O7?A bispecific VHH approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2 T cells

摘要

Vγ9Vδ2-T cells include a unique and potent subset of T cells which play an important role in tumor defense. Vγ9Vδ2-T cells recognize and can lyse butyrophilin 3A1-expressing target cells with elevated levels of non-peptide phosphoantigens (pAg), induced by cell stress or malignancy. To date, Vγ9Vδ2-T cell based cancer immunotherapeutic approaches were well tolerated and in some cases capable of inducing relevant clinical responses. In an effort to improve the efficacy and consistency of Vγ9Vδ2-T cell based cancer immunotherapy, we designed a bispecific VHH that binds to both Vγ9Vδ2-T cells and EGFR expressed by tumor cells and results in the target-specific activation of Vγ9Vδ2-T cells and subsequent lysis of colorectal cancer cell lines and primary colorectal cancer samples both in vitro and in an in vivo mouse xenograft model. Of note, tumor cell lysis was independent of mutations in KRAS and BRAF that are known to impair the efficacy of clinically registered anti-EGFR monoclonal antibodies as well as common Vγ9Vδ2-T cell receptor sequence variations. In combination with the conserved monomorphic nature of the Vγ9Vδ2-TCR and the facile replacement of the tumor-specific VHH, this immunotherapeutic approach can in principle be applied to a large group of cancer types. Disclosure Information L.A. King: None. R. Lameris: None. R.C. Roovers: None. P. Parren: None. T.D. de Gruijl: None. H.J. van der Vliet: None.