@article{db8f0b8168aa43ea9877b6237035d11b,
title = "Development of a clinically relevant reporter for chimeric antigen receptor t-cell expansion, trafficking, and toxicity",
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.",
author = "Reona Sakemura and Aditya Bansal and Siegler, {Elizabeth L.} and Mehrdad Hefazi and Nan Yang and Khadka, {Roman H.} and Newsom, {Alysha N.} and Hansen, {Michael J.} and Cox, {Michelle J.} and Roman, {Claudia Manriquez} and Schick, {Kendall J.} and Ismail Can and Tapper, {Erin E.} and Nevala, {Wendy K.} and Adada, {Mohamad M.} and Bezerra, {Evandro D.} and Fonkoua, {Lionel Aurelien Kankeu} and Paulina Horvei and Ruff, {Michael W.} and Parikh, {Sameer A.} and Pandey, {Mukesh K.} and Degrado, {Timothy R.} and Lukkana Suksanpaisan and Kay, {Neil E.} and Peng, {Kah Whye} and Russe, {Stephen J.} and Kenderian, {Saad S.} and Kenderian, {Saad S.}",
note = "Funding Information: This work was supported through grant K12CA090628 (S.S. Kenderian), the Mayo Clinic Center for Individualized Medicine (S.S. Kenderian), the Predolin Foundation (R. Sakemura), the Schulze Foundation (S.S. Kenderian), and the Exact Sciences Corporation (S.S. Kenderian). The authors are grateful to Dianna L. Glynn and Cynthia J. Vernon for their technical assistance during PET imaging. Funding Information: R. Sakemura reports grants from Henry J. Predolin Foundation during the conduct of the study, as well as a patent for CAR immunotherapy licensed to Humanigen. M.J. Cox reports a patent and royalties in the field of CART-cell therapy, outside of this work, that is licensed to Humanigen. S.A. Parikh reports grants and other support from Pharmacyclics, Janssen, and AstraZeneca; grants from TG Therapeutics, Merck, AbbVie, and Ascentage Pharma; and other support from Genentech, Innate Pharma, Adaptive Biotechnologies, and GlaxoSmithKline outside the submitted work. T.R. DeGrado reports a patent for 18F-tetrafluoroborate chemistry pending. K.-W. Peng reports other support from Imanis Life Sciences outside the submitted work, as well as a patent for NIS reporter gene technology licensed and with royalties paid from Imanis Life Sciences. S.S. Kenderian reports grants from Novartis, Gilead/Kite, Juno/Bristol-Myers Squibb, Humanigen, Lentigen, Leahlabs, Morphosys, Sunesis, and Tolero outside the submitted work, as well as patents and royalties in the field of CART-cell therapy, outside of this work, that are licensed to Novartis, Humanigen, and Mettaforge. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2021",
month = sep,
doi = "10.1158/2326-6066.CIR-20-0901",
language = "English (US)",
volume = "9",
pages = "1035--1046",
journal = "Cancer Immunology Research",
issn = "2326-6066",
publisher = "American Association for Cancer Research Inc.",
number = "9",
}