A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer

Abstract

HLA-mismatched natural killer (NK) cells have shown efficacy in acute myeloid leukemia, and their adoptive transfer in patients with other malignancies has been proven safe. This phase I clinical trial was designed to evaluate safety (primary endpoint) and possible clinical efficacy (secondary endpoint) of repetitive administrations of allogeneic, in vitro activated and expanded NK cells along with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Patients with unresectable, locally advanced/metastatic NSCLC receiving 1st/2nd line chemotherapy were eligible to receive 2-4 doses of activated NK cells from two relative donors. Donor's CD56(+) cells were cultured for 20-23 days with interleukin-15 (IL-15) and hydrocortisone (HC) and administered intravenously between chemotherapy cycles. Premedication with corticosteroids and/or H1 inhibitors was allowed. Sixteen patients (performance status 0-1) with adenocarcinoma (n = 13) or squamous cell carcinoma (n = 3) at stage IIIb (n = 5) or IV (n = 11) receiving 1st (n = 13) or 2nd (n = 3) line treatment were enrolled. Fifteen patients received 2-4 doses of allogeneic activated NK cells (0.2-29 × 10(6)/kg/dose, median 4.15 × 10(6)/kg/dose). No side effects (local or systemic) were observed. At a median 22-month follow-up (range, 16.5-26 months) 2 patients with partial response and 6 patients with disease stabilization were recorded. Median progression free survival and overall survival were 5.5 and 15 months, respectively. A 56% 1-year survival and a 19% 2-year survival were recorded. In conclusion, repetitive infusions of allogeneic, in vitro activated and expanded with IL-15/HC NK cells, in combination with chemotherapy are safe and potentially clinically effective.

Fig. 1

a Percentages of CD56⁺CD3⁻ cells among total CD56⁺ gated cells isolated from donors’ peripheral blood on day 0 and after 18–21 days of culture with 20 ng/mL IL-15 and 10⁻⁵ M HC. b Expression of activating NK receptors (NKp30, NKp44, NKp46, NKG2D and 2B4) on donor’s CD56⁺ cells expanded for 18–21 days of culture with 20 ng/mL IL-15 and 10⁻⁵M HC. Gray lines indicate isotype matched controls. Histograms from a representative donor. All donors gave similar results. c Cell growth (fold increase) and cytotoxic activity against K562 cells of donors’ CD56⁺ cells after 21–23 days of culture with 20 ng/mL IL-15 and 10⁻⁵M HC. Cytotoxicity assay was performed at an effector: target ratio 1:1. Horizontal bars indicate mean values

Fig. 2

Effect of number of infusions of allogeneic activated NK cells on progression-free survival (a) and overall survival (b) of all intended to treat non-small-cell lung cancer patients. c Overall survival of patients with stable or decreased pulmonary disease, receiving 2–3 and 4 NK cell infusions, respectively