NK-92 Therapy Is Well Tolerated, Has Minimal Toxicity and Shows Efficacy in a Phase I Trial of Patients with Relapsed/Refractory Hematological Malignancies Relapsing after Autologous Stem Cell Transplantation

Abstract Background Autologous NK cell adoptive immunotherapy has potential to treat a variety of malignancies, but is limited by patient-specific variations in numbers and quality of expanded cells. In contrast, allogeneic NK cell lines can overcome many of these limitations. The NK line, NK-92 can be manufactured under Good Manufacturing Practice (GMP) compliant conditions, and infused into patients, as demonstrated in two prior phase I trials for solid tumours. Here, we report the findings of a phase I trial of NK-92 with the highest cell dosing regimen tested to date, in patients with relapsed/refractory hematological malignancies. Methods We conducted a single-center, non-randomized, non-blinded, open-label, Phase I dose-escalation trial of irradiated NK-92 cells in adults with refractory hematological malignancies who relapsed after autologous stem cell transplantation. The objectives were to determine, safety, feasibility and evidence of activity against refractory hematological malignancies. Inclusion criteria included measurable disease, adequate organ function and ECOG performance status of < 2. Exclusion criteria were pregnancy, concurrent treatment within 28 days with other experimental therapy, known HIV, HBV or HCV infection and malignant CNS disease. Patients were treated at one of three dose levels (1x109 cells/m2, 3x109 cells/m2 and 5x109 cells/m2), given on day 1, 3 and 5 for a planned total of six monthly cycles. NK-92 cells were obtained from Conkwest, and a frozen working cell bank was established at Princess Margaret Cancer Centre and stored in liquid nitrogen. Clinical-grade NK-92 cells were then manufactured under GMP conditions by expanding a cryopreserved vial of NK-92 in Vuelife culture bags using GM1 medium. Release criteria of NK-92 for infusion included negative mycoplasma testing, day 7 culture sterility, endotoxin <0.05 EU/mL, and additionally, a negative stat gram stain and cell viability of >70%. The final NK-92 cell product was resuspended in GM2 medium (Plasma-Lyte-A medium), irradiated with 10 Gy and infused fresh intravenously over one hour. Results Twelve patients with hematological malignancies who relapsed after undergoing stem cell transplantation for relapsed/refractory disease were enrolled with the following diagnoses: multiple myeloma (5), diffuse large B-cell lymphoma (4), Hodgkin lymphoma (2) and mantle cell lymphoma (1). There were 9 males and 3 females and median age was 60 (range: 42-67) years. Patients had received 2-5 chemotherapy regimens before autologous stem cell transplantation and some also received additional chemotherapy after autotransplant and prior to receiving NK-92 infusions. The number of cycles of NK-92 administered ranged from 1-6, with 10 patients coming off study because of disease progression, and one patient proceeding to allogeneic stem cell transplantation. The only toxicity was infusion-related fever and chills (grade II) in one patient, and none had evidence of cytokine release syndrome. A patient with relapsed, refractory Hodgkin lymphoma had a complete response and remains in remission more than five years after NK-92 therapy. An additional three patients experienced transient responses. There were no significant alterations in hemoglobin, platelets, white cell count, creatinine or liver function tests in patients receiving NK-92 infusions. While six patients developed anti-HLA antibodies, none developed a T-cell immune response as determined by the mixed lymphocyte response of patient lymphocytes against NK-92. Conclusion NK-92 can be administered after autologous stem cell transplantation at very high doses with virtually no toxicity to patients with relapsed/refractory hematological malignancies. This is the first trial of NK-92 which includes patients with multiple myeloma. Surprisingly, most patients did not mount cellular immune responses against NK-92, despite receiving very large numbers of NK cells, up to a total of 150x109 cells. We conclude that high dose NK-92 therapy is safe and has the potential to induce long term survival in select patients. We propose that NK-92 can serve as a standardized off-the-shelf cellular treatment for malignancies and could provide a platform for gene-modified targeted cell therapy. Disclosures Keating: Conkwest: Other: Research funding unrelated to clinical trial.

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