High CAR intensity of expression confers enhanced antitumor effect against lymphoma without functional exhaustion

Autor: Ana Carolina Caballero, Laura Escribà-Garcia, Paula Pujol-Fernández, Eva Escudero-López, Cristina Ujaldón-Miró, Rosanna Montserrat-Torres, Jorge Sierra, Carmen Alvarez-Fernández, Javier Briones
Rok vydání: 2022
Předmět:
Zdroj: CANCER GENE THERAPY
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname
ISSN: 1476-5500
0929-1903
Popis: 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(+) T-SCM(-)LIKE enriched cells. By sorting T-cells according to CAR mean fluorescence intensity in two markedly different populations (CAR(HI) and CAR(LO)), 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 CAR(HI) T-cells improved antitumor efficacy was demonstrated in a human Hodgkin's lymphoma xenograft mouse model, where CAR30-T-SCM(-)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.
Databáze: OpenAIRE
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