1Phase I trial of expanded, activated autologous NK cell infusions with trastuzumab in patients with HER2-positive cancers.

Purpose. Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies. Patients and Methods. In a Phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day co-culture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy. Results. In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91-603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in Phase I dose escalation, trastuzumab plus NK cells were well tolerated; maximum tolerated dose was not reached. Phase IB (n=9) included multiple cycles of NK cells (1x107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of the 19 subjects who received at least 1x107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0-12.0). One patient, the only one with the high affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 post-infusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis post-treatment. Discussion. NK cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in Phase II trials.