Novel Strategies for Redirecting NK Cells in Cancer Immunotherapy

摘要

cqvip:Natural killer(NK)cells act as a first line of defense in innate immune system against new malignant transformed cells without prior exposure to tumor antigens.The activity of NK cells is tightly controlled by a balance between inhibitory receptors and activating receptors,and when activation signals outweigh inhibitory signals,NK cells can mediate a response to eliminate the targeted cells.As a bridge between the innate and adaptive immune responses to enhance destruction of tumors,NK cells kill their tumor targets through a variety of mechanisms,including receptor-mediated cytotoxicity,antibody-dependent cell-mediated cytotoxicity(ADCC),death receptor Fas/FasL signaling pathway-mediated cancer apoptosis.However,the efficacy of using NK cells for tumor immunotherapy has been limited by a lack of antigen specificity.To overcome this limitation,Vallera and colleagues developed a bispecific killer cell engager(BiKE),which is comprised of a first ScFv that recognizes a tumor antigen and a second ScFv against CD16(expressed on NK cells)to trigger ADCC.To overcome the poor expansion of NK cells in vivo,a novel trispecific killer cell engager(TriKE)was evolved from the BiKE by the same team.In this molecule,IL-15 was integrated to promote NK cell expansion,thereby eliciting superior NK cytotoxicity and NK cell persistence in vivo compared to BiKE.In order to simultaneously target drug-refractory cancer stem cells(CSC)and cancer cells,a novel tetraspecific killer engager(TetraKE)comprising anti-CD133,EpCAM,CD16 ScFvs and a sustaining IL-15 signal cross-linker was recently developed.Compared to BiKE or TriKE,TetraKE1615EpCAM133 was highly specific against EpCAM-and CD133-bearing cells,leading to enhanced NK cell proliferation,prolonged survival and a limited cytokine response.This TetraKE represents a promising new modality for immunotherapy.