SBF-SU2C Pediatric Cancer Dream Team Member Engineers Novel Imaging and Suicide Switch Strategy for CAR T Cells
Since the 2017 FDA approval of the first CAR T-cell therapy for the treatment of children with acute lymphoblastic leukemia, research on CAR T cells has been progressing at a rapid pace. CAR T cell therapy has been very successful in a subset of patients, but off-target toxicities have limited progress. To address this, scientists have been looking for highly specific targets, which have been elusive at times, especially for solid cancers. Researchers have also been working to engineer more potent CAR T cells and trying to get a better understanding of the biodistribution and durability of the CAR T response once inside the body. Two recent publications in the journals Cancer Research and Clinical Cancer Research have reported on two different kinds of PET imaging techniques to monitor the CAR T cells inside the body.
Simonetta et al published their work on a non-invasive antibody-based PET imaging technique in Clinical Cancer Research. They reported that Inducible T-cell COStimulator (ICOS), a costimulatory molecule upregulated during T-cell activation, can be targeted by creating a radiolabeled (Zr89) anti-ICOS monoclonal antibody. They used this antibody to successfully image CD19 CAR T cells in the bone marrow of a tumor-bearing (B cell lymphoma) mouse model. Additionally, they showed that tracer doses of this antibody did not interfere with CAR T-cell persistence or antitumor efficacy, suggesting that this approach could be safe to use in humans.
In another work published in the journal Cancer Research, Murty et al used a novel PET imaging technique coupled with a suicide switch for CAR T cells. The investigators engineered CAR T cells against B7H3, a molecule expressed on various pediatric solid tumors such as sarcoma and glioma. The B7H3 cells were also engineered to express the herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene. They utilized a mutated HSV1-tk reporter gene (HSV1-sr39tk) for imaging the CAR T cells. The HSV1-sr39TK enzyme phosphorylated the radiolabeled probe [18F]-fluoro-3-hydroxymethyl]butyl)guanine ([18F]FHBG) and trapped it within the cell, and thus the [18F]FHBG signal was used to non-invasively monitor the cells in mice via PET/CT imaging. Interestingly, HSV1-sr39tk could also be used as a suicide switch for the CAR T cells via administration of the antiviral ganciclovir. The HSV1-sr39tk enzyme can phosphorylate ganciclovir, which led to premature DNA chain termination and cell death. This work is the first to show the possibility of incorporating the sr39tk gene for both monitoring and control of CAR T cells inside the body.
The research in both papers was supported in part by the St. Baldrick’s Foundation-SU2C Pediatric Cancer Dream Team Research Grant. Dr. Crystal Mackall, one of the co-authors on both papers is the Co-Leader of the Pediatric Cancer Dream Team, which comprises some of the pioneering researchers and clinicians in treating children with CAR T therapy. Both studies were preclinical, with the possibility of translation into the clinical setting.