Chimeric Antigen Receptor T Cells Engineered to Secrete CD40 Agonist Antibodies Enhance Antitumor Efficacy

Abstract

BackgroundAlthough chimeric antigen receptor (CAR) T-cell therapy has made remarkable achievements against hematological malignancies, the efficacy of it against solid tumors has been limited. By being combined with immune checkpoint inhibitors, such as PD-1, PD-L1, or CTLA-4 antibodies, this therapy has been shown to be a promising strategy to enhance the antitumor efficacy of CAR-T cells. However, due to the fact that acquired resistance to checkpoint inhibitors will occur in most patients, it is vital to investigate other strategies to further improve the antitumor efficacy of CAR-T cell therapy in solid tumors. Recently, CD40 agonist antibodies have been shown to possess potential antitumor efficacy by activating the CD40 pathway.ResultsBased on the piggyBac transposon system, rather than the widely used viral vector, we constructed a meso3-CD40 CAR-T targeting region III of mesothelin (MSLN) that possesses the ability to secrete anti-CD40 antibodies. The results show that compared with meso3 CAR-T, which does not secrete the anti-CD40 antibody, meso3-CD40 CAR-T secreted more cytokines and had a relatively higher proportion of central memory T (TCM) cells after being stimulated by the target antigen. In addition, compared with meso3 CAR-T, we found that meso3-CD40 CAR-T had a more powerful cytotoxicity effect on target cells at a relatively low effector to target ratio. More importantly, we demonstrated that meso3-CD40 CAR-T also had enhanced antitumor activity in a human ovarian cancer xenograft in vivo.ConclusionsIn conclusion, these results showed that anti-CD40-secreting CAR-T cells generated by non-viral vectors could be a potential clinical strategy for improving the efficacy of CAR-T cell therapies.

The Role of Macrophages in Cancer Development and Therapy

“…ABBV-428 is currently being studied in Phase 1 clinical trial as monotherapy or in combination with nivolumab for the treatment of patients with advanced solid tumors (clinical trial: NCT02955251). Recently, CAR T cells secreting CD40 antibodies showed efficacy in a human ovarian cancer xenograft model in vivo [ 146 ]. Currently, at least ten therapeutics targeting CD40 are being studied in clinical trials.…”