Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells

Yvette Robbins; Sarah Greene; Jay Friedman; Paul E. Clavijo; Carter Van Waes; Kellsye P. Fabian; Michelle R. Padget; Houssein Abdul Sater; John H. Lee; Patrick Soon-Shiong; James Gulley; Jeffrey Schlom; James W. Hodge; Clint T. Allen

doi:10.1101/2020.01.30.926535

Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells

Yvette Robbins, Sarah Greene, Jay Friedman, Paul E. Clavijo, Carter Van Waes, Kellsye P. Fabian, Michelle R. Padget, Houssein Abdul Sater, John H. Lee, Patrick Soon-Shiong, James Gulley, Jeffrey Schlom, James W. Hodge, Clint T. Allen

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1 dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted.

Original language	English (US)
Journal	Unknown Journal
DOIs	https://doi.org/10.1101/2020.01.30.926535
State	Published - Jan 30 2020

Keywords

chimeric antigen receptor
myeloid cell
NK cell therapy
programmed death-ligand 1
syngeneic
xenograft

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Immunology and Microbiology(all)
Neuroscience(all)
Pharmacology, Toxicology and Pharmaceutics(all)

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10.1101/2020.01.30.926535

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title = "Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells",

abstract = "Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1 dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted.",

keywords = "chimeric antigen receptor, myeloid cell, NK cell therapy, programmed death-ligand 1, syngeneic, xenograft",

author = "Yvette Robbins and Sarah Greene and Jay Friedman and Clavijo, {Paul E.} and {Van Waes}, Carter and Fabian, {Kellsye P.} and Padget, {Michelle R.} and Sater, {Houssein Abdul} and Lee, {John H.} and Patrick Soon-Shiong and James Gulley and Jeffrey Schlom and Hodge, {James W.} and Allen, {Clint T.}",

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doi = "10.1101/2020.01.30.926535",

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AU - Robbins, Yvette

AU - Greene, Sarah

AU - Friedman, Jay

AU - Clavijo, Paul E.

AU - Van Waes, Carter

AU - Fabian, Kellsye P.

AU - Padget, Michelle R.

AU - Sater, Houssein Abdul

AU - Lee, John H.

AU - Soon-Shiong, Patrick

AU - Gulley, James

AU - Schlom, Jeffrey

AU - Hodge, James W.

AU - Allen, Clint T.

N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/1/30

Y1 - 2020/1/30

N2 - Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1 dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted.

AB - Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1 dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted.

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KW - syngeneic

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Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells

Abstract

Keywords

ASJC Scopus subject areas

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