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TEM8 Tri-specific Killer Engager binds both tumor and tumor stroma to specifically engage natural killer cell
Michael F Kaminski1, Laura Bendzick2, Rachel Hopps2
1Hematology, Oncology, and Transplantation, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA.
Background:
The 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.
Methods:
A 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.
Results:
cam1615TEM8 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.
Conclusions:
Our 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.
Insights
A novel Tri-specific Killer Engager (TriKE) targeting TEM8 activates natural killer (NK) cells to combat solid tumors and their supportive stroma. This therapy offers a new approach against difficult-to-treat cancers.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Tumor microenvironment contains stromal cells that promote tumor growth and hinder immune responses.
- Targeting tumor stromal cells is challenging due to modest efficacy and toxicity of current therapies.
- TEM8, a surface antigen on tumor and stromal cells, presents a potential therapeutic target for NK cell engagement.
Purpose of the Study:
- To develop and evaluate a Tri-specific Killer Engager (TriKE) targeting TEM8 for cancer therapy.
- To assess the efficacy of the cam1615TEM8 TriKE in activating NK cells and mediating tumor and stromal cell killing.
- To investigate the in vivo effects of cam1615TEM8 on NK cell function and anti-tumor activity.
Main Methods:
- Generated a TriKE (cam1615TEM8) targeting TEM8 using a mammalian expression system.
- Assessed NK cell degranulation, cytokine production, and killing of tumor/stroma cell lines in vitro.
- Evaluated NK cell proliferation, STAT5 phosphorylation, tumor infiltration, and in vivo tumor/endothelium killing in NSG mice.
Main Results:
- cam1615TEM8 selectively activated NK cells, enhancing degranulation and cytokine production against TEM8+ cells.
- Superior NK cell killing of TEM8+ tumor spheroids and enhanced NK cell proliferation, survival, and tumor infiltration in vivo.
- cam1615TEM8 demonstrated NK cell-mediated killing of tumor and tumor endothelial cells in vivo.
Conclusions:
- The cam1615TEM8 TriKE is a novel multifunctional therapy targeting tumor cells, tumor stroma, and tumor angiogenesis.
- This therapy selectively activates NK cells and directs them to TEM8+ tumor cells and stroma.
- cam1615TEM8 shows promise as a new treatment for patients with solid tumors.
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