SMAD7 overexpression boosts EGFR-CAR-T function against NSCLC
Epidermal growth factor receptor (EGFR)-mothers against decapentaplegic homologue 7 (SMAD7)-Chimeric antigen receptor (CAR) T-cell therapy against nonsmall-cell lung cancer (NSCLC) is on a par with EGFR-dominant‒negative transforming growth factor (TGFbeta) receptor 2 (DNR)-CAR-T in terms of efficacy and resistance to negative TGFβ regulation, a study has shown.
A team of investigators had transduced human T-cells with the lentivirus constructs to produce three types of CAR T-cell therapy, namely (1) EGFR-CAR-T, (2) EGFR-DNR-CAR-T, and (3) EGFR-SMAD7-CAR-T. They described the proliferation, expression of proinflammatory cytokines, activation profiles, and lysis capacity in co-cultures with A549 lung carcinoma cells with and without TGFβ neutralizing antibodies.
Finally, the therapeutic potential of EGFR-SMAD7-CAR-T was tested in the A549 cells tumour-bearing mice model.
Based on the results, EGFR-DNR-CAR-T and EGFR-SMAD7-CAR-T both exhibited a higher proliferation rate and lysis capacity to A549 compared with EGFR-CAR-T. Notably, neutralization of TGFβ by the antibodies improved the performance of EGFR-CAR-T.
In vivo, EGFR-DNR-CAR-T and EGFR-SMAD7-CAR-T brought about complete tumour resorption by day 20, while conventional CAR T-cell therapy only generated a partial effect.
“Recent advancements in immunotherapy led to the development of CAR T-cell therapy,” the investigators said.
“CAR-T cell therapy in NSCLC is hindered by overexpression of TGFβ in the cancer cells that have a negative regulatory role on T-cells activity. This study characterized CAR-T with overexpression of SMAD, a negative regulator of TGFβ downstream signaling,” they added.