肿瘤细胞治疗研究
英文原题：An Oral PROTAC Targeting HPK1 Degradation Potentiates Anti-Solid Tumor Immunity.
An Oral PROTAC Targeting HPK1 Degradation Potentiates Anti-Solid Tumor Immunity.
造血祖细胞激酶1（HPK1）敲除已被确定为增强抗肿瘤免疫应答的有效途径。
造血祖细胞激酶1（HPK1）敲除已被认为是增强抗肿瘤免疫应答的有效途径。本研究开发了一种靶向HPK1的口服蛋白水解靶向嵌合体（PROTAC），以高效、选择性地降解HPK1，从而改善免疫治疗结局。在NSG小鼠的人宫颈癌术后肿瘤模型中，口服PROTAC可进入肿瘤、下调局部给药CAR-T细胞中的HPK1水平，并提高其抑制实体瘤复发的效能，达到50%的部分缓解（PR）率和50%的完全缓解（CR）率。此外，在BALB/c小鼠CT26实体瘤模型中，口服PROTAC可增强抗PD-L1抗体对肿瘤生长的抑制能力；其作用伴随肿瘤内CD45阳性免疫细胞比例由0.7%升至1.5%，CD3阳性T细胞比例由0.2%升至0.5%。
Hematopoietic progenitor pinase1 (HPK1) knockout has been identified as an efficient route to enhance anti-tumor immune response. Here, this work develops an oral proteolysis targeting chimera (PROTAC) targeting HPK1 to efficiently and selectively degrade HPK1 to augment immunotherapeutic outcomes. In a postoperative tumor model of human cervical cancer in NSG mice, the orally-administrated PROTAC can reach tumors, down-regulate HPK1 levels in locally-administrated CAR-T cells, and promote their efficiency in inhibiting solid tumor recurrence, achieving 50% partial response (PR) and 50% complete response (CR). In addition, oral administration of PROTAC can amplify the suppression capability of the anti-PD-L1 antibody on the growth of CT26 solid tumors in BALB/c mice by promoting the infiltration of CD45-positive immune cells from 0.7% to 1.5% and CD3-positive T cells from 0.2% to 0.5% within the tumors.
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