Relapsed/refractory patients

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 (5 mM) and interleukin-15 (IL-15) (20 ng/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 2nd 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.

References
  1. Bachanova V. et al. 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 #242. 2019 TCT Transplantation and Cellular Therapy Meetings of ASBMT and CIBMTR, Houston, Texas, USA.
  2. Frei G.M. et al. Nicotinamide, a Form of Vitamin B3, Promotes Expansion of Natural Killer Cells That Display Increased In Vivo Survival and Cytotoxic Activity. Blood. 2011. http://www.bloodjournal.org/content/118/21/4035?sso-checked=true
  3. Clinicaltrials.gov. Ph I Trial of NAM NK Cells and IL-2 for Adult Pts With MM and NHL. https://clinicaltrials.gov/ct2/show/NCT03019666 [accessed 2019 March 12]
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