111 Armored CAR T cells secreting 4–1BB ligand crosslinked to PD-1 checkpoint inhibitor for enhanced solid tumor efficacy

Background Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematological malignancies but yet to achieve similar success in solid tumors due a lack persistence and function tumor microenvironment. We previously reported augmentation CAR an engineered model through secretion anti-PD-1 scFv, as shown by enhanced antitumor efficacy, expansion, vitality. 1 have since matured platform create superior cellular product – cells secreting single-chain trimeric 4-1BB ligand crosslinked scFv (αPD1-41BBL). signaling promotes cytotoxic lymphocytes proliferation survival targeting with agonist antibodies clinic been hindered low activity high toxicity. using endodomain for costimulatory signals demonstrated milder anti-tumor response longer compared costimulated CD28 endodomain. have, first time, secrete fusion protein containing soluble ligand. Methods hypothesized that crosslinking current would provide additional benefits is potentially translational value management resistant PD-1 blockade function. Therefore, we novel immunomodulatory consisting format ligand, which three extracellular domain units 41BBL are connected polypeptide linkers. The were then characterized vitro subcutaneous models. Results In vivo, CAR19.αPD1-41BBL exhibited reduced inhibitory upregulation, proliferation, less differentiated memory status without 4-1BB:4-1BBL costimulation. Accordingly, cell-treated mice displayed significantly improved growth control overall survival. Spurred on our preclinical CD19 antigen, produced mesothelin-targeting confirmed efficacy αPD1-41BBL cells. Conclusions Given better therapeutic expressing over αPD1 cells, believe it adopt improve especially given large number patients PD1/PD-L1 resistant. References Li S, Siriwon N, Zhang X, Yang Jin T, He F, et al. Enhanced cancer immunotherapy chimeric receptor–modified checkpoint inhibitors. Clin Cancer Res 2017;23(22):6982–92.