Selected publications:

Velasco Cárdenas, R. M., Brandl, S. M., Meléndez, A. V., Schlaak, A. E., Buschky, A., Peters, T., Beier, F., Serrels, B., Taromi, S., Raute, K., Hauri, S., Gstaiger, M., Lassmann, S., Huppa, J. B., Boerries, M., Andrieux, G., Bengsch, B., Schamel, W. W., & Minguet, S. (2023). Harnessing CD3 diversity to optimize CAR T cells. Nature immunology: 24(12), 2135–2149. doi.org/10.1038/s41590-023-01658-z

Tomisch, J., Busse, V., Rosato, F., Makshakova, O. N., Salavei, P., Kittel, A. S., Gillon, E., Lataster, L., Imberty, A., Meléndez, A. V., & Römer, W. (2023). A Shiga Toxin B-Subunit-Based Lectibody Boosts T Cell Cytotoxicity towards Gb3-Positive Cancer Cells. Cells: 12(14), 1896. doi.org/10.3390/cells12141896

Xu, M., Antonova, M., Salavei, P., Illek, K., Meléndez, A. V., Omidvar, R., Thuenauer, R., Makshakova, O., & Römer, W. (2023). Dimeric Lectin Chimeras as Novel Candidates for Gb3-Mediated Transcytotic Drug Delivery through Cellular Barriers.Pharmaceutics: 15(1), 225. doi.org/10.3390/pharmaceutics15010225

Rosato, F., Pasupuleti, R., Tomisch, J., Meléndez, A. V., Kolanovic, D., Makshakova, O. N., Wiltschi, B., & Römer, W. (2022). A bispecific, crosslinking lectibody activates cytotoxic T cells and induces cancer cell death. Journal of translational medicine: 20(1), 578. https://doi.org/10.1186/s12967-022-03794-w

Meléndez, A. V., Velasco Cárdenas, R. M., Lagies, S., Strietz, J., Siukstaite, L., Thomas, O. S., Tomisch, J., Weber, W., Kammerer, B., Römer, W., & Minguet, S. (2022). Novel lectin-based chimeric antigen receptors target Gb3-positive tumour cells. Cellular and molecular life sciences: CMLS, 79(10), 513. doi.org/10.1007/s00018-022-04524-7

Frensch, M., Jäger, C., Müller, P. F., Tadić, A., Wilhelm, I., Wehrum, S., Diedrich, B., Fischer, B., Meléndez, A. V., Dengjel, J., Eibel, H., & Römer, W. (2021). Bacterial lectin BambL acts as a B cell superantigen. Cellular and molecular life sciences: CMLS, 78(24), 8165–8186. doi.org/10.1007/s00018-021-04009-z

Brandel, A., Aigal, S., Lagies, S., Schlimpert, M., Meléndez, A. V., Xu, M., Lehmann, A., Hummel, D., Fisch, D., Madl, J., Eierhoff, T., Kammerer, B., & Römer, W. (2021). The Gb3-enriched CD59/flotillin plasma membrane domain regulates host cell invasion by Pseudomonas aeruginosa. Cellular and molecular life sciences: CMLS, 78(7), 3637–3656. doi.org/10.1007/s00018-021-03766-1

Østevold, K., Meléndez, A. V., Lehmann, F., Schmidt, G., Aktories, K., & Schwan, C. (2017). Septin remodeling is essential for the formation of cell membrane protrusions (microtentacles) in detached tumor cells.Oncotarget: https://doi.org/10.18632/oncotarget.20805

Improving CAR T cell efficacy from a signaling perspective

CAR T cell therapy has transformed cancer immunotherapy, although it faces challenges, particularly with solid tumors and side effects. Current FDA-approved CAR designs combine the specificity of monoclonal antibodies with the activation subunit of the T-cell receptor (TCR) z.

In a previous work under the CIBSS framework, our group demonstrated that the replacement of the ζ domain of a conventional CAR with the CD3ε, CD3δ or CD3γ subunits of the TCR-CD3 complex can improve its antitumor activity. Moreover, our group discovered that incorporating CD3ε into the cytoplasmic tail of an anti-CD19 ζCAR enhanced antitumor activity in vivo, leading to improved survival rates in a preclinical model compared to conventional ζCARs. Mechanistically, this enhanced performance was linked to the recruitment of the signaling kinase LCK to the CAR.

Building on these findings my research aims to explore dual combinations of the CD3 subunits in different configurations, either within the same CAR molecule or on separate CARs but still in the same cell. We hypothesize that not only the presence of distinct signaling domains but also their localization and interaction partners influence the CAR functionality. Our early findings indicate that specific dual combinations improve antitumor efficacy, supporting the hypothesis about the role of the subunit localization in the CAR. Currently, with the support of the CIBSS Launchpad funds, I investigate the mechanisms underlying the signaling differences of these dual combinations, which could have therapeutic potential.

1. Hartl, F. A. et al. Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function. Nat. Immunol. 21, 902–913 (2020). https://doi.org/10.1038/s41590-020-0732-3
2. Velasco Cárdenas, R. M. H. et al. Harnessing CD3 diversity to optimise CAR T cells. Nat. Immunol (2023). doi:10.1038/s41590-023-01658-z