Radiation therapy (RT) has been successfully employed to mitigate antigen loss in a preclinical model of pancreatic adenocarcinoma (PDAC) heterogeneously expressing sialyl Lewis-A (sLeA) as a model CAR target. However, antigen loss remains a major hurdle against optimal CAR T cell activity in patients. Considerable progress has been made to extend the persistence and functionality of CAR T cells by genetic alterations of the CAR-coding construct. While multiple mechanisms of acquired resistance to CAR T cell therapy have been identified, including limited persistence of the CAR T cell product upon infusion and functional CAR T cell exhaustion, B cell neoplasms often evade recognition and killing by CAR T cells as they reduce or completely lose expression of the antigenic CAR target, a phenomenon that is commonly known as antigen loss. CD19-targeting CAR T cell therapy elicits objective responses (frequently complete remission) in 60-80% of patients with chemotherapy refractory disease, resulting in considerably improved progression-free survival (PFS) and overall survival (OS) in a patient population otherwise difficult to treat. With the exception of idecabtagene vicleucel and ciltacabtagene autoleucel, which recognize the MM-associated antigen TNF receptor superfamily member 17 (TNFRSF17, best known as BCMA), all FDA-approved CAR T cell products target CD19, which is expressed by both malignant and normal B cells. These data encourage the initiation of clinical trials combining LD-TBI with CAR T cells in patients with hematological malignancies.Īs of December 2022, no less than six distinct chimeric antigen receptor (CAR) T cell products are licensed by the US Food and Drug Administration (FDA) for the treatment of advanced/refractory B cell neoplasms including acute lymphoblastic leukemia (ALL), B cell lymphoma, follicular lymphoma, mantle cell lymphoma (MCL) and multiple myeloma (MM). Such an improved therapeutic activity was accompanied by a superior expansion of CAR T cells 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. In a human model of CD19 + acute lymphoblastic leukemia (ALL), we also observed DR upregulation by RT, both in vitro and in vivo. 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. Radiation therapy (RT) has been successfully employed to circumvent the loss of CAR targets in preclinical models of pancreatic cancer. While CAR T cells induce objective responses in a majority of patients, relapse frequently occurs upon loss of CD19 expression by neoplastic cells. Autologous T cells engineered to express a chimeric antigen receptor (CAR) specific for CD19 are approved for the treatment of various CD19 + hematological malignancies.
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