GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts
GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts
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DOI：
10.1182/blood-2018-10-881722
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发表时间：
2019-02-14
期刊：
影响因子：
20.3
通讯作者：
Kenderian, Saad S.
中科院分区：
文献类型：
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作者：
Sterner, Rosalie M.;Sakemura, Reona;Kenderian, Saad S.
嵌合抗原受体T(CAR-T)细胞治疗是肿瘤治疗的新支柱，但其应用受到相关毒副作用的限制。这些包括细胞因子释放综合征(CRS)和神经毒性。尽管IL-6R拮抗剂tocilizumab已被批准用于CRS的治疗，但与CD19靶向CAR-T(CART19)细胞治疗相关的神经毒性尚无批准的治疗方法。最近的数据表明，单核细胞和巨噬细胞参与了CRS的发生和CAR-T细胞治疗后的神经毒性。因此，我们研究了中和粒细胞巨噬细胞集落刺激因子(GM-CSF)作为一种潜在的策略来管理CART19细胞相关的毒性。在这项研究中，我们表明，在体外和体内，用伦齐卢单抗中和GM-CSF并不抑制CART19细胞的功能。此外，在患者来源的异种移植中，用Lenzilumab中和GM-CSF后，CART19细胞的增殖得到了促进，白血病的持久控制得到了更好的维持。在急性淋巴细胞白血病患者CRS和神经炎症(NI)的异种移植模型中，GM-CSF中和导致中枢神经系统髓系和T细胞浸润减少，NI显著减少和CRS的预防。最后，我们通过在CAR-T细胞生产过程中破坏GM-CSF的CRISPR/Cas9，产生了GM-CSF缺陷的CART19细胞。与CART19细胞相比，这些GM-CSFk/o CAR-T细胞保持了正常的功能，体内抗肿瘤活性增强，总存活率提高。总之，这些研究阐明了一种通过GM-CSF中和来消除NI和CRS的新方法，这可能会潜在地增强CAR-T细胞的功能。Lenzilumab与CART19细胞治疗相结合的第二阶段研究正在计划中。
Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics; however, its application is limited by the associated toxicities. These include cytokine release syndrome (CRS) and neurotoxicity. Although the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19-targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential strategy to manage CART19 cell-associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 cell function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient-derived xenografts after GM-CSF neutralization with lenzilumab. In a patient acute lymphoblastic leukemia xenograft model of CRS and neuroinflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF-deficient CART19 cells through CRISPR/Cas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSFk/o CAR-T cells maintained normal functions and had enhanced antitumor activity in vivo, as well as improved overall survival, compared with CART19 cells. Together, these studies illuminate a novel approach to abrogate NI and CRS through GM-CSF neutralization, which may potentially enhance CAR-T cell function. Phase 2 studies with lenzilumab in combination with CART19 cell therapy are planned.