The adoptive transfer of chimeric antigen receptor T cells (CAR-T cells) has demonstrated impressive clinical benefits in patients with hematological malignancies, however, no equivalent successes have been observed yet in solid tumors. The unsatisfactory outcome with solid tumors could be partly attributed to the lack of appropriate tumor-specific antigens. Here, we describe a novel strategy of tumor retargeting universal chimeric antigen receptor T cell therapy (TRUE-CAR T).
EGFRvIII antigenic peptide (EvIII) was conjugated with DSPE-PEG-Mal and was applied to construct fusogenic nanoparticles. Particle size, surface charge and stability of the nanoparticles were characterized. The antigen modification effect of EvIII-NP was evaluated through flow cytometry and confocal microscopy. In vivo anti-tumor effect and safety profile of TRUE-CAR-T were evaluated through tumor growth curve and tumor survival curve in subcutaneous and abdominal dissemination model of gastric cancer.
MALDI-TOF-MS analysis demonstrated that EvIII antigenic peptide was successfully conjugated to DSPE-PEG-Mal. The particle size and surface charge of EvIII-NP was 113.1±1.24 nm and 11.2±0.12mV respectively. Flow cytometry and confocal image verified that EvIII-NP can modify tumor cells with antigen on their membrane. Near-infrared imaging indicated that the accumulation of intravenously transfusing EvIII-NPs in subcutaneous tumor reached its peak in 24 hours after administration. In vivo experiment demonstrated that the combination therapy of EvIII-NPs and EvIII CAR-T cells adoptive transfer effectively suppressed tumor growth and prolonged the life of experimental animals without obvious toxicity and side effects, in the subcutaneous and abdominal dissemination model of gastric cancer.
The TRUE-CAR T strategy possesses great clinical application potential with feasibility, universality and safety, providing new perspectives for CAR-T cells therapy in solid tumors.
Legal entity responsible for the study
Mouse studies were approved by the Laboratory Animal Care and Use Committee of the Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School.
Grants from the National Natural Science Foundation of China (grant number 81930080, 82072926, 81572601), Natural Science Foundation of Jiangsu Province (grant number BK20191114), and Nanjing Medical Science and Technique Development Foundation (No. QRX17038).
All authors have declared no conflicts of interest.