Development of a Clinically Relevant Reporter for Chimeric Antigen Receptor T-cell Expansion, Trafficking, and Toxicity
| Autor: | Mohamad M. Adada, Mehrdad Hefazi, Timothy R. DeGrado, Reona Sakemura, Lukkana Suksanpaisan, Lionel A. Kankeu Fonkoua, Erin E. Tapper, Stephen J. Russell, Michael J. Hansen, Neil E. Kay, Kah-Whye Peng, Mukesh K. Pandey, Kendall J. Schick, Roman H. Khadka, Michael W. Ruff, Alysha N Newsom, Sameer A. Parikh, Ismail Can, Nan Yang, Claudia Manriquez Roman, Evandro D. Bezerra, Michelle J. Cox, Paulina Horvei, Saad S. Kenderian, Aditya Bansal, Wendy K. Nevala, Elizabeth L. Siegler |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Sodium-iodide symporter Cancer Research medicine.medical_treatment T cell Antigens CD19 Immunology Receptors Antigen T-Cell Article Antigen immune system diseases In vivo Neoplasms mental disorders Animals Humans Medicine health care economics and organizations Receptors Chimeric Antigen Symporters business.industry virus diseases medicine.disease Xenograft Model Antitumor Assays In vitro Chimeric antigen receptor Disease Models Animal Cytokine release syndrome Cytokine medicine.anatomical_structure nervous system Positron-Emission Tomography Cancer research Female K562 Cells business |
| Zdroj: | Cancer Immunol Res |
| ISSN: | 2326-6074 2326-6066 |
| Popis: | 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 (NIS+CART19 and NIS+BCMA-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. NIS+CART19 and NIS+BCMA-CART cells were generated through dual transduction with two vectors and demonstrated exclusive 125I uptake in vitro. 18F-TFB-PET detected NIS+CART cells in vivo to a sensitivity level of 40,000 cells. 18F-TFB-PET confirmed NIS+BCMA-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 CART-cell 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. |
| Databáze: | OpenAIRE |
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