First-in-Human Phase I Study of Nicotinamide-Expanded Related Donor Natural Killer Cells for the Treatment of Relapsed/Refractory Non-Hodgkin Lymphoma and Multiple Myeloma

Abstract

Background Adoptive transfer of cytolytic natural killer (NK) cells is limited by the short-term persistence of NK cells and their impaired effector function after infusion. We have previously shown that ex-vivo expansion of NK cells with nicotinamide (NAM) resulted in potent cytotoxicity against multiple tumor cell lines, and robust homing, proliferation and retention in vivo (Blood 2017 130:657). We now report the first-in-human experience of NAM-NK in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). Methods Following donor apheresis, CD3-depleted mononuclear cells were cultured for 2 weeks in the presence of NAM (5mM) and IL-15 (20ng/ml). Patients received lymphodepleting chemotherapy followed by two doses of NAM-NK (Days 0 and 2) and low-dose IL-2. Rituximab or elotuzumab was administered to patients with NHL or MM, respectively, to facilitate tumor targeting and antibody-dependent cellular cytotoxicity. Results As of Oct 2018, 9 patients were enrolled. Of 7 evaluable patients, 5 had refractory NHL (3 follicular and 2 diffuse large cell lymphoma) and 2 had MM. Final NAM-NK product (n=7) contained a median of 98% NK cells. In vitro culture with NAM and IL15 resulted in a 3.8-fold increase in TNC and 40-fold increase in NK cells after 14-16 day culture; expression of homing receptor CD62L increased from 2.9% in apheresis to 21% in final product. CD3 content was kept Conclusions NAM-NK cells have been safely administered, were well tolerated and proliferated and persisted in vivo. Promising early evidence of clinical activity was observed in patients with advanced disease. Dose escalation will be followed by an expansion cohort at the MTD.