Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Mol Ther. 2022 Jun 1;30(6):2315-2326. doi: 10.1016/j.ymthe.2022.02.005. Epub 2022 Feb 9.
We have reported previously that CD33 myeloid-derived suppressor cells (MDSCs) play a direct role in the pathogenesis of myelodysplastic syndromes (MDSs) and that their sustained activation contributes to hematopoietic and immune impairment, including modulation of PD1/PDL1. MDSCs can also limit the clinical activity of immune checkpoint inhibition in solid malignancies. We hypothesized that depletion of MDSCs may ameliorate resistance to checkpoint inhibitors and, hence, targeted them with AMV564 combined with anti-PD1 in MDS bone marrow (BM) mononuclear cells (MNCs) enhanced activation of cytotoxic T cells. AMV564 was active in vivo in a leukemia xenograft model when co-administered with healthy donor peripheral blood MNCs (PBMCs). Our findings provide a strong rationale for clinical investigation of AMV564 as a single agent or in combination with an anti-PD1 antibody and in particular for treatment of cancers resistant to checkpoint inhibitors.
我们之前曾报道过，CD33 髓系来源的抑制细胞（MDSCs）在骨髓增生异常综合征（MDS）的发病机制中发挥直接作用，其持续激活导致造血和免疫功能受损，包括 PD1/PDL1 的调节。MDSCs 还可以限制免疫检查点抑制剂在实体恶性肿瘤中的临床活性。我们假设耗尽 MDSCs 可能会改善对检查点抑制剂的耐药性，因此，我们在 MDS 骨髓（BM）单核细胞（MNC）中用 AMV564 联合抗 PD1 靶向 MDSC，增强了细胞毒性 T 细胞的激活。当与健康供体外周血 MNC（PBMC）联合使用时，AMV564 在白血病异种移植模型中具有体内活性。我们的研究结果为 AMV564 作为单一药物或与抗 PD1 抗体联合使用的临床研究提供了强有力的依据，特别是用于治疗对检查点抑制剂耐药的癌症。
