没有反应，或在短期内复发。与抗 CD38 联合使用可能解决单独靶向 BCMA 的问题。我们旨在评估 BCMA 和 CD38（BCMA-CD38）双特异性 CAR-T 细胞在 R/R MM 患者中的疗效和安全性。

方法：我们在中国长江大学第二附属医院进行了一项单中心、单臂临床研究。符合纳入标准的患者在 CAR-T 细胞输注前接受氟达拉滨和环磷酰胺治疗。输注后评估反应和不良事件。这项研究在中国临床试验注册中心（ChiCTR1900026286）注册。

结果：首先，我们发现 BCMA-CD38 CAR-T 细胞在体外对 BCMA+CD38+细胞的杀伤作用优于 BCMA CAR-T 和 CD38 CAR-T 细胞。我们进一步证明了它在体内的抗肿瘤活性。然后，我们招募了 16 名 R/R MM 患者进行安全性和疗效分析。在 16 名可评估的患者中，14 名（87.5%）对治疗有反应，包括 13 名严格完全缓解（sCR）和 1 名部分缓解（PR），而 2 名患者没有反应。在中位随访 11.5 个月时，在 13 名达到 sCR 的患者中，76.9%（10/13）在随访期间没有复发或进展。3 名患者（患者 2、3 和 4）在达到 sCR 后复发。总的来说，有 4 名患者死亡，其中 1 名死于严重细胞因子释放综合征（CRS）继发的噬血细胞性淋巴组织细胞增生症，3 名死于疾病进展或复发。1 年无进展生存率为 68.8%。1 年总生存率为 75.0%。62.5%（5/8）的患者消除了骨髓外病变。CAR-T 输注后最常见的症状是血细胞减少（16，100%）、发热（10，62.5%）、疲劳（8，50.0%）和肌痛（8，50.0%）。12 名患者（75.0%）出现不同程度的 CRS，其中 5 名患者（31.3%）出现严重 CRS（≥3 级）。CAR+细胞扩增水平与 CRS 的严重程度相关。CAR-T 输注后观察到短暂的同种型转换。

结论：我们的结果证实，BCMA-CD38 CAR-T 细胞疗法在治疗 R/R MM 患者中是可行的，具有高反应率、低复发率和可管理的 CRS，这将是 R/R MM 的一种有前途的治疗选择。

临床试验注册：ChiCTR1900026286，于 2019 年 9 月 29 日注册，回顾性注册，网址：https://www.chictr.org.cn/showproj.aspx?proj=43805。