We use our in-depth knowledge of TCR signaling to develop new strategies that improve chimeric antigen receptor (CAR) T-cell therapies and to identify ligands that target tumors more precisely.
Immunotherapies Inspired by TCR Research
- Next-generation CAR T cells: We have used insights from TCR signaling to rationally design improved CD3ε-, CD3δ-, and CD3γ-based CARs, offering alternatives to traditional ζ-based CARs (Velasco et al 2023).
- Enhanced anti-tumor CARs: We improved the function of a clinically approved CAR by incorporating the RK motif from CD3ε, enhancing its signaling properties (Hartl et al 2020).
Novel Tumor-Targeting Ligands
- We have developed novel CARs targeting a BCR light chain neoepitope defined by an oncogenic point mutation (IGLV3-21R110) selectively targeting a poor-risk subset of chronic lymphocytic leukemia (CLL). These unique CARs eradicate IGLV3-21R110- expressing cells while sparing non-pathogenic B cells (Märkl et al 2024).
- Gb3-binding lectin-CARs have demonstrated target-specific cytotoxicity against Burkitt’s lymphoma-derived cell lines as well as solid tumor cells from colorectal and triple-negative breast cancer, revealing the big potential of lectin-based CARs (Meléndez et al 2022).
References
Minguet S, Maus MV, Schamel WW (2024) From TCR fundamental research to innovative chimeric antigen receptor design. Nat Rev Immunol
Mühlgrabner V, Peters T, Velasco Cárdenas RM, Salzer B, Göhring J, Plach A, Höhrhan M, Perez ID, Goncalves VDR, Farfán JS, Lehner M, Stockinger H, Schamel WW, Schober K, Busch DH, Hudecek M, Dushek O, Minguet S, Platzer R, Huppa JB (2024) TCR/CD3-based synthetic antigen receptors (TCC) convey superior antigen sensitivity combined with high fidelity of activation. Sci Adv 10(36):eadj4632.
Woessner NM, Brandl SM, Hartmann S, Schamel WW, Hartl FA*, Minguet S* (2024) Phospho-mimetic CD3ε variants prevent TCR and CAR signaling. Front Immunol 15:1392933.
Märkl F, Schultheiß C, Ali M, Chen S, Zintchenko M, Egli L, Mietz J, Chijioke O, Paschold L, Spajic S, Holtermann A, Dörr J, Stock S, Zingg A, Läubli H, Piseddu I, Anz D, Minden MD, Zhang T, Nerreter T, Hudecek M, Minguet S, Chiorazzi N, Kobold S, Binder M (2024) Mutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia. Nat Commun 15(1):993.
Velasco Cárdenas RMH, Brandl SM, Meléndez AV*, Schlaak AE*, Buschky A, Peters T, Beier F, Serrels B, Taromi S, Raute K, Hauri S, Gstaiger M, Lassmann S, Huppa JB, Boerries M, Andrieux G, Bengsch B, Schamel WW, Minguet S (2023) Harnessing CD3 diversity to optimize CAR T cells. Nat Immunol 24(12):2135-2149
Langenbach M*, Giesler S*, Richtsfeld S*, da Costa-Pereira S, Rindlisbacher L, Wertheimer T, Braun LM, Andrieux G, Duquesne S, Pfeifer D, Woessner NM, Menssen HD, Taromi S, Duyster J, Boerries M, Brummer T, Blazar BR, Minguet S, Turko P, Levesque MP*, Becher B*, Zeiser R* (2023) MDM2 inhibition enhances immune checkpoint inhibitor efficacy by increasing IL-15 and MHC class II production. Mol Cancer Res 21(8):849-864.
Meléndez AV, Velasco Cárdenas RM, Lagies S, Strietz J, Siukstaite L, Thomas OS, Tomisch J, Weber W, Kammerer B, Römer W, Minguet S (2022) Novel lectin-based chimeric antigen receptors target Gb3-positive tumour cells. Cell Mol Life Sci 79(10):513
Hartl FA, Beck-Garcìa E, Woessner NM, Flachsmann LJ, Velasco Cárdenas RMH, Brandl SM, Taromi S, Fiala GJ, Morath A, Mishra P, Yousefi OS, Zimmermann J, Hoefflin N, Köhn M, Wöhrl BM, Zeiser R, Schweimer K, Günther S, Schamel WW, Minguet S (2020) Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function. Nat Immunol 21:902–913.
