Enhancing NK Cell Therapy for Multiple Myeloma: The Role of CD38 Disruption and Daratumumab Synergy in FT538 Development

Monoclonal antibodies are widely used in cancer treatment, with the potential to be further improved by enhancing their interaction with natural killer (NK) cells, which can boost antibody-dependent cellular cytotoxicity (ADCC). CD38-targeted monoclonal antibodies like daratumumab are effective against multiple myeloma, but their efficacy can be compromised due to NK cell depletion caused by fratricide when NK cells, which express high levels of CD38, are activated.

FT538 is a novel NK cell therapy derived from induced pluripotent stem cells (iPSCs) that are genetically modified to lack CD38 expression, thus avoiding fratricide induced by anti-CD38 antibodies. It also features an engineered IL-15 receptor alpha fusion protein to improve cell longevity and a high-affinity CD16 to increase ADCC. This therapy has been developed with a focus on clinical applicability, with a clinical-grade master pluripotent stem cell line established for consistent and scalable production.

In vitro studies have shown that FT538 maintains a mature NK cell phenotype and is resistant to daratumumab-induced fratricide, unlike peripheral blood NK cells. It also demonstrates sustained cytotoxic capacity upon repeated exposure to daratumumab and multiple myeloma target cells, unlike non-engineered iPSC-derived NK cells. The combination of IL-15RF expression and CD38 knockout in FT538 enhances its cytotoxicity against multiple myeloma tumor spheroids, supporting its potential for clinical use.

Disclosures indicate that several authors are affiliated with Fate Therapeutics, Inc., and some have received consultancy fees, research funding, or hold memberships on advisory boards or boards of directors for various entities, including Fate Therapeutics and other biotechnology companies.