Combined 4-1BB and ICOS co-stimulation improves anti-tumor efficacy and persistence of dual anti-CD19/CD20 chimeric antigen receptor T cells

Chimeric antigen receptor (CAR) T-cell therapy is a promising therapeutic strategy against lymphoma. However, post-treatment relapses due to antigen loss remain a challenge. Here the authors designed a novel bicistronic CAR construct and tested its functions in vitro and in vivo. The CAR construct consisted of individual anti-CD19 and antiCD20 single-chain fragment variables equipped with ICOS-CD3z and 4-1BB-CD3z intracellular domains, respectively. The CD19 and CD20 bicistronic CAR T cells exhibited tumor lytic capacities equivalent to corresponding monospecific CART cells. Moreover, when stimulated with CD19 and CD20 simultaneously, the bicistronic CAR T cells showed prolonged persistence and enhanced cytokine generation compared with single stimulations. Interestingly, the authors found that the 4-1BB signal was predominant in the signaling profiles of ICOS and 4-1BB doubly activated CART cells. In vivo study using a CD19/CD20 double-positive tumor model revealed that the bicistronic CART cells were more efficient than monospecific CD19 CART cells in eradicating tumors and prolonging mouse survival. The authors' novel bicistronic CD19/CD20 CAR T cells demonstrate improved anti-tumor efficacy in response to dual antigen stimulations. These data provide optimism that this novel bicistronic CAR construct can improve treatment outcomes in patients with relapsed/refractory B cell malignancy. (c) 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.

Automated summary

The authors designed a novel bicistronic CAR construct and demonstrated its enhanced anti-tumor efficacy in response to dual antigen stimulations. The bicistronic CAR T cells showed prolonged persistence and improved cytokine generation when stimulated with CD19 and CD20 simultaneously, making them more efficient in eradicating tumors and prolonging survival in a double-positive tumor model.