Pluripotent stem cell–derived NK cells with high-affinity noncleavable CD16a mediate improved antitumor activity

Autor: Jianming Wu, Ramzey Abujarour, Pei Fang Tsai, Dan S. Kaufman, Svetlana Gaidarova, Robert Blum, Gregory B. Bonello, Bruce Walcheck, Bahram Valamehr, Paul Rogers, Ryan Bjordahl, Huang Zhu, Jeffrey S. Miller, Tom Tong Lee
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Lymphoma
Hematopoiesis and Stem Cells
Fc receptor
Mice
SCID
Cardiorespiratory Medicine and Haematology
Biochemistry
Cell therapy
Mice
Antineoplastic Agents
Immunological
Mice
Inbred NOD
Receptors
Monoclonal
Killer Cells
Induced pluripotent stem cell
Cancer
Antibody-dependent cell-mediated cytotoxicity
Ovarian Neoplasms
Tumor
Stem Cell Research - Induced Pluripotent Stem Cell - Human
biology
Chemistry
Antibodies
Monoclonal
Hematology
Killer Cells
Natural
Immunological
Natural
Female
Development of treatments and therapeutic interventions
Antibody
Biotechnology
Lymphoma
B-Cell
IgG
medicine.drug_class
Clinical Sciences
Immunology
Induced Pluripotent Stem Cells
Antineoplastic Agents
SCID
Monoclonal antibody
Antibodies
Cell Line
Paediatrics and Reproductive Medicine
Rare Diseases
Antigen
Cell Line
Tumor
medicine
Animals
Humans
CD20
Antigens
Stem Cell Research - Induced Pluripotent Stem Cell
5.2 Cellular and gene therapies
Receptors
IgG
B-Cell
Antibody-Dependent Cell Cytotoxicity
Cell Biology
Stem Cell Research
Antigens
CD20
Cell culture
biology.protein
Cancer research
Inbred NOD
Zdroj: Blood
Blood, vol 135, iss 6
Popis: Antibody-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.
Databáze: OpenAIRE
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