An Oral PROTAC Targeting HPK1 Degradation Potentiates Anti‐Solid Tumor Immunity

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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Publication Details

Journal
Advanced Materials
Published
2024-11-20
DOI
https://doi.org/10.1002/adma.202411454
Citations
14
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
3.96

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article

An Oral PROTAC Targeting HPK1 Degradation Potentiates Anti‐Solid Tumor Immunity

Ziyan Liao, Zhen Gu, Xiaowu Dong, Yinxian Yang et al.
14 citations
Advanced Materials
CAR-T cell therapy research
3.96
article

An Oral PROTAC Targeting HPK1 Degradation Potentiates Anti‐Solid Tumor Immunity

Ziyan Liao, Zhen Gu, Xiaowu Dong, Yinxian Yang, Wei Wu, Yugang Guo, Jiaqi Shi, Jinxin Che, Yanfang Wang, Yuejun Yao, Jinqiang Wang, Mingfei Wu, Xinwei Wei, Jianchang Xu, Yun Liu
article en
14 citations

Abstract

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.

Advanced MaterialsVol. 37(3)
Ministry of Education of the People's Republic of China (CN), Sir Run Run Shaw Hospital (CN), Jinhua Academy of Agricultural Sciences (CN), Second Affiliated Hospital of Zhejiang University (CN), Zhejiang University (CN)
National Natural Science Foundation of China, Fundamental Research Funds for the Central Universities, Fundamental Research Funds for Central Universities of the Central South University, Natural Science Foundation of Zhejiang Province
Good health and well-being
Openalex Percentile: Top 5%
CAR-T cell therapy research
3.96
DOISourceOpenAlex
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