Title | Radiation therapy improves CAR T cell activity in acute lymphoblastic leukemia. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Sugita M, Yamazaki T, Alhomoud M, Martinet J, Latouche J-B, Golden E, Boyer O, Van Besien K, Formenti SC, Galluzzi L, Guzman ML |
Journal | Cell Death Dis |
Volume | 14 |
Issue | 5 |
Pagination | 305 |
Date Published | 2023 May 04 |
ISSN | 2041-4889 |
Keywords | Animals, Hematologic Neoplasms, Humans, Immunotherapy, Adoptive, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Antigen, T-Cell, Receptors, Chimeric Antigen, T-Lymphocytes |
Abstract | Autologous T cells engineered to express a chimeric antigen receptor (CAR) specific for CD19 are approved for the treatment of various CD19 hematological malignancies. While CAR T cells induce objective responses in a majority of patients, relapse frequently occurs upon loss of CD19 expression by neoplastic cells. Radiation therapy (RT) has been successfully employed to circumvent the loss of CAR targets in preclinical models of pancreatic cancer. At least in part, this reflects the ability of RT to elicit death receptor (DR) expression by malignant cells, enabling at least some degree of CAR-independent tumor killing. In a human model of CD19 acute lymphoblastic leukemia (ALL), we also observed DR upregulation by RT, both in vitro and in vivo. Moreover, low-dose total body irradiation (LD-TBI) delivered to ALL-bearing mice prior to CAR T cell infusion considerably extended the overall survival benefit afforded by CAR T cells alone. Such an improved therapeutic activity was accompanied by a superior expansion of CAR T cells in vivo. These data encourage the initiation of clinical trials combining LD-TBI with CAR T cells in patients with hematological malignancies. |
DOI | 10.1038/s41419-023-05829-6 |
Alternate Journal | Cell Death Dis |
PubMed ID | 37142568 |
PubMed Central ID | PMC10160073 |
Grant List | R21 AG066552 / AG / NIA NIH HHS / United States R21 CA245454 / CA / NCI NIH HHS / United States R01 CA234478 / CA / NCI NIH HHS / United States R01 CA098571 / CA / NCI NIH HHS / United States U54 CA274291 / CA / NCI NIH HHS / United States |