Carlsten, Mattias (NHLBI)
A highly efficient method to genetically modify natural killer (NK) cells to induce expression of high affinity CD16 (HA-CD16) through mRNA electroporation, to potentiate NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). ADCC is mediated by CD16+ NK cells following adoptive NK cell transfer, but most humans express CD16 which has a relatively low affinity for IgG1 antibodies. However, a single nucleotide polymorphism (SNP rs396991) in the CD16 gene, resulting in an amino acid substitution at position 158 (F158V), is associated with substantially higher affinity and superior NK cell-mediated ADCC than those with the 158F genotype. This HA-CD16-158V polymorphism has also been linked to enhanced ADCC capacity in vivo. The nearly 100% efficiency of our method resulted in: a) sustained surface expression of transgenes at high levels for up to 4 days without compromising NK cell cytotoxicity and viability; and b) augmented ADCC against Daratumumab coated multiple myeloma cells by ex vivo expanded NK cells electroporated with mRNA coding for HA-CD16. This system is GMP compliant and has been used previously in FDA approved clinical trials.
- Infusion of a large number of highly cytotoxic autologous ex vivo expanded NK cells expressing high-affinity CD16 into patients, to induce a more profound anti-malignancy response to specific monoclonal antibodies, including: multiple myeloma (Daratumumab); lymphoma (Rituximab); breast cancer (Trastuzumab); and colon cancer (Cetuximab).
- High efficiency
- GMP compliant