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01-03-2018 | Original Article

Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells

Authors: Veronika Bachanova, Dhifaf Sarhan, Todd E. DeFor, Sarah Cooley, Angela Panoskaltsis-Mortari, Bruce R. Blazar, Julie M. Curtsinger, Linda Burns, Daniel J. Weisdorf, Jeffrey S. Miller

Published in: Cancer Immunology, Immunotherapy | Issue 3/2018

Abstract

We report a novel phase 2 clinical trial in patients with poor prognosis refractory non-Hodgkin lymphoma (NHL) testing the efficacy of haploidentical donor natural killer (NK) cell therapy (NK dose 0.5–3.27 × 10⁷ NK cells/kg) with rituximab and IL-2 (clinicaltrials.gov NCT01181258). Therapy was tolerated without graft-versus-host disease, cytokine release syndrome, or neurotoxicity. Of 14 evaluable patients, 4 had objective responses (29%; 95% CI 12–55%) at 2 months: 2 had complete response lasting 3 and 9 months. Circulating donor NK cells persisted for at least 7 days after infusion at the level 0.6–16 donor NK cells/µl or 0.35–90% of total CD56 cells. Responding patients had lower levels of circulating host-derived Tregs (17 ± 4 vs. 307 ± 152 cells/µL; p = 0.008) and myeloid-derived suppressor cells at baseline (6.6 ± 1.4% vs. 13.0 ± 2.7%; p = 0.06) than non-responding patients. Lower circulating Tregs correlated with low serum levels of IL-10 (R ² = 0.64; p < 0.003; n = 11), suggestive of less immunosuppressive milieu. Low expression of PD-1 on recipient T cells before therapy was associated with response. Endogenous IL-15 levels were higher in responders than non-responding patients at the day of NK cell infusion (mean ± SEM: 30 ± 4; n = 4 vs. 19.0 ± 4.0 pg/ml; n = 8; p = 0.02) and correlated with day 14 NK cytotoxicity as measured by expression of CD107a (R ² = 0.74; p = 0.0009; n = 12). In summary, our observations support development of donor NK cellular therapies for advanced NHL as a strategy to overcome chemoresistance. Therapeutic efficacy may be further improved through disruption of the immunosuppressive environment and infusion of exogenous IL-15.

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Title: Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells
Authors: Veronika Bachanova
Dhifaf Sarhan
Todd E. DeFor
Sarah Cooley
Angela Panoskaltsis-Mortari
Bruce R. Blazar
Julie M. Curtsinger
Linda Burns
Daniel J. Weisdorf
Jeffrey S. Miller
Publication date: 01-03-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 3/2018
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-017-2100-1

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