Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape

Abstract

CD19 chimeric antigen receptors (CARs) have demonstrated great efficacy against a range of B cell malignancies. However, antigen escape and, more generally, heterogeneous antigen expression pose a challenge to applying CAR therapy to a wide range of cancers. We find that low-dose radiation sensitizes tumor cells to immune rejection by locally activated CAR T cells. In a model of pancreatic adenocarcinoma heterogeneously expressing sialyl Lewis-A (sLeA), we show that not only sLeA + but also sLeAtumor cells exposed to low-dose radiation become susceptible to CAR therapy, reducing antigennegative tumor relapse. RNA sequencing analysis of low-dose radiation-exposed tumors reveals the transcriptional signature of cells highly sensitive to TRAIL-mediated death. We find that sLeA-targeted CAR T cells produce TRAIL upon engaging sLeA + tumor cells, and eliminate sLeA À tumor cells previously exposed to systemic or local low-dose radiation in a TRAILdependent manner. These findings enhance the prospects for successfully applying CAR therapy to heterogeneous solid tumors. Local radiation is integral to many tumors' standard of care and can be easily implemented as a CAR conditioning regimen.

UniCAR T cell immunotherapy enables efficient elimination of radioresistant cancer cells

“…For example, in preclinical glioblastoma and pancreatic tumor mouse models, the combination of radiation with CAR T cell therapy has proven to act synergistically. [53][54][55] In terms of successful implementation of such combined radioimmunotherapeutic approaches, the rise and induction of radioresistant tumor cells are a significant aspect that should be taken into consideration. Therefore, the major focus of this work was to analyze the effect of (Uni)CAR T cells on radioresistant HNSCC cells.…”

Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system

“…They also observed that radiation significantly induced the expression of NKG2D ligands on malignant cells, possibly explaining the synergy between the two methods described above. DeSelm and colleagues [202] further confirmed that low-dose radiation conditioning sensitizes tumor cells (not only sLeA + but also sLeA -) to CARsLeA T cells in a model of heterogeneous pancreatic adenocarcinoma.…”

Preclinical Activity of Embryonic Annexin A2-Specific Chimeric Antigen Receptor T Cells Against Ovarian Cancer

“…While radiotherapy is rarely used in the treatment of ovarian cancer [37], recent evidence suggests that radiotherapy may be an effective preconditioning regimen for CAR T cell therapy [38]. In addition to promoting T cell infiltration into the tumour, radiation also upregulates the expression of cell death ligands such as Fas and TRAIL that induce T cell cytotoxicity against tumour cells [38,39].…”