Abstract
AbstractAntibody-dependent cellular cytotoxicity (ADCC) is a key effector mechanism of natural killer (NK) cells that is mediated by therapeutic monoclonal antibodies (mAbs). This process is facilitated by the Fc receptor CD16a on human NK cells. CD16a appears to be the only activating receptor on NK cells that is cleaved by the metalloprotease a disintegrin and metalloproteinase-17 upon stimulation. We previously demonstrated that a point mutation of CD16a prevents this activation-induced surface cleavage. This noncleavable CD16a variant is now further modified to include the high-affinity noncleavable variant of CD16a (hnCD16) and was engineered into human induced pluripotent stem cells (iPSCs) to create a renewable source for human induced pluripotent stem cell–derived NK (hnCD16-iNK) cells. Compared with unmodified iNK cells and peripheral blood–derived NK (PB-NK) cells, hnCD16-iNK cells proved to be highly resistant to activation-induced cleavage of CD16a. We found that hnCD16-iNK cells were functionally mature and exhibited enhanced ADCC against multiple tumor targets. In vivo xenograft studies using a human B-cell lymphoma demonstrated that treatment with hnCD16-iNK cells and anti-CD20 mAb led to significantly improved regression of B-cell lymphoma compared with treatment utilizing anti-CD20 mAb with PB-NK cells or unmodified iNK cells. hnCD16-iNK cells, combined with anti-HER2 mAb, also mediated improved survival in an ovarian cancer xenograft model. Together, these findings show that hnCD16-iNK cells combined with mAbs are highly effective against hematologic malignancies and solid tumors that are typically resistant to NK cell–mediated killing, demonstrating the feasibility of producing a standardized off-the-shelf engineered NK cell therapy with improved ADCC properties to treat malignancies that are otherwise refractory.
Highlights
Because CD16 is a key activating receptor on NK cells that mediates antibody-dependent cell-mediated cytotoxicity (ADCC), we examined the ability of high-affinity noncleavable version of CD16a (hnCD16)-iNK cells to mediate ADCC against multiple cancer cell lines, including Raji cells, A549 cells, SKOV-3 cells, and Cal[27] cells
HnCD16-iNK cells mediated ADCC better than did WTCD16-iNK cells. These results demonstrate that noncleavable CD16 contributes to the improved ADCC in hnCD16-iNK cells
We examined whether multiple doses of NK cells 1 anti-CD20 monoclonal antibodies (mAbs) would further augment in vivo ADCC
Summary
Cell-based anticancer immunotherapies have experienced great advances in the past few years.[1]. Mice were given 1 3 105 to 2.5 3 105 Luc-expressing tumor cells IV or via intraperitoneal injection. One day prior to NK cell injection, mice were assayed for tumor burden using bioluminescent imaging (BLI) and placed into equivalent. (hnCD16-iNK cells) exhibit potent ADCC against hematological malignancies and solid tumors. A multidose regimen of hnCD16-iNK cells derived from an engineered clonal human iPSC line administered with anti-CD20 mAb treatment mediated potent activity and improved long-term survival in a mouse xenograft lymphoma model. Standardized off-the-shelf hnCD16iNK cells with enhanced ADCC effector function, in combination with readily available anti-tumor mAbs, provide a novel clinical strategy to treat cancer. For the quantification of in vivo image, data are presented as the mean 6 SEM, and differences between groups were analyzed using a 2-tailed Student t test.
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