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

Pippa Kennedy; Daniel A. Vallera; Brianna Ettestad; Caroline Hallstrom; Behiye Kodal; Deborah A Todhunter; Laura E Bendzick; Peter Hinderlie; Joshua T Walker; Brittany Pulkrabek; Ira Pastan; Robert A Kratzke; Naomi Fujioka; Jeffrey S Miller; Martin Felices

doi:10.3389/fimmu.2023.1060905

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

Pippa Kennedy, Daniel A. Vallera, Brianna Ettestad, Caroline Hallstrom, Behiye Kodal, Deborah A Todhunter, Laura E Bendzick, Peter Hinderlie, Joshua T Walker, Brittany Pulkrabek, Ira Pastan, Robert A Kratzke, Naomi Fujioka, Jeffrey S Miller, Martin Felices

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12 Scopus citations

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.

Original language	English (US)
Article number	1060905
Journal	Frontiers in immunology
Volume	14
DOIs	https://doi.org/10.3389/fimmu.2023.1060905
State	Published - 2023

Bibliographical note

Funding Information:
This work was supported in part by NCI P01 CA111412 and R35 CA197292; DoD CA200922; NCI P30 CA077598; Minnesota Masonic Charities, Killebrew-Thompson Memorial Fund; the Masonic Cancer Center, University of Minnesota, the Eagles 5th District Cancer Telethon and the Varsity Team Rally; and National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) grant UL1TR002494. Clinical data was provided by the University of Minnesota’s Clinical and Translational Science Institute, Best Practices Integrated Informatics Core. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH)’s National Center for Advancing Translational Sciences.

Funding Information:
This work was supported in part by NCI P01 CA111412 and R35 CA197292; DoD CA200922; NCI P30 CA077598; Minnesota Masonic Charities, Killebrew-Thompson Memorial Fund; the Masonic Cancer Center, University of Minnesota, the Eagles 5th District Cancer Telethon and the Varsity Team Rally; and National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) grant UL1TR002494. Clinical data was provided by the University of Minnesota’s Clinical and Translational Science Institute, Best Practices Integrated Informatics Core. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH)’s National Center for Advancing Translational Sciences. Acknowledgments

Publisher Copyright:
Copyright © 2023 Kennedy, Vallera, Ettestad, Hallstrom, Kodal, Todhunter, Bendzick, Hinderlie, Walker, Pulkrabek, Pastan, Kratzke, Fujioka, Miller and Felices.

Keywords

NK cell
NSCLC
TriKE
biologic
cancer
immunotherapy
lung

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3389/fimmu.2023.1060905

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Kennedy, P., Vallera, D. A., Ettestad, B., Hallstrom, C., Kodal, B., Todhunter, D. A., Bendzick, L. E., Hinderlie, P., Walker, J. T., Pulkrabek, B., Pastan, I., Kratzke, R. A., Fujioka, N., Miller, J. S., & Felices, M. (2023). A tri-specific killer engager against mesothelin targets NK cells towards lung cancer. Frontiers in immunology, 14, Article 1060905. https://doi.org/10.3389/fimmu.2023.1060905

Kennedy, P , Vallera, DA, Ettestad, B, Hallstrom, C, Kodal, B , Todhunter, DA , Bendzick, LE , Hinderlie, P , Walker, JT, Pulkrabek, B, Pastan, I, Kratzke, RA , Fujioka, N , Miller, JS & Felices, M 2023, 'A tri-specific killer engager against mesothelin targets NK cells towards lung cancer', Frontiers in immunology, vol. 14, 1060905. https://doi.org/10.3389/fimmu.2023.1060905

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title = "A tri-specific killer engager against mesothelin targets NK cells towards lung cancer",

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{\textregistered}) 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.",

keywords = "NK cell, NSCLC, TriKE, biologic, cancer, immunotherapy, lung",

author = "Pippa Kennedy and Vallera, {Daniel A.} and Brianna Ettestad and Caroline Hallstrom and Behiye Kodal and Todhunter, {Deborah A} and Bendzick, {Laura E} and Peter Hinderlie and Walker, {Joshua T} and Brittany Pulkrabek and Ira Pastan and Kratzke, {Robert A} and Naomi Fujioka and Miller, {Jeffrey S} and Martin Felices",

note = "Funding Information: This work was supported in part by NCI P01 CA111412 and R35 CA197292; DoD CA200922; NCI P30 CA077598; Minnesota Masonic Charities, Killebrew-Thompson Memorial Fund; the Masonic Cancer Center, University of Minnesota, the Eagles 5th District Cancer Telethon and the Varsity Team Rally; and National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) grant UL1TR002494. Clinical data was provided by the University of Minnesota{\textquoteright}s Clinical and Translational Science Institute, Best Practices Integrated Informatics Core. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH){\textquoteright}s National Center for Advancing Translational Sciences. Funding Information: This work was supported in part by NCI P01 CA111412 and R35 CA197292; DoD CA200922; NCI P30 CA077598; Minnesota Masonic Charities, Killebrew-Thompson Memorial Fund; the Masonic Cancer Center, University of Minnesota, the Eagles 5th District Cancer Telethon and the Varsity Team Rally; and National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) grant UL1TR002494. Clinical data was provided by the University of Minnesota{\textquoteright}s Clinical and Translational Science Institute, Best Practices Integrated Informatics Core. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH){\textquoteright}s National Center for Advancing Translational Sciences. Acknowledgments Publisher Copyright: Copyright {\textcopyright} 2023 Kennedy, Vallera, Ettestad, Hallstrom, Kodal, Todhunter, Bendzick, Hinderlie, Walker, Pulkrabek, Pastan, Kratzke, Fujioka, Miller and Felices.",

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doi = "10.3389/fimmu.2023.1060905",

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AU - Kennedy, Pippa

AU - Vallera, Daniel A.

AU - Ettestad, Brianna

AU - Hallstrom, Caroline

AU - Kodal, Behiye

AU - Todhunter, Deborah A

AU - Bendzick, Laura E

AU - Hinderlie, Peter

AU - Walker, Joshua T

AU - Pulkrabek, Brittany

AU - Pastan, Ira

AU - Kratzke, Robert A

AU - Fujioka, Naomi

AU - Miller, Jeffrey S

AU - Felices, Martin

N1 - Funding Information: This work was supported in part by NCI P01 CA111412 and R35 CA197292; DoD CA200922; NCI P30 CA077598; Minnesota Masonic Charities, Killebrew-Thompson Memorial Fund; the Masonic Cancer Center, University of Minnesota, the Eagles 5th District Cancer Telethon and the Varsity Team Rally; and National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) grant UL1TR002494. Clinical data was provided by the University of Minnesota’s Clinical and Translational Science Institute, Best Practices Integrated Informatics Core. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH)’s National Center for Advancing Translational Sciences. Funding Information: This work was supported in part by NCI P01 CA111412 and R35 CA197292; DoD CA200922; NCI P30 CA077598; Minnesota Masonic Charities, Killebrew-Thompson Memorial Fund; the Masonic Cancer Center, University of Minnesota, the Eagles 5th District Cancer Telethon and the Varsity Team Rally; and National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) grant UL1TR002494. Clinical data was provided by the University of Minnesota’s Clinical and Translational Science Institute, Best Practices Integrated Informatics Core. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH)’s National Center for Advancing Translational Sciences. Acknowledgments Publisher Copyright: Copyright © 2023 Kennedy, Vallera, Ettestad, Hallstrom, Kodal, Todhunter, Bendzick, Hinderlie, Walker, Pulkrabek, Pastan, Kratzke, Fujioka, Miller and Felices.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - NK cell

KW - NSCLC

KW - TriKE

KW - biologic

KW - cancer

KW - immunotherapy

KW - lung

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

Abstract

Bibliographical note

Keywords

UN SDGs

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

Abstract

Bibliographical note

Keywords

UN SDGs

Publisher link

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Nikon A1RSI Confocal with SIM Super Resolution

University Imaging Centers

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