Editors' ChoiceCancer

Turning BiKEs into TriKEs to fight cancer

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Science Translational Medicine  02 Mar 2016:
Vol. 8, Issue 328, pp. 328ec35
DOI: 10.1126/scitranslmed.aaf3855

Bispecific antibodies, capable of simultaneous recognition of tumor cells and lymphocytes or natural killer (NK) cells, and antibody-cytokine fusion proteins (also termed immunocytokines) are new types of immunotherapeutic agents. These therapeutics are designed to increase specificity and facilitate a more direct interaction between immune cells and tumors while decreasing systemic toxicity.

In a recent article, Vallera and colleagues report the successful generation of a functional trispecific killer engager (TriKE) consisting of a bispecific antibody that recognizes CD16 on NK cells and CD33 on myeloid cancer cells and also contains a modified human IL-15 crosslinker. The authors found that TriKEs directed NK-mediated killing of CD33+ acute myeloid leukemia (AML) blasts and simultaneously stimulated self-sustaining proliferation and survival of NK cells by signaling through IL-15. Indeed, compared with the bispecific killer engagers (BiKEs), which only recognize CD16 and CD33, TriKEs induced superior NK cell cytotoxicity, degranulation, and cytokine production against CD33+ human acute promyelocytic leukemia HL-60 cells in vitro, and the costimulation provided by the IL-15 linker greatly increased the survival and proliferation of NK cells. Similarly, when NK cells from normal donors or from patients who recently underwent allogeneic stem cell transplantation were placed in culture medium with HL-60 cells, TriKEs were superior in restoring potent antigen-specific NK cell responses against AML targets and mediated robust and specific NK cell proliferation compared with the BiKEs. These results were confirmed in a murine xenograft HL-60-Luc tumor model, where TriKEs exhibited superior antitumor activity and induced in vivo persistence of human NK cells for at least 3 weeks. The authors also showed that the platform can be adapted to target other tumors by switching the anti-CD33 portion for one targeting a different tumor antigen, such as EpCAM, which is present on solid tumor targets. The robust killing of CD33-EpCAM+ colorectal carcinoma HT-29 cells mediated by the anti-EpCAM TriKE highlighted the versatility of this platform for self-sustained NK cell–based immunotherapies.

Recent molecular characterization of the mechanisms used by tumors to evade immune detection has sharpened the focus of cancer immunotherapy to develop targeted molecules with increased immune specificity, better tolerability, and a more favorable side-effect profile than that of high dose IL-2, the first FDA-approved nonspecific immunomodulator. Clinical success with these new biopharmaceuticals will likely require the availability of good-quality, dependable tumor-associated antigens, the activation of multiple cell types (such as T cells and NK cells), and the ability of these agents to diffuse into solid tumor masses to mediate targeted cell killing.

D. A. Vallera et al., IL-15 trispecific killer engagers (TriKEs) make natural killer cells specific to CD33+ targets while also inducing in vivo expansion, and enhanced function. Clin. Cancer Res. 10.1158/1078-0432.CCR-15-2710 (2016).[Abstract]

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