CD28 Co-Stimulus Achieves Superior CAR T Cell Effector Function against Solid Tumors Than 4-1BB Co-Stimulus
| Autor: | Maria Stecklum, Michael C. Jensen, Kathleen Anders, Johannes H. Schulte, Silke Schwiebert, Ana Textor, Laura Grunewald, Jana Rolff, Thomas Blankenstein, Uta E. Höpken, Annika Winkler, Anton G. Henssen, Angelika Eggert, Annette Künkele, Anika Klaus |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research preclinical mouse models L1 T cell Biology lcsh:RC254-282 Article 03 medical and health sciences neuroblastoma 0302 clinical medicine Antigen Neuroblastoma CAR design medicine Effector CD28 lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Chimeric antigen receptor CAR T cell trafficking 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Monoclonal Cancer research human activities |
| Zdroj: | Cancers Volume 13 Issue 5 Cancers, Vol 13, Iss 1050, p 1050 (2021) |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers13051050 |
| Popis: | Simple Summary Efficient trafficking and survival of CAR T cells within the hostile tumor microenvironment are important prerequisites for potent solid tumor attack that have not yet been achieved. We deployed monospecific murine instead of polyclonal human T cells for CAR T cell generation to evaluate second generation L1CAM- and HER2-specific CARs with different spacer length and either the CD28 or 4-1BB co-stimulatory domain in mouse models of neuroblastoma and ovarian carcinoma. This mouse-in-mouse approach ensured CAR T cell trafficking unhindered by species-specific discrepancies and demonstrated superior solid tumor attack by CAR T cells harboring the CD28 compared to 4-1BB co-stimulatory domain. Our approach has the potential to improve prediction and selection of promising clinical CAR candidates against solid tumors in the future. 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. |
| Databáze: | OpenAIRE |
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