TY - JOUR
T1 - γδ-Enriched CAR-T cell therapy for bone metastatic castrate-resistant prostate cancer
AU - Frieling, Jeremy S.
AU - Tordesillas, Leticia
AU - Bustos, Xiomar E.
AU - Ramello, Maria Cecilia
AU - Bishop, Ryan T.
AU - Cianne, Junior E.
AU - Snedal, Sebastian A.
AU - Li, Tao
AU - Lo, Chen Hao
AU - de la Iglesia, Janis
AU - Roselli, Emiliano
AU - Benzaïd, Ismahène
AU - Wang, Xuefeng
AU - Kim, Youngchul
AU - Lynch, Conor C.
AU - Abate-Daga, Daniel
N1 - Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved.
PY - 2023
Y1 - 2023
N2 - Immune checkpoint blockade has been largely unsuccessful for the treatment of bone metastatic castrate-resistant prostate cancer (mCRPC). Here, we report a combinatorial strategy to treat mCRPC using γδ-enriched chimeric antigen receptor (CAR) T cells and zoledronate (ZOL). In a preclinical murine model of bone mCRPC, γδ CAR-T cells targeting prostate stem cell antigen (PSCA) induced a rapid and significant regression of established tumors, combined with increased survival and reduced cancer-associated bone disease. Pretreatment with ZOL, a U.S. Food and Drug Administration–approved bisphosphonate prescribed to mitigate pathological fracture in mCRPC patients, resulted in CAR-independent activation of γδ CAR-T cells, increased cytokine secretion, and enhanced antitumor efficacy. These data show that the activity of the endogenous Vγ9Vδ2 T cell receptor is preserved in CAR-T cells, allowing for dual-receptor recognition of tumor cells. Collectively, our findings support the use of γδ CAR-T cell therapy for mCRPC treatment.
AB - Immune checkpoint blockade has been largely unsuccessful for the treatment of bone metastatic castrate-resistant prostate cancer (mCRPC). Here, we report a combinatorial strategy to treat mCRPC using γδ-enriched chimeric antigen receptor (CAR) T cells and zoledronate (ZOL). In a preclinical murine model of bone mCRPC, γδ CAR-T cells targeting prostate stem cell antigen (PSCA) induced a rapid and significant regression of established tumors, combined with increased survival and reduced cancer-associated bone disease. Pretreatment with ZOL, a U.S. Food and Drug Administration–approved bisphosphonate prescribed to mitigate pathological fracture in mCRPC patients, resulted in CAR-independent activation of γδ CAR-T cells, increased cytokine secretion, and enhanced antitumor efficacy. These data show that the activity of the endogenous Vγ9Vδ2 T cell receptor is preserved in CAR-T cells, allowing for dual-receptor recognition of tumor cells. Collectively, our findings support the use of γδ CAR-T cell therapy for mCRPC treatment.
UR - https://www.scopus.com/pages/publications/85159547174
U2 - 10.1126/sciadv.adf0108
DO - 10.1126/sciadv.adf0108
M3 - Article
C2 - 37134157
AN - SCOPUS:85159547174
SN - 2375-2548
VL - 9
JO - Science advances
JF - Science advances
IS - 18
M1 - eadf0108
ER -