Rationally designed approaches to augment CAR-T therapy for solid tumor treatment

Chaojie Zhu; Qing Wu; Tao Sheng; Jiaqi Shi; Xinyuan Shen; Jicheng Yu; Yang Du; Jie Sun; Tingxizi Liang; Kaixin He; Yuan Ding; Hongjun Li; Zhen Gu; Weilin Wang

doi:10.1016/j.bioactmat.2023.11.002

Rationally designed approaches to augment CAR-T therapy for solid tumor treatment

Bioact Mater. 2023 Nov 26:33:377-395. doi: 10.1016/j.bioactmat.2023.11.002. eCollection 2024 Mar.

Authors

Chaojie Zhu^{1

2

3}, Qing Wu^{1

3}, Tao Sheng^{1

3}, Jiaqi Shi^{1

3}, Xinyuan Shen^{1

3}, Jicheng Yu¹, Yang Du², Jie Sun^{3

4}, Tingxizi Liang¹, Kaixin He¹, Yuan Ding^{2

5

6}, Hongjun Li^{1

2

3}, Zhen Gu^{1

3

7

8}, Weilin Wang^{2

5

6}

Affiliations

¹ Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
² Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
³ Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China.
⁴ Department of Cell Biology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
⁵ Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, 310009, China.
⁶ ZJU-Pujian Research & Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, 310058, China.
⁷ Jinhua Institute of Zhejiang University, Jinhua, 321299, China.
⁸ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.

Abstract

Chimeric antigen receptor T cell denoted as CAR-T therapy has realized incredible therapeutic advancements for B cell malignancy treatment. However, its therapeutic validity has yet to be successfully achieved in solid tumors. Different from hematological cancers, solid tumors are characterized by dysregulated blood vessels, dense extracellular matrix, and filled with immunosuppressive signals, which together result in CAR-T cells' insufficient infiltration and rapid dysfunction. The insufficient recognition of tumor cells and tumor heterogeneity eventually causes cancer reoccurrences. In addition, CAR-T therapy also raises safety concerns, including potential cytokine release storm, on-target/off-tumor toxicities, and neuro-system side effects. Here we comprehensively review various targeting aspects, including CAR-T cell design, tumor modulation, and delivery strategy. We believe it is essential to rationally design a combinatory CAR-T therapy via constructing optimized CAR-T cells, directly manipulating tumor tissue microenvironments, and selecting the most suitable delivery strategy to achieve the optimal outcome in both safety and efficacy.

Keywords: CAR construct design; CAR-T therapy; Cancer immunotherapy; Delivery strategy; Drug delivery; Tumor modulation.