PT  - JOURNAL ARTICLE
AU  - Xiaohui Wang
AU  - Wei Qiu
AU  - Haoyu Liu
AU  - Min He
AU  - Wei He
AU  - Zhan Li
AU  - Zhiqiang Wu
AU  - Xiang Xu
AU  - Ping Chen
TI  - The inducible secreting TLR5 agonist, CBLB502, enhances the anti-tumor activity of CAR133-NK92 cells in colorectal cancer
AID  - 10.20892/j.issn.2095-3941.2023.0033
DP  - 2023 Sep 15
TA  - Cancer Biology & Medicine
PG  - 662--681
VI  - 20
IP  - 9
4099  - http://www.cancerbiomed.org/content/20/9/662.short
4100  - http://www.cancerbiomed.org/content/20/9/662.full
SO  - Cancer Biology & Medicine2023 Sep 15; 20
AB  - Objective: CAR-T/NK cells have had limited success in the treatment of solid tumors, such as colorectal cancer (CRC), in part because of the heterogeneous nature of tumor-associated antigens that lead to antigen-negative relapse after the initial response. This barrier might be overcome by enhancing the recruitment and durability of endogenous immune cells.Methods: Immunohistochemistry and flow cytometry were used to assess the expression of CD133 antigen in tissue microarrays and cell lines, respectively. Retroviral vector transduction was used to generate CBLB502-secreting CAR133-NK92 cells (CAR133-i502-NK92). The tumor killing capacity of CAR133-NK92 cells in vitro and in vivo were quantified via LDH release, the RTCA assay, and the degranulation test, as well as measuring tumor bioluminescence signal intensity in mice xenografts.Results: We engineered CAR133-i502-NK92 cells and demonstrated that those cells displayed enhanced proliferation (9.0 × 104 cells vs. 7.0 × 104 cells) and specific anti-tumor activities in vitro and in a xenogeneic mouse model, and were well-tolerated. Notably, CBLB502 secreted by CAR133-i502-NK92 cells effectively activated endogenous immune cells. Furthermore, in hCD133+/hCD133− mixed cancer xenograft models, CAR133-i502-NK92 cells suppressed cancer growth better than the counterparts (n = 5, P = 0.0297). Greater T-cell infiltration was associated with greater anti-tumor potency (P < 0.0001).Conclusions: Armed with a CBLB502 TLR5 agonist, CAR133-NK92 cells were shown to be capable of specifically eliminating CD133-positive colon cancer cells in a CAR133-dependent manner and indirectly eradicating CD133-negative colon cancer cells in a CBLB502-specific endogenous immune response manner. This study describes a novel technique for optimizing CAR-T/NK cells for the treatment of antigenically-diverse solid tumors.The data generated in this study are available upon request from the corresponding author.