1 Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
2 Department of Microbiology, Immunology, and Molecular Genetics, University of California , Los Angeles, Los Angeles, California.
J Interferon Cytokine Res. 2018 Jun;38(6):239-254. doi: 10.1089/jir.2018.0030.
An important emerging form of immunotherapy targeting B cell malignancies is chimeric antigen receptor (CAR) T cell therapy. Despite encouraging response rates of anti-CD19 CAR T cell therapy in B cell lymphomas, limited durability of response necessitates further study to potentiate CAR T cell efficacy. Antibody-targeted interferon (IFN) therapy is a novel approach in immunotherapy. Given the ability of IFNs to promote T cell activation and survival, target cell recognition, and cytotoxicity, we asked whether antibody-targeted IFN could enhance the antitumor effects of anti-CD19 CAR T cells. We produced an anti-CD20-IFN fusion protein containing the potent type 1 IFN isoform alpha14 (α14), and demonstrated its ability to suppress proliferation and induce apoptosis of human B cell lymphomas. Indeed, with the combination of anti-CD20-hIFNα14 and CAR T cells, we found enhanced cell killing among B cell lymphoma lines. Importantly, for all cell lines pretreated with anti-CD20-hIFNα14, the subsequent cytokine production by CAR T cells was markedly increased regardless of the degree of cell killing. Thus, several activities of CD19 CAR T cells were enhanced in the presence of anti-CD20-hIFNα14. These data suggest that antibody-targeted IFN may be an important novel approach to improving the efficacy of CAR T cell therapy.
一种针对 B 细胞恶性肿瘤的重要新兴免疫疗法是嵌合抗原受体 (CAR) T 细胞疗法。尽管抗 CD19 CAR T 细胞疗法在 B 细胞淋巴瘤中具有令人鼓舞的反应率，但反应的持久性有限，需要进一步研究以增强 CAR T 细胞的疗效。抗体靶向干扰素 (IFN) 治疗是免疫疗法中的一种新方法。鉴于 IFNs 能够促进 T 细胞激活和存活、靶细胞识别和细胞毒性，我们想知道抗体靶向 IFN 是否可以增强抗 CD19 CAR T 细胞的抗肿瘤作用。我们生产了一种包含强效 I 型 IFN 亚型α14 (α14) 的抗 CD20-IFN 融合蛋白，并证明其能够抑制人 B 细胞淋巴瘤的增殖并诱导其凋亡。事实上，我们发现，在抗 CD20-hIFNα14 和 CAR T 细胞的联合作用下，B 细胞淋巴瘤系的细胞杀伤作用增强。重要的是，对于所有用抗 CD20-hIFNα14 预处理的细胞系，CAR T 细胞随后产生的细胞因子明显增加，而与细胞杀伤程度无关。因此，在存在抗 CD20-hIFNα14 的情况下，CD19 CAR T 细胞的几种活性得到了增强。这些数据表明，抗体靶向 IFN 可能是一种提高 CAR T 细胞疗法疗效的重要新方法。
