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 5

CD155 CAR-T cells show strong antitumor effects against solid tumors.

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CD155 CAR-T cells show strong antitumor effects against solid tumors. (A...
(A and B) Representative flow cytometry plots (left) and statistics (right) showing the percentage of A549 (A) or Capan-1 (B) cell death cocultured at indicated ratios with mock T or CD155 CAR-T cells for 4 hours (n = 4 individual donors). (C and D) A549 or Capan-1 cells were cultured at the indicated ratios with mock T or CD155 CAR-T cells for 72 hours. Real-time cell analysis of the cytotoxicity of mock T or CD155 CAR-T cells against A549 (C) or Capan-1 (D) tumor cells is presented as the growth index of the residual cancer cells (n = 4 individual donors). (E) Diagram of the treatment scheme used for in vivo experiments. A549 tumor cells (n = 1 × 105) 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. Capan-1 tumor cells (n = 1 × 105) were i.p. injected into NSG mice, followed by an i.p. infusion of indicated number of mock T cells or CD155 CAR-T cells. (F–H) Bioluminescence images (BLIs) (F), quantification of tumor burden (G), and survival curves (H) in A549 tumor-bearing mice after different treatments (n = 5 mice per group). (I–K) Bioluminescence images (I), quantification of tumor burden (J), and survival curves (K) in Capan-1 tumor-bearing mice after different treatments (n = 3 mice in mock T group; n = 4 mice in CD155 CAR-T group). Data represent the mean ± SD (A and B) and were analyzed by 2-way ANOVA with repeated measures (A, B, G, and J). For Kaplan-Meier survival curves, statistical significance was calculated with a log-rank test (H and K).