CAR-modified memory-like NK cells exhibit potent responses to NK-resistant lymphomas

Abstract

<jats:p>NK cells are a promising cellular immunotherapy for cancer. Cytokine-induced memory-like (ML) NK cells differentiate after activation with IL-12, IL-15, and IL-18, exhibit potent anti-tumor responses, and safely induce complete remissions in patients with leukemia. However, many cancers are not fully recognized via NK cell receptors. Chimeric antigen receptors (CAR) have been utilized to enhance tumor-specific recognition by effector lymphocytes. We hypothesized that memory-like differentiation and CAR-engineering would result in complementary improvements in NK cell responses against NK-resistant cancers. To test this idea, peripheral blood ML NK cells were modified to express an anti-CD19 CAR (19-CAR-ML), which displayed significantly increased IFN-γ production, degranulation, and specific killing against NK-resistant lymphoma lines and primary targets, compared to non-specific control CAR-ML NK cells or conventional CAR NK cells. The 19-CAR and ML responses were synergistic, CAR-specific, and required ITAM signaling. Furthermore, 19-CAR-ML NK generated from lymphoma patients exhibited improved responses against their autologous lymphoma. 19-CAR-ML NK cells controlled lymphoma burden in vivo and improved survival in human xenograft models. Thus, CAR engineering of ML NK cells enhanced responses against resistant cancers and warrant further investigation, with the potential to broaden ML NK cell recognition against a variety of NK cell-resistant tumors.</jats:p>

Natural Killer Cells in Immunotherapy: Are We Nearly There?

“…Clinical trials are currently ongoing to assess the efficacy of these memory-like NK cells to treat AML and/or MDS (NCT01898793, NCT02782546, NCT03068819, NCT04024761, NCT04354025) [25], and head and neck squamous cell carcinoma (NCT04290546). Using memory-like NK cells to generate CAR-NK cells is an exciting prospect to improve CAR-NK therapy, as demonstrated in a recent study which showed that memory-like CD19-directed CAR-NK cells display improved functional responses, compared to conventionally generated CAR-NK cells [165].…”

Human cytokine-induced memory-like NK cells preserve increased glycolysis but the glycolytic-dependence of their effector functions differ between stimuli

“…IL-12/15/18-preactivated NK cells have emerged as a powerful tool to treat leukemia 11 , and their potential is also being explored in therapies against other malignancies [13][14][15]17 .…”

“…These cells have been proven to be useful in mouse and rat models of several malignancies, including acute myeloid leukemia, T-cell acute lymphoblastic leukemia, multiple myeloma, lymphoma, melanoma, ovarian cancer and hepatocellular carcinoma [11][12][13][14][15][16][17] . Regarding to humans, CIML NK cells have shown their safety and efficacy in the treatment of acute myeloid leukemia patients 11 , and are currently being tested in several clinical trials (NCT01898793, NCT02782546, NCT03068819, NCT04024761, NCT04290546 and NCT04354025, from clinicaltrials.gov).…”

Using Gene Editing Approaches to Fine-Tune the Immune System

“…Their effector capacity depends on the balance between activating and inhibiting signals triggered by specific receptors that recognize ligands on stressed cells such as tumoral and infected cells ( 79 ). Recent studies show that NK cells can be genetically engineered to express chimeric antigen receptors (CARs) ( 80 – 82 ). However, few studies have reported gene editing modifications in NK cells due to their low rates of transduction with viral systems and the difficulty of NK expansion in vitro ( 83 , 84 ).…”