4.6 Article

Development of a Clinically Relevant Reporter for Chimeric Antigen Receptor T-cell Expansion, Trafficking, and Toxicity

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CANCER IMMUNOLOGY RESEARCH
卷 9, 期 9, 页码 1035-1046

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-20-0901

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资金

  1. Mayo Clinic Center for Individualized Medicine [K12CA090628]
  2. Predolin Foundation
  3. Schulze Foundation
  4. Exact Sciences Corporation

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The study successfully utilized NIS as an imaging platform to design NIS(+)CART cells and confirmed that F-18-TFB-PET can detect the in vivo expansion and migration of CART cells, correlating with the development of CRS.
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(+)CART 19 and NIS(+)BCMA-CART, respectively) and tested the sensitivity of F-18-TFB-PET to detect trafficking and expansion in systemic and localized tumor models and in a CART-cell toxicity model. NIS(+)CART 19 and NIS+BCM A-CART cells were generated through dual transduction with two vectors and demonstrated exclusive I-125 uptake in vitro. F-18-TFB-PET detected NIS(+)CART cells in vivo to a sensitivity level of 40,000 cells. F-18-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, F-18-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. F-18-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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