Journal Article

Chimeric antigen receptor engineered NK cellular immunotherapy overcomes the selection of T-cell escape variant cancer cells

Clavijo, Paul E, Schlom, Jeffrey, Tsong, Edward, Hinrichs, Christian, Hodge, James, Lee, Maxwell Y, Allen, Clint, Friedman, Jay, Soon-Shiong, Patrick, Silvin, Chris, Judd, Nancy, Abdul Sater, Houssein, Sievers, Cem, Robbins, Yvette, Padget, Michelle R

2021

Overview

BackgroundAs heterogeneous tumors develop in the face of intact immunity, tumor cells harboring genomic or expression defects that favor evasion from T-cell detection or elimination are selected. For patients with such tumors, T cell-based immunotherapy alone infrequently results in durable tumor control.MethodsHere, we developed experimental models to study mechanisms of T-cell escape and demonstrated that resistance to T-cell killing can be overcome by the addition of natural killer (NK) cells engineered to express a chimeric antigen receptor (CAR) targeting programmed death ligand-1 (PD-L1).ResultsIn engineered models of tumor heterogeneity, PD-L1 CAR-engineered NK cells (PD-L1 t-haNKs) prevented the clonal selection of T cell-resistant tumor cells observed with T-cell treatment alone in multiple models. Treatment of heterogenous cancer cell populations with T cells resulted in interferon gamma (IFN-γ) release and subsequent upregulation of PD-L1 on tumor cells that escaped T-cell killing through defects in antigen processing and presentation, priming escape cell populations for PD-L1 dependent killing by PD-L1 t-haNKs in vitro and in vivo.ConclusionsThese results describe the underlying mechanisms governing synergistic antitumor activity between T cell-based immunotherapy that results in IFN-γ production, upregulation of PD-L1 on T-cell escape cells, and the use of PD-L1 CAR-engineered NK cells to target and eliminate resistant tumor cell populations.

• Publisher: BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Animals / Antigens / Automation / B7-H1 Antigen - genetics / B7-H1 Antigen - metabolism / Basic Tumor Immunology / Cancer / Cell Line, Tumor / Cloning / CRISPR / CRISPR-Cas Systems / Cytokeratin / Databases, Genetic / Experiments / Flow cytometry / Gene Editing / Gene expression / Head & neck cancer / Head and Neck Neoplasms - genetics / Head and Neck Neoplasms - immunology / Head and Neck Neoplasms - metabolism / Head and Neck Neoplasms - therapy / HLA Antigens - metabolism / Human papillomavirus / Humans / Immunotherapy / Immunotherapy, Adoptive / Interferon-gamma - metabolism / Killer Cells, Natural - immunology / Killer Cells, Natural - metabolism / Killer Cells, Natural - transplantation / Lymphocyte Activation / Lymphocytes / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - metabolism / Mice / Mice, Inbred NOD / Mice, SCID / Mutation / Plasmids / Receptors, Chimeric Antigen - genetics / Receptors, Chimeric Antigen - immunology / Software / Squamous Cell Carcinoma of Head and Neck - genetics / Squamous Cell Carcinoma of Head and Neck - immunology / Squamous Cell Carcinoma of Head and Neck - metabolism / Squamous Cell Carcinoma of Head and Neck - therapy / T cell receptors / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / T-Lymphocytes - transplantation / Tumor Burden / Tumor Escape / Tumor Microenvironment / Tumors / Xenograft Model Antitumor Assays