CELL INTELLIGENCE · 肿瘤细胞治疗研究

Solid tumors often evade TCR-engineered T cells when antigen expression varies or when the restricting Human Leukocyte Antigen (HLA) allele is lost. 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 T cell signatures are associated with improved outcome across cancers, recognition itself is broad and still selected within the thymus just as 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 TCR could graft oncogenic-driver specificity onto T cells while leaving the endogenous TCR intact. We knocked the KRASG12V/HLA-A*11:01 TCR A11v into primary human T cells. Engineered cells co-expressed the transgenic TCR and the endogenous 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 A11v T cells and polyclonal bystander T cells to kill mesothelin + targets, accompanied by development of higher A11v T cell counts in vivo. In humanized mice bearing mixed HLA-A*11:01 + and HLA-A*11:01 - KRASG12V tumors, 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.