Radiation therapy improves CAR T cell activity in acute lymphoblastic leukemia.
Mayumi SugitaTakahiro YamazakiMohammad AlhomoudJérémie MartinetJean-Baptiste LatoucheEncouse GoldenOlivier BoyerKoen Van BesienSilvia C FormentiLorenzo GalluzziMonica L GuzmanPublished in: Cell death & disease (2023)
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.
Keyphrases
- acute lymphoblastic leukemia
- radiation therapy
- low dose
- poor prognosis
- clinical trial
- traumatic brain injury
- induced apoptosis
- cell therapy
- signaling pathway
- end stage renal disease
- ejection fraction
- stem cells
- cell cycle arrest
- chronic kidney disease
- newly diagnosed
- nk cells
- endothelial cells
- artificial intelligence
- single cell
- bone marrow
- oxidative stress
- cell death
- high dose
- mesenchymal stem cells
- electronic health record
- severe traumatic brain injury
- peritoneal dialysis
- deep learning
- adipose tissue
- wild type
- rectal cancer
- locally advanced