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

• DOI: 10.1136/jitc-2021-sitc2021.111
• Publication Date: 2021-11-09T15:02:49Z
• Authors: Zachary Dunn; Yun Qu; Melanie MacMullan; Xianhui Chen; Gunce Cinay; Pin Wang
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

<h3>Background</h3> 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. <h3>Methods</h3> 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. <h3>Results</h3> 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. <h3>Conclusions</h3> Given better therapeutic expressing over αPD1 cells, believe it adopt improve especially given large number patients PD1/PD-L1 resistant. <h3>References</h3> Li S, Siriwon N, Zhang X, Yang Jin T, He F, et al. Enhanced cancer immunotherapy chimeric receptor–modified checkpoint inhibitors. <i>Clin Cancer Res</i> 2017;23(22):6982–92.