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 × 10 7 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.
Bibliographical noteFunding Information:
Conflict of interest Eisai Inc has provided denileukin diftitox for this trial and supported the correlative assays. Veronika Bachanova receives funding from GT Biopharma Inc, Novartis and serves on advisory board for Seattle-Genetics. Other authors have no relevant conflicts of interest to report. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Research reported in this publication was supported by NIH Grant P30 CA77598 utilizing the Biostatistics and Bioinformatics Core and the Translational Therapy Laboratory shared resources of the Masonic Cancer Center, University of Minnesota and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114. This work was also supported by American Society of Hematology Scholar Award (Veronika Bachanova), P01 CA65493, P01 CA111412, R01 CA72669.
© 2017, Springer-Verlag GmbH Germany, part of Springer Nature.
- Adoptive transfer NK cells
- Cellular therapy
- Chemotherapy-refractory non-Hodgkin lymphoma
- Immunosuppressive environment