A Phase 1 Trial of CNDO-109-Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia

Abstract

Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cell-resistant cell lines. To translate this finding to the clinic, CNDO-109-activated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3 × 105 (n = 3), 1 × 106 (n = 3), and 3 × 106 (n = 6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse-free survival (RFS) by dose level was 105 (3 × 105), 156 (1 × 106), and 337 (3 × 106) days. Two patients remained relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted.

Keywords: Acute myeloid leukemia; CNDO-109–activated natural killer cells.

Conflict of interest statement

Conflict of Interest Disclosures

TMH, NS, MS, LG, ER are paid employees of Fortress Biotech. MWL has ownership interest in CNDO-109-NK cells. TAF served as a consultant for Fortress Biotech in 2016, 2 years after completion of this phase 1 trial. All other authors declare no competing conflicts of interest.

Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Kaplan-Meier Curve of Relapse-free Survival (FAS)

RFS was defined as the time from the date of CR1 to the date of relapse (per IWG response criteria for AML) or death due to any cause through the date cut-off of 10 February 2017. Dose level cohorts are indicated. FAS: full analysis set.

Figure 2. Donor Activated NK Cells Detected by Flow Cytometry Chimerism and Elevated CD69 Expression on NK cells in the Blood of 4 of 8 Patients Evaluated

All results in figures A-D are from plots gated on CD56+CD3- lymphocytes (NK cells). For 6 patients it was possible to evaluate chimerism in blood and bone marrow samples using donor-specific anti-HLA mAbs. In (A) and (B), rectangle gates include cells with the donor HLA type; numbers shown are the frequency of donor cells in the total NK cell population. (A) Circulating donor cells were detected by HLA antibodies in day 7 blood of 5 of the 6 patients with an identifying HLA antibody. (B) The 6th patient, patient 08-004, had insufficient cells to perform flow cytometry chimerism analysis on day 7; flow chimerism analysis of subsequent samples detected donor cells by anti-HLA antibody as late as day 56 in the blood and bone marrow. In 8 patients, total NK cells in the blood (both donor and recipient) were evaluated for elevated expression of CD69. In (C) and (D), numbers shown are the percent of NK cells. (C) Representative plots from subject 08-006 (Pt 9) showing expression of CD69 vs NKG2A on total NK cells in the blood on days 7, 14, 28 and 56 post-infusion. (D) Fraction of total NK cells expressing CD69 in the blood of the 4 patients with elevated CD69 expression.