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A tri-specific killer engager against mesothelin targets NK cells towards lung cancer
Philippa R Kennedy1, Daniel A Vallera2, Brianna Ettestad1
1Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States.
Abstract:
New treatments are required to enhance current therapies for lung cancer. Mesothelin is a surface protein overexpressed in non-small cell lung cancer (NSCLC) that shows promise as an immunotherapeutic target in phase I clinical trials. However, the immunosuppressive environment in NSCLC may limit efficacy of these therapies. We applied time-of-flight mass cytometry to examine the state of circulating mononuclear cells in fourteen patients undergoing treatment for unresectable lung cancer. Six patients had earlier stage NSCLC (I-IVA) and eight had highly advanced NSCLC (IVB). The advanced NSCLC patients relapsed with greater frequency than the earlier stage patients. Before treatment, patients with very advanced NSCLC had a greater proportion of CD14- myeloid cells than patients with earlier NSCLC. These patients also had fewer circulating natural killer (NK) cells bearing an Fc receptor, CD16, which is crucial to antibody-dependent cellular cytotoxicity. We designed a high affinity tri-specific killer engager (TriKE®) to enhance NK cytotoxicity against mesothelin+ targets in this environment. The TriKE consisted of CD16 and mesothelin binding elements linked together by IL-15. TriKE enhanced proliferation of lung cancer patient NK cells in vitro. Lung cancer lines are refractory to NK cell killing, but the TriKE enhanced cytotoxicity and cytokine production by patient NK cells when challenged with tumor. Importantly, TriKE triggered NK cell responses from patients at all stages of disease and treatment, suggesting TriKE can enhance current therapies. These pre-clinical studies suggest mesothelin-targeted TriKE has the potential to overcome the immunosuppressive environment of NSCLC to treat disease.
Insights
New treatments for lung cancer are needed. A novel mesothelin-targeted TriKE therapy enhanced natural killer (NK) cell activity against non-small cell lung cancer (NSCLC) in pre-clinical studies.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Mesothelin is overexpressed in non-small cell lung cancer (NSCLC), presenting a potential target for immunotherapy.
- The immunosuppressive tumor microenvironment in NSCLC can limit the effectiveness of current therapies.
- Patients with advanced NSCLC exhibit distinct circulating immune cell profiles, including reduced CD16+ natural killer (NK) cells.
Purpose of the Study:
- To investigate the immune landscape of NSCLC patients undergoing treatment.
- To develop and evaluate a novel immunotherapeutic agent, TriKE, targeting mesothelin-expressing NSCLC.
- To assess TriKE's ability to overcome the immunosuppressive environment and enhance NK cell anti-tumor activity.
Main Methods:
- Time-of-flight mass cytometry was used to analyze circulating mononuclear cells from NSCLC patients.
- A tri-specific killer engager (TriKE) targeting mesothelin and CD16, incorporating IL-15, was designed.
- In vitro assays assessed TriKE's effect on NK cell proliferation, cytotoxicity, and cytokine production against NSCLC lines.
Main Results:
- Advanced NSCLC patients showed a higher proportion of CD14- myeloid cells and fewer CD16+ NK cells compared to earlier stage patients.
- TriKE significantly enhanced NK cell proliferation and cytotoxicity against NSCLC cells in vitro.
- TriKE stimulated NK cell responses across all disease stages and treatment statuses in patient-derived cells.
Conclusions:
- Mesothelin-targeted TriKE demonstrates potential to overcome the immunosuppressive tumor microenvironment in NSCLC.
- TriKE enhances NK cell-mediated anti-tumor immunity and may serve as a valuable addition to current lung cancer therapies.
- These pre-clinical findings support further investigation of TriKE for NSCLC treatment.
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