Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
JCI Insight. 2018 Apr 19;3(8). doi: 10.1172/jci.insight.120505.
Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019).
Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT). All subjects had relapsed/refractory multiple myeloma and had previously undergone ASCT with less than 1 year progression-free survival (PFS).
ASCT + CTL019 was safe and feasible, with most toxicity attributable to ASCT and no severe cytokine release syndrome. Two of 10 subjects exhibited significantly longer PFS after ASCT + CTL019 compared with prior ASCT (479 vs. 181 days; 249 vs. 127 days). Correlates of favorable clinical outcome included peak CTL019 frequency in bone marrow and emergence of humoral and cellular immune responses against the stem-cell antigen Sox2. Ex vivo treatment of primary myeloma samples with a combination of CTL019 and CAR T cells against the plasma cell antigen BCMA reliably inhibited myeloma colony formation in vitro, whereas treatment with either CAR alone inhibited colony formation inconsistently.
CTL019 may improve duration of response to standard multiple myeloma therapies by targeting and precipitating secondary immune responses against myeloma-propagating cells.
Clinicaltrials.gov identifier NCT02135406.
Novartis, NIH, Conquer Cancer Foundation.
多发性骨髓瘤通常由于连续复发而导致致命，这些复发对治疗的反应逐渐变得耐药。CD19 通常不存在于主要的多发性骨髓瘤细胞群体上，但可能存在于具有独特骨髓瘤传播特性的次要亚群上。为了靶向骨髓瘤传播细胞，我们临床评估了针对 CD19 的嵌合抗原受体 (CAR) 修饰的自体 T 细胞 (CTL019)。
在挽救性高剂量美法仑和自体干细胞移植 (ASCT) 后，受试者接受 CTL019 治疗。所有受试者均患有复发性/难治性多发性骨髓瘤，并且在无进展生存期 (PFS) 少于 1 年的情况下之前已接受 ASCT。
ASCT+CTL019 是安全且可行的，大多数毒性归因于 ASCT，且无严重细胞因子释放综合征。与之前的 ASCT 相比，10 例受试者中有 2 例在接受 ASCT+CTL019 后 PFS 显著延长 (479 天 vs. 181 天；249 天 vs. 127 天)。有利临床结果的相关因素包括骨髓中 CTL019 的峰值频率以及针对干细胞抗原 Sox2 出现的体液和细胞免疫反应。体外用 CTL019 和针对浆细胞抗原 BCMA 的 CAR T 细胞联合处理原发性骨髓瘤样本可可靠地抑制骨髓瘤集落形成，而单独用任何一种 CAR 处理则不一致地抑制集落形成。
CTL019 通过靶向和引发针对骨髓瘤传播细胞的继发性免疫反应，可能改善多发性骨髓瘤标准治疗的反应持续时间。
Clinicaltrials.gov 标识符 NCT02135406。
诺华、NIH、征服癌症基金会。
