TCT Meeting 2019 | Nicotinamide-expanded related donor natural killer cells for the treatment of relapsed/refractory multiple myeloma and non-Hodgkin lymphoma: results from the first-in-human phase I study

On 20 February 2019, at the 2019 TCT | Transplantation and Cellular Therapy Meetings of ASBMT and CIBMTR in Houston, Texas, USA, Veronika Bachanova, from the University of Minnesota, USA, presented the results of the first-in-human phase I trial (NCT03019666) of nicotinamide-expanded natural killer (NAM-NK) cells for, the treatment of relapsed/refractory multiple myeloma (MM) or non-Hodgkin lymphoma (NHL).¹

The primary endpoint of this study is to determine the maximum tolerated dose (MTD) of NAM-NK cells whilst maintaining safety, measured by the occurrence of grade 4 or greater adverse events or grade 3 or 4 acute graft-versus­-host disease. The human leukocyte antigen (HLA)-haploidentical and HLA-mismatched related donor NK cells are expanded with NAM with the aim of enhancing NK cell expansion.^2,3

Study design:

• Patients had relapsed/refractory MM (RRMM) or CD20-positive NHL
• NAM-NK cell generation:
  • Apheresis was conducted on donors
  • CD3-depleted mononuclear cells were cultured with NAM (5mM) and interleukin-15 (IL-15) (20ng/ml) for 2 weeks
• Patients received:
  • Lymphodepleting chemotherapy
  • Two doses of NAM-NK cells (days 0 and 2) in combination with low-dose IL-2
  • Elotuzumab was given to patients with MM
  • Rituximab was given to patients with NHL
• Nine patients were enrolled and of these, seven were evaluable
• Refractory NHL (n = 5)
  • Follicular lymphoma (FL) (n = 3) and diffuse large cell lymphoma (n = 2)
• RRMM (n = 2)
• Product contained, median, 98% NK cells
• In vitro culture with NAM + IL-15 for 14-16 days provided:
  • NK cells: 40x increase
  • CD62L expression increased from 2.9% to 21%
  • CD3 content remained <0.5%
• Three patients received NAM-NK at an initial dose of 2x10⁷/kg (n = 3)
• Four patients then received the 2^nd dose level of NAM-NK of 1x10⁸/kg

Safety results:

• At the initial dose:
  • No dose-limiting toxicities (DLTs) were observed
  • Transient neutropenia (n = 3)
  • Neutropenic fever (n = 1)
• At the second dose level:
  • No grade 3/4 adverse events were observed
  • No cytokine release syndrome or neurotoxicity

Response assessment at 2 months:

• Complete metabolic remission (n = 3)
  • FL (n = 2)
  • Transformed lymphoma (n = 1)
• Stable disease (n = 1)
  • MM
• Progressive disease (n = 1)
  • MM

Data shown as host NK cells versus NAM-NK cells

• Analysis by flow cytometry of peripheral blood
• Proliferation of NAM-NK between days 2–7 in all patients (2–55%)
• CD16 expression: 68% vs 82%
• Proliferation (median Ki67): 81% vs 99%

These initial first-in-human results have shown NAM-NK cells can be safely administered and persist in vivo. They were well-tolerated and demonstrated evidence of clinical activity in both RRMM and CD20-positive NHL, advanced-stage diseases. In the ongoing study, dose escalation will be followed by an expansion cohort at the MTD.