Development of a clinically relevant reporter for chimeric antigen receptor t-cell expansion, trafficking, and toxicity

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Abstract

Although chimeric antigen receptor T (CART)-cell therapy has been successful in treating certain hematologic malignancies, wider adoption of CART-cell therapy is limited because of minimal activity in solid tumors and development of life-threatening toxicities, including cytokine release syndrome (CRS).There is a lack of a robust, clinically relevant imaging platform to monitor in vivo expansion and trafficking to tumor sites.To address this, we utilized the sodium iodide symporter (NIS) as a platform to image and track CART cells.We engineered CD19-directed and B-cell maturation antigen (BCMA)-directed CART cells to express NIS (NISCART19 and NISBCMA-CART, respectively) and tested the sensitivity of 18F-TFB-PET to detect trafficking and expansion in systemic and localized tumor models and in a CART-cell toxicity model.NISCART19 and NISBCMA-CART cells were generated through dual transduction with two vectors and demonstrated exclusive 125I uptake in vitro.18F-TFB-PET detected NISCART cells in vivo to a sensitivity level of 40,000 cells.18F-TFB-PET confirmed NISBCMA-CART-cell trafficking to the tumor sites in localized and systemic tumor models.In a xenograft model for CART-cell toxicity, 18F-TFB-PET revealed significant systemic uptake, correlating with CART-cell in vivo expansion, cytokine production, and development of CRS-associated clinical symptoms.NIS provides a sensitive, clinically applicable platform for CARTcell imaging with PET scan.18F-TFB-PET detected CART-cell trafficking to tumor sites and in vivo expansion, correlating with the development of clinical and laboratory markers of CRS.These studies demonstrate a noninvasive, clinically relevant method to assess CART-cell functions in vivo.

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Sakemura, R., Bansal, A., Siegler, E. L., Hefazi, M., Yang, N., Khadka, R. H., … Kenderian, S. S. (2021). Development of a clinically relevant reporter for chimeric antigen receptor t-cell expansion, trafficking, and toxicity. Cancer Immunology Research, 9(9), 1035–1046. https://doi.org/10.1158/2326-6066.CIR-20-0901

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