Journal of Hematology & Oncology · Published 2026-07-30 · DOI 10.1186/s13045-026-01836-0
Ángel Ramírez-Fernández, Adham S. Bear, Elahe Kamali, Robert Bartoszek, Matthew Ho, Gregory M. Chen, Devin Dersh, Laura Córdoba-Espejo, Jiageng Liu, Mosha Deng, Miriam Velasco-Sidro, Ankita Jain, Julia Han Noll, Caitlin R Hopkins, Owen Koucky, Janna Minehart, Alexander J. Dimitri, Erik Williams, Maya Lavorando, Alejandro Segura-Tudela, John Scholler, Julie Barber-Rotenberg, Julie K. Jadlowsky, Daniel J. Powell, Anne Chew, Vanessa E. Gonzalez, Donald L. Siegel, Bruce L. Levine, Michael T. Lotze, Carl H. June, James L. Riley, Robert H. Vonderheide, Friederike Herbst, Joseph A. Fraietta
Abstract Solid tumors often evade TCR-engineered αβ T cells when antigen expression varies or when the restricting Human Leukocyte Antigen (HLA) allele is lost. γδ T cells, in contrast, detect cellular dysregulation through non-peptide/Major Histocompatibility Complex (MHC) cues, including phosphoantigens and stress ligands, and can be developed as allogeneic therapies. Although intratumoral γδ T cell signatures are associated with improved outcome across cancers, γδ recognition itself is broad and still selected within the thymus just as αβ T cell receptors (TCRs) are. It does not, however, anchor specificity to a defined driver-mutation pMHC epitope. We therefore asked whether a high-affinity, co-receptor–independent αβ TCR could graft oncogenic-driver specificity onto γδ T cells while leaving the endogenous γδ TCR intact. We knocked the KRASG12V/HLA-A*11:01 TCR A11v into primary human γδ T cells. Engineered cells co-expressed the transgenic αβ TCR and the endogenous γδ TCR and lysed KRASG12V/HLA-A*11:01+ tumor cells in vitro and in vivo. To cover potential resistance through loss of HLA-A*11:01, we delivered an mRNA lipid nanoparticle (LNP) encoding a secreted mesothelin×CD3 (M5) bispecific T cell engager (TCE). LNP-M5 produced circulating TCE that redirected γδ A11v T cells and polyclonal bystander T cells to kill mesothelin+ targets, accompanied by development of higher γδ A11v T cell counts in vivo. In humanized mice bearing mixed HLA-A*11:01+ and HLA-A*11:01 − KRASG12V tumors, γδ A11v T cells produced transient control, whereas adding LNP-M5 yielded complete responses and prolonged survival. Thus, this two-part therapy couples invariant driver targeting to tunable redirection and addresses loss of the restricting HLA allele, a central escape route for TCR-based therapy. It provides an off-the-shelf reagent to enable KRAS-anchored treatment with the ability to redeliver the reagent.
Abstract from DOAJ. Public domain (CC0 1.0).
Read the article at the publisher →
Ramírez-Fernández, Á., Bear, A., Kamali, E., et al. (2026). A modular γδ TCR-T platform combining KRAS pMHC targeting with re-dosable mRNA engager redirection. Journal of Hematology & Oncology. https://doi.org/10.1186/s13045-026-01836-0