![]() ![]() ![]() IL12, a well-known potent proinflammatory cytokine composed of p35 and p40 subunits, has biological significance in both adaptive and innate immunity ( 6, 7). One such candidate is Interleukin 12(IL12), which strongly enhances the response of innate and adoptive immune cells to cancer cells ( 6). A strategy for overcoming the suppression involves the use of the fourth generation of CARs, which are CAR T cells engineered to constitutively or inducibly express proinflammatory cytokines ( 5). Despite encouraging success in the hematologic malignancies, however, solid tumors still escape immune detection and elimination because of the immunosuppressive tumor microenvironment. CARs are synthetic receptors that are able to confer antigen-binding and activating functions on T cells with the aim of therapeutically targeting cancer cells ( 4). At present, two anti-CD19 CAR-T cells have been approved by the US Food and Drug Administration (FDA). T cells genetically engineered to express chimeric antigen receptors (CAR) constitute the most clinically advanced form of ACT approved to date for the treatment of leukemias and lymphomas ( 3). Local expression of IL12 by synNotch-engineered NK92 cells might be a safe approach to enhance the clinical outcome of CAR-T cell therapy.Īdoptive cell transfer (ACT)–based immunotherapy with autologous tumor infiltrating lymphocytes has mediated dramatic tumor regressions in patients with melanoma ( 1, 2). Taken together, our results demonstrated that IL12 supplementation by synNotch-engineered NK92 cells could secrete IL12 in a target-dependent manner, and promote the antitumor efficiency of CAR-T cells. In vivo GPC3-Syn-IL12-NK92 cells controlling IL12 production could enhance the antitumor ability of GPC3-redirected CAR T cells and increase the infiltration of T cells without inducing toxicity. NK92 cells transduced with the GPC3-specific synNotch receptor could produce the proinflammatory cytokine IL12 (GPC3-Syn-IL12-NK92) in response to GPC3 antigen expressed in cancer cells. Compared with the nuclear factor of activated T-cells (NFATs) responsive promoter, which is another regulatory element, the synNotch receptor was better at controlling the expression of cytokines. Here, we explored the possibility of using synNotch receptor-engineered NK92 cells to selectively secrete IL12 at the tumor site and increase the antitumor activities of chimeric antigen receptor (CAR)-modified T cells. NK92 cell is a human natural killer (NK) cell line which has been developed as tools for adjuvant immunotherapy of cancer. Recently, synthetic Notch (synNotch) receptors have been developed that induce transcriptional activation and deliver therapeutic payloads in response to the reorganization of specific antigens. However, systemic administration of IL12 has serious side effects that limit its clinical application in patients. IL12 is an immune-stimulatory cytokine for key immune cells including T cells and NK cells. ![]() 2State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.Hong Luo 1 †, Xiuqi Wu 2 †, Ruixin Sun 2, Jingwen Su 2, Yi Wang 1, Yiwei Dong 2, Bizhi Shi 2, Yansha Sun 2, Hua Jiang 2 and Zonghai Li 1,2,3 * ![]()
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