Transfection of chimeric anti‐CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells

Abstract

Reprogramming of NK cells with a chimeric antigen receptor (CAR) proved an effective strategy to increase NK cell reactivity and recognition specificity toward tumor cells. To enhance the cytotoxicity of NK cells against CD138-positive multiple myeloma (MM) cells, we generated genetically modified NK-92MI cells carrying a CAR that consists of an anti-CD138 single-chain variable fragment (scFv) fused to the CD3ζ chain as a signaling moiety. The genetic modification through a lentiviral vector did not affect the intrinsic cytolytic activity of NK-92MI toward human erythroleukemic cell line K562 cells or CD138-negative targets. However, these retargeted NK-92MI (NK-92MI-scFv) displayed markedly enhanced cytotoxicity against CD138-positive human MM cell lines (RPMI8226, U266 and NCI-H929) and primary MM cells at various effector-to-target ratios (E:T) as compared to the empty vector-transfected NK-92MI (NK-92MI-mock). In line with the enhanced cytotoxicity of NK-92MI-scFv, significant elevations in the secretion of granzyme B, interferon-γ and proportion of CD107a expression were also found in NK-92MI-scFv in response to CD138-positive targets compared with NK-92MI-mock. Most importantly, the enhancement in the cytotoxicity of NK-92MI-scFv did not attenuate with 10Gy-irradiation that sufficiently blocked cell proliferation. Moreover, the irradiated NK-92MI-scFv exerted definitely intensified anti-tumor activity toward CD138-positive MM cells than NK-92MI-mock in the xenograft NOD-SCID mouse model. This study provides the rationale and feasibility for adoptive immunotherapy with CD138-specific CAR-modified NK cells in CD138-positive plasmacytic malignancies, which potentially further improves remission quality and prolongs the remission duration of patients with MM after upfront chemotherapy.

NK cells and cancer: you can teach innate cells new tricks

“…142) and CD20 (REF. 143) expressed on B cell malignancies; disialoganglioside G D2 , a glycolipid expressed on neuroblastoma 144 and various other cancer types 145 ; HER2 (also known as ERBB2), an antigen expressed by tumours of epithelial origin [146][147][148] ; epithelial cell adhesion molecule (EPCAM), a molecule over expressed by carcinomas and cancer stem cells 149 ; HLA-A2 loaded with the mela noma antigen gp100 (also known as PMEL) 150 ; prostate stem cell antigen (PSCA) 151 ; and CD138 (also known as SYND1), which is expressed by multiple myeloma cells 152 . Because NK-92 cells are a tumour cell line infected with Epstein-Barr virus (EBV), they must be irradiated to prevent their proliferation before being adoptively transferred.…”

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

“…This CAR approach is now being explored in myeloma, with a number of potential targets identified, including CD138, CD38, CD44v, kappa light chain, Lewis Y, CS1/SLAMF7 and BCMA. Preclinical studies have shown that T cells or in some cases, NK cells expressing CARs specific for these targets can kill myeloma cells in vitro and in xenograft models, [86][87][88][89][90][91] and several have now entered early-phase clinical trials. One target of interest is B-cell maturation Ag (BCMA).…”

Targeting B-Cell Maturation Antigen in Multiple Myeloma

“…Since CD19 is rarely expressed in patient MM cells, clinical use of anti-CD19 CAR-transduced T cells could be limited in MM. CS1 (SLAMF7), CD138 and CD38 are candidate TAAs for CAR-expressing effector cells, as recently reported in preclinical studies of CAR CD138 NK cells [53] and CAR CS1 NK [54] and T cells [55,56]. However, their expression profiles are not as restricted as BCMA on PCs versus other normal cells.…”