guest ::
| Home > Publications database > Targeting mutated KRAS by HLA-A*02:01 restricted anti-KRAS TCR-mimic CAR and bispecific T cell engager. |
| Home > Publications database > Targeting mutated KRAS by HLA-A*02:01 restricted anti-KRAS TCR-mimic CAR and bispecific T cell engager. |
| Journal Article | DKFZ-2025-01675 |
; ; ; ; ; ; ; ; ;
2025
Springer
New York, NY
This record in other databases: 
Please use a persistent id in citations: doi:10.1007/s00109-025-02585-2
Abstract: Mutations in the KRAS proto-oncogene, particularly at codon 12, are among the most frequent genetic alterations in various cancers, and KRASG12V accounts for about 25% of all KRAS mutations observed in lung, pancreatic, and colorectal adenocarcinomas. Despite improved treatment regimes using targeted therapy and checkpoint inhibitors, cellular immunotherapy options for KRAS-mutated cancers remain elusive. We therefore developed two TCR-mimic (TCRm) anti-KRASG12V/HLA-A*02:01 chimeric antigen receptors (CARs) containing different hinge regions and, alternatively, a TCRm anti-KRASG12V/HLA-A*02:01 bispecific T cell engager (BiTE) to explore immunotherapy to the highly prevalent KRASG12V neoantigen. CAR-redirected or BiTE-exposed JNL-reporter cells demonstrated potent signaling capacity upon recognition of KRASG12V. Moreover, human CAR T and NK cells elicited IFN-γ release and cellular cytotoxicity upon encountering target cells pulsed with KRASG12V peptide, and the anti-KRASG12V Strep-tagII hinge CAR showed superior reactivity compared to a human IgG1-Fc hinge CAR. Similarly, a novel TCRm BiTE induced strong T cell immunity to KRASG12V. In contrast, we observed only very low CAR or BITE-mediated responses to naturally presented KRASG12V/HLA-A*02:01 complexes. In summary, this study demonstrates that the mutation-derived KRASG12V5-14 peptide can be effectively targeted by TCRm CAR and BiTE-redirected T cells, suggesting that TCRm anti-KRASG12V CAR or BiTE represent promising formats to advance immunotherapy to mutated KRAS neoepitopes. KEY MESSAGES: Successful development of TCRm CAR and BiTE targeting mutated KRAS/HLA-A*02:01. Anti-KRASG12V TCRm CAR and BiTE induce potent immunity to KRASG12V neoepitope. Anti-KRAS/HLA-I TCRm CARs and BiTEs are novel therapeutics for cancer immunotherapy.
Keyword(s): Chimeric antigen receptor ; Immunotherapy ; KRAS neoepitopes ; T cell therapy ; TCR-mimic CAR ; TCR-mimic bispecific antibody
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Springer ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection
|
The record appears in these collections: |
