Adenosine Deaminase 1 Overexpression Enhances the Antitumor Efficacy of Chimeric Antigen Receptor-Engineered T Cells
| Autor: | Melanie A. MacMullan, Yun Qu, Fangheng Hu, Gunce E. Cinay, Pin Wang, Zachary S. Dunn, Xianhui Chen, Hsuan-Yao Wang, Jiangyue Liu |
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| Rok vydání: | 2022 |
| Předmět: |
Adenosine
Adenosine Deaminase T-Lymphocytes T cell Receptors Antigen T-Cell Immunotherapy Adoptive Cell therapy Mice Immune system Adenosine deaminase immune system diseases Albumins Cell Line Tumor Genetics medicine Animals Humans cvg Molecular Biology Research Articles Receptors Chimeric Antigen biology Armored car Chemistry cvg.computer_videogame hemic and immune systems Xenograft Model Antitumor Assays Chimeric antigen receptor medicine.anatomical_structure Cancer cell Cancer research biology.protein Molecular Medicine Collagen medicine.drug |
| Zdroj: | Hum Gene Ther |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/hum.2021.050 |
| Popis: | Chimeric antigen receptor (CAR) T cell therapy mediates unprecedented benefit in certain leukemias and lymphomas, but has yet to achieve similar success in combating solid tumors. A substantial body of work indicates that the accumulation of adenosine in the solid tumor microenvironment (TME) plays a crucial role in abrogating immunotherapies. Adenosine deaminase 1 (ADA) catabolizes adenosine into inosine and is indispensable for a functional immune system. We have, for the first time, engineered CAR T cells to overexpress ADA. To potentially improve the pharmacokinetic profile of ADA, we have modified the overexpressed ADA in two ways, through the incorporation of a (1) albumin-binding domain or (2) collagen-binding domain. ADA and modified ADA were successfully expressed by CAR T cells and augmented CAR T cell exhaustion resistance. In a preclinical engineered ovarian carcinoma xenograft model, ADA and collagen-binding ADA overexpression significantly enhanced CAR T cell expansion, tumor tissue infiltration, tumor growth control, and overall survival, whereas albumin-binding ADA overexpression did not. Furthermore, in a syngeneic colon cancer solid tumor model, the overexpression of mouse ADA by cancer cells significantly reduced tumor burden and remodeled the TME to favor antitumor immunity. The overexpression of ADA for enhanced cell therapy is a safe, straightforward, reproducible genetic modification that can be utilized in current CAR T cell constructs to result in an armored CAR T product with superior therapeutic potential. |
| Databáze: | OpenAIRE |
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