TriKEs and BiKEs join CARs on the cancer immunotherapy highway.

Unprecedented clinical success has recently been achieved in cancer immunotherapy using cytotoxic T cells armed with activating tumor-specific Chimeric Antigen Receptors (CARs). Natural killer (NK) cells, potent cytotoxic effectors, also hold potential to be effectively harnessed for immunotherapy. The anti-tumor efficacy of NK cell therapies has been limited by a lack of antigen specificity and the poor persistence of NK cells in vivo. To address these limitations, Vallera and colleagues developed novel Trispecific Killer cell Engagers (TriKEs), reported in the Feb. 2016 issue of Clinical Cancer Research. The novel TriKE immunomodulator evolved from the Bispecific Killer cell Engager (BiKE), a precursor developed by the same team. BiKEs comprise 2 antibody fragments, a first recognizing a tumor antigen and a second directed against CD16 on NK cells, which together trigger antibody-dependent cell-mediated cytotoxicity. IL-15 was further integrated to create TriKEs in order to drive NK cell expansion. Compared to BiKEs, TriKEs elicit far superior NK cytotoxicity and NK cell persistence in a xenograft tumor model in vivo, and are proposed to be effective adjuncts to existing NK transfer protocols. Importantly, TriKEs provide a versatile and cost-effective platform onto which novel targeting ligands can be incorporated and hold the potential to stimulate endogenous NK cells in order to circumvent the need for cell transfers altogether, heralding a new generation of immunotherapeutics.