TEM8 Tri-specific Killer Engager binds both tumor and tumor stroma to specifically engage natural killer cell anti-tumor activity

Abstract

BackgroundThe tumor microenvironment contains stromal cells, including endothelial cells and fibroblasts, that aid tumor growth and impair immune cell function. Many solid tumors remain difficult to cure because of tumor-promoting stromal cells, but current therapies targeting tumor stromal cells are constrained by modest efficacy and toxicities. TEM8 is a surface antigen selectively upregulated on tumor and tumor stromal cells, endothelial cells and fibroblasts that may be targeted with specific natural killer (NK) cell engagement.MethodsA Tri-specific Killer Engager (TriKE) against TEM8—‘cam1615TEM8’—was generated using a mammalian expression system. Its function on NK cells was assessed by evaluation of degranulation, inflammatory cytokine production, and killing against tumor and stroma cell lines in standard co-culture and spheroid assays. cam1615TEM8-mediated proliferation and STAT5 phosphorylation in NK cells was tested and compared with T cells by flow cytometry. NK cell proliferation, tumor infiltration, and tumor and tumor-endothelium killing by cam1615TEM8 and interleukin-15 (IL-15) were assessed in NOD scid gamma (NSG) mice.Resultscam1615TEM8 selectively stimulates NK cell degranulation and inflammatory cytokine production against TEM8-expressing tumor and stromal cell lines. The increased activation translated to superior NK cell killing of TEM8-expressing tumor spheroids. cam1615TEM8 selectively stimulated NK cell but not T cell proliferation in vitro and enhanced NK cell proliferation, survival, and tumor infiltration in vivo. Finally, cam1615TEM8 stimulated NK cell killing of tumor and tumor endothelial cells in vivo.ConclusionsOur findings indicate that the cam1615TEM8 TriKE is a novel anti-tumor, anti-stroma, and anti-angiogenic cancer therapy for patients with solid tumors. This multifunctional molecule works by selectively targeting and activating NK cells by costimulation with IL-15, and then targeting that activity to TEM8+ tumor cells and TEM8+ tumor stroma.

NK cells are never alone: crosstalk and communication in tumour microenvironments

“…Although most NKCEs are currently in the preclinical stage and their safety and efficacy need further evaluation, it is undeniable that they are emerging as highly promising tumour therapeutic strategies and have the potential to overcome the suppressive TME due to their target specificity [ 235 ]. It has been observed that 161,533 TriKE exhibits excellent antitumour activity and promotes NK cell persistence in vivo [ 236 ].…”

A tri-specific killer engager against mesothelin targets NK cells towards lung cancer

“…Circulating NK cells would have to migrate from the periphery in order to kill tumor cells. The IL-15 component in TriKEs enhances NK cell mobility in vitro (53) and a TriKE targeting the tumor stroma was able to enhance NK cell infiltration into the tumor in an animal model (57). We would predict, therefore, that the IL-15 component of this TriKE, which targets lung cancer, would also enhance infiltration of NK cells directly into the tumor, but this remains to be shown.…”

Tri-specific killer engager: unleashing multi-synergic power against cancer

“…The last domain of TriKE is antigen-specific which takes a role in specifically target the cancer cells to complete their bridge function which connects enhanced NK cells to the targeted cancer cells. Previously, various types of specificity were designed, such as anti-CD33 AML [ 7 , 25 ], anti-EpCAM against carcinomas [ 13 ], anti-CD19 against B-CLL [ 15 ] anti-TEM8 and anti-mesothelin against NSCLC [ 10 , 27 ], anti-CLEC12A against AML [ 9 ], and anti-HER2 against ovarian cancer [ 26 ]. However, there are some interesting target antigens those have been used as potential target immunotherapy in other platforms, like monoclonal antibody (mAb), CAR-T cell, and other immune cell-engager: T cell engager and macrophage engager which can be applied to TriKEs construction [ 47 ].…”