Expanded CD56superbrightCD16+ NK Cells from Ovarian Cancer Patients Are Cytotoxic against Autologous Tumor in a Patient-Derived Xenograft Murine Model

Abstract

Natural killer (NK) cells are useful for cancer immunotherapy and have proven clinically effective against hematologic malignancies. However, immunotherapies for poor prognosis solid malignancies, including ovarian cancer, have not been as successful due to immunosuppression by solid tumors. Although rearming patients' own NK cells to treat cancer is an attractive option, success of that strategy is limited by the impaired function of NK cells from cancer patients and by inhibition by self-MHC. In this study, we show that expansion converts healthy donor and immunosuppressed ovarian cancer patient NK cells to a cytotoxic CD56CD16 subset with activation state and antitumor functions that increase with CD56 brightness. We investigated whether these expanded NK cells may overcome the limitations of autologous NK cell therapy against solid tumors. Peripheral blood- and ascites-derived NK cells from ovarian cancer patients were expanded and then adoptively transferred into cell-line and autologous patient-derived xenograft models of human ovarian cancer. Expanded ovarian cancer patient NK cells reduced the burden of established tumors and prolonged survival. These results suggest that CD56 NK cells harbor superior antitumor function compared with CD56 cells. Thus, NK cell expansion may overcome limitations on autologous NK cell therapy by converting the patient's NK cells to a cytotoxic subset that exerts a therapeutic effect against autologous tumor. These findings suggest that the value of expanded autologous NK cell therapy for ovarian cancer and other solid malignancies should be clinically assessed. .

Cellular therapy: Adoptive immunotherapy with expanded natural killer cells

“…We initially shared the cell line freely for academic use with over 50 investigators worldwide, until several complications with rights and ownership of the cell line precluded further distribution. The original cell line we described (Clone9.mbIL21) proved very effective in propagating NK cells from peripheral blood of normal donors, patients, and cord blood, and a master cell bank (MCB) with full compendial testing for human clinical use was established to generate NK cells for clinical trials …”

“…Discrimination of CD56 expression into bright and dim subsets has long been an important tool in identifying NK cell subsets with both maturational (young and old, respectively) and functional (cytokine‐producing vs cytotoxic, respectively) differences. Ex vivo expansion generates postmature, hyperfunctional (cytokine‐producing and cytotoxic) NK cells that are CD56 bright , challenging the reliability of CD56 as a biologic marker.…”

“…The original cell line we described (Clone9. mbIL21) proved very effective in propagating NK cells from peripheral blood of normal donors, [65][66][67][68][69] patients, [70][71][72][73] and cord blood, 74,75 and a master cell bank (MCB) with full compendial testing for human clinical use was established to generate NK cells for clinical trials. 69,75,76 Subsequently, and occasionally in response to our inability to continue sharing the cell line, several groups have replicated the findings or identified variations that support our initial findings.…”

Shining light on the significance of NK cell CD56 brightness

“…Indeed, following expansion with K562 feeder cells that express 4-1BBL and membrane-bound (mb)IL-21, the majority of the expanded NK cell population consisted of CD56 superbright cells, again with a combined capacity for high levels of anti-tumor cytokine production and cytotoxicity. 11 In fact, expanded CD56 bright NK cells exhibited greater degranulation in response to tumor targets than expanded CD56 dim NK cells. 11 These recent studies expose a new facet of CD56 bright NK cells as critical cytotoxic effectors.…”

“…11 In fact, expanded CD56 bright NK cells exhibited greater degranulation in response to tumor targets than expanded CD56 dim NK cells. 11 These recent studies expose a new facet of CD56 bright NK cells as critical cytotoxic effectors.…”