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Published on: September 18, 2013
C-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial
Shiyu Zuo1,2, Chuo Li1,2,3, Xiaolei Sun1,2
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Abstract:
Chimeric antigen receptor (CAR) T cells show suboptimal efficacy in acute myeloid leukemia (AML). We find that CAR T cells exposed to myeloid leukemia show impaired activation and cytolytic function, accompanied by impaired antigen receptor downstream calcium, ZAP70, ERK, and C-JUN signaling, compared to those exposed to B-cell leukemia. These defects are caused in part by the high expression of CD155 by AML. Overexpressing C-JUN, but not other antigen receptor downstream components, maximally restores anti-tumor function. C-JUN overexpression increases costimulatory molecules and cytokines through reinvigoration of ERK or transcriptional activation, independent of anti-exhaustion. We conduct an open-label, non-randomized, single-arm, phase I trial of C-JUN-overexpressing CAR-T in AML (NCT04835519) with safety and efficacy as primary and secondary endpoints, respectively. Of the four patients treated, one has grade 4 (dose-limiting toxicity) and three have grade 1-2 cytokine release syndrome. Two patients have no detectable bone marrow blasts and one patient has blast reduction after treatment. Thus, overexpressing C-JUN endows CAR-T efficacy in AML.
Insights
Overexpressing C-JUN in chimeric antigen receptor (CAR) T cells improves their function against acute myeloid leukemia (AML). This approach, tested in a Phase I trial, showed promising anti-leukemia activity and manageable safety.
Area of Science:
- Immunotherapy
- Cancer Biology
- Cellular Signaling
Background:
- Chimeric antigen receptor (CAR) T cells exhibit limited effectiveness in treating acute myeloid leukemia (AML).
- CAR T cells encounter functional impairments when exposed to myeloid leukemia, unlike B-cell leukemia, due to specific signaling pathway defects.
Purpose of the Study:
- To investigate the mechanisms behind CAR T-cell dysfunction in AML.
- To evaluate the therapeutic potential of enhancing C-JUN signaling in CAR T-cells for AML treatment.
- To assess the safety and efficacy of C-JUN-overexpressing CAR T-cells in a Phase I clinical trial for AML.
Main Methods:
- Comparative analysis of CAR T-cell activation and signaling pathways upon exposure to myeloid versus B-cell leukemia.
- Genetic engineering of CAR T-cells to overexpress C-JUN.
- Conducting an open-label, single-arm, Phase I clinical trial (NCT04835519) to evaluate C-JUN-overexpressing CAR T-cells in AML patients.
Main Results:
- CAR T-cells showed impaired activation and cytolytic function against AML, linked to defects in calcium, ZAP70, ERK, and C-JUN signaling, partly due to high CD155 expression on AML cells.
- Overexpression of C-JUN, but not other signaling components, significantly restored anti-tumor function by enhancing costimulatory molecules and cytokines via ERK signaling or transcriptional activation.
- The Phase I trial reported one case of dose-limiting toxicity (grade 4) and three cases of cytokine release syndrome (grade 1-2) among four treated patients. Two patients achieved no detectable bone marrow blasts, and one showed blast reduction.
Conclusions:
- C-JUN overexpression can overcome CAR T-cell dysfunction in AML.
- Enhanced C-JUN signaling rejuvenates CAR T-cell anti-tumor activity, offering a potential strategy to improve immunotherapy for AML.
- The Phase I trial suggests that C-JUN-overexpressing CAR T-cells have potential therapeutic efficacy in AML with manageable toxicity.
