Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma
Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma
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DOI：
10.1172/jci.insight.120505
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发表时间：
2018-04-19
期刊：
影响因子：
8
通讯作者：
June, Carl H.
中科院分区：
文献类型：
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作者：
Garfall, Alfred L.;Stadtmauer, Edward A.;June, Carl H.
背景多发性骨髓瘤通常是致命的，因为连续复发对治疗变得越来越难治。CD 19通常不存在于显性多发性骨髓瘤细胞群中，但可能存在于具有独特骨髓瘤增殖特性的次要亚群中。为了靶向骨髓瘤增殖细胞，我们临床评估了用针对CD 19（CTL 019）的嵌合抗原受体（CAR）转导的自体T细胞。受试者在补救性高剂量美法仑和自体干细胞移植（ASCT）后接受CTL 019。所有受试者均患有复发性/难治性多发性骨髓瘤，既往接受过ASCT，无进展生存期（PFS）小于1年。ASCT + CTL 019安全可行，大部分毒性可归因于ASCT，无严重细胞因子释放综合征。10例受试者中有2例在ASCT + CTL 019后的PFS显著长于既往ASCT（479 vs. 181天; 249 vs. 127天）。有利的临床结果的相关性包括骨髓中的峰值CTL 019频率和针对干细胞抗原Sox 2的体液和细胞免疫应答的出现。用CTL 019和CAR T细胞联合抗浆细胞抗原BCMA体外处理原发性骨髓瘤样品可靠地抑制了骨髓瘤集落形成，而单独用CAR处理抑制集落形成不一致。CTL 019可以通过靶向和促进针对骨髓瘤增殖细胞的二次免疫应答来改善对标准多发性骨髓瘤疗法的应答持续时间。
BACKGROUND. 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).METHODS. 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).RESULTS. 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.CONCLUSION. CTL019 may improve duration of response to standard multiple myeloma therapies by targeting and precipitating secondary immune responses against myeloma-propagating cells.