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

Reona Sakemura, Aditya Bansal, Elizabeth L. Siegler, Mehrdad Hefazi, Nan Yang, Roman H. Khadka, Alysha N. Newsom, Michael J. Hansen, Michelle J. Cox, Claudia Manriquez Roman, Kendall J. Schick, Ismail Can, Erin E. Tapper, Wendy K. Nevala, Mohamad M. Adada, Evandro D. Bezerra, Lionel Aurelien Kankeu Fonkoua, Paulina Horvei, Michael W. Ruff, Sameer A. ParikhMukesh K. Pandey, Timothy R. Degrado, Lukkana Suksanpaisan, Neil E. Kay, Kah Whye Peng, Stephen J. Russe, Saad S. Kenderian, Saad S. Kenderian

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1035-1046
Number of pages12
JournalCancer Immunology Research
Volume9
Issue number9
DOIs
StatePublished - Sep 2021

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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