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

Abstract

Allogeneic natural killer (NK) cell adoptive transfer has shown the potential to induce remissions in relapsed or refractory leukemias and lymphomas, but strategies to enhance NK cell survival and function are needed to improve clinical efficacy. Here, we demonstrated that NK cells cultured ex vivo with interleukin-15 (IL-15) and nicotinamide (NAM) exhibited stable induction of l -selectin (CD62L), a lymphocyte adhesion molecule important for lymph node homing. High frequencies of CD62L were associated with elevated transcription factor forkhead box O1 (FOXO1), and NAM promoted the stability of FOXO1 by preventing proteasomal degradation. NK cells cultured with NAM exhibited metabolic changes associated with elevated glucose flux and protection against oxidative stress. NK cells incubated with NAM also displayed enhanced cytotoxicity and inflammatory cytokine production and preferentially persisted in xenogeneic adoptive transfer experiments. We also conducted 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 multiple myeloma (MM) (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 in this study support further development as a cancer therapy.

Nicotinic acid suppresses liver cancer metastasis via histone lysine nicotinylation

“…Recently numerous studies focused on vitamins as new therapeutic strategies to target at metabolism underlying malignant tumour progression [7][8][9][10] .To evaluate the correlation of vitamin B3 components NA/nicotinamide (NAM) and metastasis of hepatocellular carcinoma (HCC), in vivo tumorigenicity assay were performed in C57BL/6J mice that were administered normal saline (NS), NA, or NAM respectively. We found that quite different from NAM, NA supplement suppressed tumour size in the liver and metastatic nodule numbers (Fig.…”

Harnessing natural killer cells for refractory/relapsed non-Hodgkin lymphoma: biological roles, clinical trials, and future prospective

“…PFS at 1 and 2 years was estimated at 50% and 35%, respectively. The OS at 2 years was 73% Cichocki et al [ 156 ] 4 phase I UMIN000014072 R/R CD20 + lymphoma including DLBCL ( n = 5), FL ( n = 4) PB The PBMC were culture for 3 weeks in SCGM media supplemented with IL-15 (10 ng/mL), IL-2 (5 ng/mL), anti-CD3 mAb (10–1,000 ng/mL), tacrolimus (0.1 ng/mL) and dalteparin sodium (5–10 U/mL) The final products contained 80.5% CD56 + CD3 – NK cells and 26.2 ± 11.6% of CD56 + CD3 + NKT cells 1 to 10 × 10 6 cells/kg Not disclosed Rituximab There was no AEs related to NK cells infusion Of 9 patients, seven (78%) patients achieved CR with a median duration of 44 months Tanaka et al [ 153 ] 5 phase I NCT03778619 R/R NHL including DLBCL ( n = 6), MCL ( n = 2) and MZL ( n = 1) PB CD3 depleted cells were culture in CellGro SCGM media with 1% autoplasma, irradiated autologous PBMCs, anti-CD3 mAb (10 ng/mL) and IL2 (500 IU/mL) Viability > 90% with CD16 + CD56 + NK cells > 95%, level 1:1 × 10 7 , level 2: 3 × 10 7 , level 3: 9 × 10 7 cells/kg in association with IL-2 Cyclophosphamide and fludarabine Rituximab CRS in 1 patient. GVHD, neurotoxicity, and DLTs were not observed Of 9 patients, 4 (44%) patients achieved PR, one (11%) achieved CR and 4 (44%) showed PD.…”

Obesity, bone marrow adiposity, and leukemia: Time to act

“…Therefore, it would be interesting to observe the impact of nicotinamide on the BM adipocyte metabolism and adiposity. Furthermore, nicotinamide treatment also increases the antitumor action of NK cells in NHL patients by reprogramming their immunometabolism and increasing the CD62L expression in NHL patients 355 . Thus, it would be interesting to investigate this effect in NHL patients with obesity.…”