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| Item Type: | Article |
|---|---|
| Title: | CD28 co-stimulus achieves superior CAR T cell effector function against solid tumors than 4-1BB co-stimulus |
| Creators Name: | Textor, A., Grunewald, L., Anders, K., Klaus, A., Schwiebert, S., Winkler, A., Stecklum, M., Rolff, J., Henssen, A.G., Höpken, U.E., Eggert, A., Schulte, J.H., Jensen, M.C., Blankenstein, T. and Künkele, A. |
| Abstract: | Spacer or co-stimulatory components in chimeric antigen receptor (CAR) design influence CAR T cell effector function. Few preclinical mouse models optimally support CAR candidate pre-selection for clinical development. Here we use a model in which murine CAR T cells can be exploited with human tumor xenografts. This mouse-in-mouse approach avoids limitations caused by species-specific factors crucial for CAR T cell survival, trafficking and function. We compared trafficking, expansion and tumor control for T cells expressing different CAR construct designs targeting two antigens (L1CAM or HER2), structurally identical except for spacer (long or short) or co-stimulatory (4-1BB or CD28) domains to be evaluated. Using monoclonal, murine-derived L1CAM-specific CAR T cells in Rag-/- mice harboring established xenografted tumors from a human neuroblastoma cell line revealed a clear superiority in CAR T cell trafficking using CD28 co-stimulation. L1CAM-targeting short spacer-CD28/ζ CAR T cells expanded the most at the tumor site and induced initial tumor regression. Treating patient-derived neuroblastoma xenografts with human L1CAM-targeting CAR T cells confirmed the superiority of CD28 co-stimulus. CD28 superiority was also demonstrated with HER2-specific CAR T cells (targeting ovarian carcinoma xenografts). Our findings encourage incorporating CD28 signaling into CAR design for adoptive T cell treatment of solid tumors. |
| Keywords: | CAR Design, CAR T Cell Trafficking, Preclinical Mouse Models, Neuroblastoma, Animals, Mice |
| Source: | Cancers |
| ISSN: | 2072-6694 |
| Publisher: | MDPI |
| Volume: | 13 |
| Number: | 5 |
| Page Range: | 1050 |
| Date: | 2 March 2021 |
| Official Publication: | https://doi.org/10.3390/cancers13051050 |
| PubMed: | View item in PubMed |
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