Nicotinamide enhances natural killer cell function and yields remissions in patients with non-Hodgkin lymphoma

Natural killer (NK) cells are innate cytotoxic lymphocytes that play an important role in surveillance and elimination of cancer. Allogeneic NK cell adoptive transfer has shown the potential to induce remissions in relapsed/refractory acute myeloid leukemia (AML) and lymphomas, but strategies to enhance NK cell survival and function are needed to improve clinical efficacy. Here, preclinical data is presented demonstrating that NK cells cultured ex vivo with IL-15 and nicotinamide (NAM) exhibited significant and stable induction of CD62L, a lymphocyte adhesion molecule important for lymph node homing. High frequencies of CD62L were associated with elevated levels of the transcription factor forkhead box O1 (FOXO1), and NAM promoted the stability of FOXO1 by preventing ubiquitin-mediated proteasomal degradation. NK cells cultured with NAM exhibited metabolic changes associated with elevated glucose flux through the tricarboxylic acid cycle and protection against oxidative stress. Importantly, NK cells incubated with NAM displayed enhanced cytotoxicity and inflammatory cytokine production in vitro and were maintained at high levels xenogeneic adoptive transfer experiments. We report results from a first-in-human phase 1 clinical trial testing adoptive transfer of NK cells expanded ex vivo with IL-15 and NAM (GDA-201) combined with monoclonal antibodies in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and myeloma (NCT03019666). Cellular therapy with GDA-201 and rituximab was well-tolerated and yielded an overall response rate of 74% in 19 patients with advanced NHL. Thirteen patients had a complete response, and 1 patient had a partial response. GDA-201 cells were detected for up to 14 days in blood, bone marrow, and tumor tissues and maintained a favorable metabolic profile. The safety and efficacy of GDA-201 justify further development as a cancer therapy. Peripheral blood was collected for the clinical trial testing NAM-expanded NK cells. From 3 donors, NK cells were sorted from apheresis products before ex vivo expansion. NK cells were also sorted from cells expanded with IL-15 and NAM prior to adoptive transfer. From 3 patients, donor and host NK cells were sorted using antibodies against HLA to distinguish doner and host. All cells were analyzed by single cell RNA-seq.