CAR-T cells targeting CD155 reduce tumor burden in preclinical models of leukemia and solid tumors
Tianchen Xiong, Ge Wang, Peng Yu, Zhenlong Li, Debao Li, Jianying Zhang, Song Lu, Ruiqi Yang, Xiaolong Lian, Jianhong Mi, Rui Ma, Zhiyao Li, Guido Marcucci, Tingting Zhao, Michael A. Caligiuri, Jianhua Yu
Tianchen Xiong, Ge Wang, Peng Yu, Zhenlong Li, Debao Li, Jianying Zhang, Song Lu, Ruiqi Yang, Xiaolong Lian, Jianhong Mi, Rui Ma, Zhiyao Li, Guido Marcucci, Tingting Zhao, Michael A. Caligiuri, Jianhua Yu
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Research Article Oncology

CAR-T cells targeting CD155 reduce tumor burden in preclinical models of leukemia and solid tumors

Abstract

CAR-T cells are a powerful yet expensive tool in cancer immunotherapy. Although their use in targeting hematological malignancies is well established, using a single CAR-T cell therapy to treat both hematological and solid tumors, which can reduce cost, remains largely unexplored. In this study, we identified CD155, an adhesion molecule that is upregulated during tumor progression, as a target for CAR-T cell therapy in both leukemia and solid tumors. We engineered CAR-T cells using human and mouse anti–CD155 antibodies generated from a Berkeley Lights’ Beacon platform. These CAR-T cells demonstrated potent antitumor activity, significantly reducing tumor burden in preclinical models of acute myeloid leukemia, non–small cell lung cancer, and pancreatic cancer. To reduce potential allogeneic rejection, we generated CAR-T cells using humanized anti–CD155 antibody sequences that retained efficacy. Additionally, murine CAR-T cells targeting mouse CD155 exhibited limited toxic side effects in immunocompetent mice, highlighting the favorable safety profile of this therapy. These findings suggest that CD155 can be targeted by CD155 CAR-T cells safely and effectively, representing an innovative cellular therapeutic strategy that has the potential to expand its scope across both AML and multiple solid tumors, thereby lowering the cost of cellular immunotherapy, especially as allogenic, universal, and off-the-shelf CAR-T cell therapies advance to the clinic.

Authors

Tianchen Xiong, Ge Wang, Peng Yu, Zhenlong Li, Debao Li, Jianying Zhang, Song Lu, Ruiqi Yang, Xiaolong Lian, Jianhong Mi, Rui Ma, Zhiyao Li, Guido Marcucci, Tingting Zhao, Michael A. Caligiuri, Jianhua Yu

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Figure 4

CD155 CAR-T cells efficiently lyse primary AML blasts in vitro and in vivo.

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CD155 CAR-T cells efficiently lyse primary AML blasts in vitro and in vi...
(A) Representative flow cytometry plots of the percentage showing CD155 expression on primary AML blasts. FSC-H (forward scatter height) was used to assess cell size. (B) Representative flow cytometry plots (left) and statistics (right) showing the percentage of primary AML blasts cell death cocultured at indicated ratios with mock T or CD155 CAR-T cells for 4 hours (n = 4 individual donors). (C) Representative flow cytometry plots (left) and statistics (right) showing the percentage of IFN-γ+ and TNF+ T cells in mock T or CD155 CAR-T cells cocultured with primary AML blasts for 4 hours (n = 4 individual donors). IFN-γ was detected using a phycoerythrin-conjugated antibody (IFN-γ–PE), and TNF was detected using a Brilliant Violet 650–conjugated antibody (TNF-BV650). (D) Diagram of the treatment scheme used for in vivo experiments. AML blasts (n = 2 × 106) were i.v. injected into NSG mice, followed by an i.v. infusion of indicated number of mock T cells or CD155 CAR-T cells (n = 5 mice per group). (E) Quantitative analysis of tumor cells in peripheral blood of mice treated with mock T or CD155 CAR-T cells. (F) Survival curves of AML-bearing mice after different treatments. Data represent the mean ± SD and were analyzed by 2-way ANOVA with repeated measures (B) or 2-tailed Student’s t tests (C and E). For Kaplan-Meier survival curves, statistical significance was calculated with a log-rank test (F).