Abstract
Identifying factors that ameliorates clinical outcomes following CART therapy represents an unmet need. We hypothesized that CAR expression level would have a significant impact on CART efficacy and tested this with CAR30+ TSCM-LIKE enriched cells. By sorting T-cells according to CAR mean fluorescence intensity in two markedly different populations (CARHI and CARLO), we showed that a high CAR expression enhances antitumor efficacy in vitro, that is sustained after sequential re-exposures to tumor cells and is not associated with T-cell exhaustion or differentiation. Furthermore, we found a correlation between high surface CAR expression and antitumor effect with CAR19+ T-cells, thus validating our findings with CAR30. Definitive proof of CARHI T-cells improved antitumor efficacy was demonstrated in a human Hodgkin’s lymphoma xenograft mouse model, where CAR30-TSCM-LIKE enriched products with high intensity of CAR expression achieved superior tumor control in vivo and longer survival than those with a low intensity of CAR expression. Our data suggest that modulation of CAR intensity of expression represents an additional strategy to increase CART therapy clinical efficacy.
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Data availability
The main data supporting the results in this study are available within the paper and its Supplementary Information. All data generated in this study are available from the corresponding authors on reasonable request.
Change history
02 December 2022
A Correction to this paper has been published: https://doi.org/10.1038/s41417-022-00564-0
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Acknowledgements
This work was supported in part by grants from La Marató TV3 (Exp. 20130710), Deutsche José Carreras Leukämie Stiftung (DJCSL 10R/2016), Beca Carlos Antonio López (Gobierno paraguayo), Instituto de Salud Carlos III (PI15/1383y PI18/01023; Fondos FEDER), Fundación Bancaria ‘La Caixa’, TerCel (SG/11/2008), Ministerio de Economía y Competitividad (RETOS; RTC 2015-3393-1), AGAUR (2017SGR1395) and Red de Terapias Avanzadas (RICORS, ISCIII; RD21/0017/0011; Fondos Next Generation, UE). Graphical abstract was created with BioRender.com support.
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A.C.C., C.A.F., L.E.G., P.P.F., E.E.L., C.U.M., and R.M.T. conducted the experiments. A.C.C, C.A.F., and J.B. conceived study. A.C.C, C.A.F., and J.B. designed the experiments. A.C.C., L.E.G., C.A.F., and J.B. wrote the paper. J.S. and J.B. supplied essential samples or reagents. All authors reviewed and approved the final version of the manuscript.
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Caballero, A.C., Escribà-Garcia, L., Pujol-Fernández, P. et al. High CAR intensity of expression confers enhanced antitumor effect against lymphoma without functional exhaustion. Cancer Gene Ther 30, 51–61 (2023). https://doi.org/10.1038/s41417-022-00518-6
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DOI: https://doi.org/10.1038/s41417-022-00518-6