Complete responses in patients with second-line or greater metastatic triple negative breast cancer (TNBC) following first-in-human immunotherapy combining NK and T cell activation with off-the-shelf high-affinity CD16 NK cell line (haNK)

Abstract

Abstract Background TNBC is an aggressive subtype with limited treatment options. We hypothesize that effective response against TNBC requires a coordinated approach that orchestrates both the innate and adaptive immune system. We further hypothesize that by orchestrating the activation of the entire immune system, we could accomplish immunogenic cell death with durable responses in this disease. We describe a first-in-human novel combination immunotherapy protocol of chemoradiation, cytokine-induced NK and T cell activation, checkpoint inhibition, and off-the-shelf high-affinity NK cell infusion. Methods We instituted this novel immunotherapy protocol consisting of low-dose metronomic chemoradiation therapy, combined with a novel IgG1 Fc-engineered IL-15-complexed protein (NabFc-N803), adenoviral and yeast tumor-associated antigen vaccines (MUC1, brachyury, CEA), a PD-L1 checkpoint inhibitor, and off-the-shelf high-affinity NK cells (haNK). A phase 1b trial in pts with metastatic TNBC was initiated in 9 pts, 8 of whom had relapsed after two or more lines of prior therapy (3rd-line). All pts received this combination therapy instituted over a three-week cycle as outpatients. Safety was assessed and efficacy confirmed by CT. Results Nine pts have been treated to date. All pts received at least 3 treatment cycles. 8 grade ≥3 treatment-related AEs were observed in 4 pts to date, of which 2 had haNK-related SAEs consisting of fever and fatigue. No pts experienced cytokine release syndrome. To date, early efficacy results are as follows: a disease control rate (CR+PR+SD) of 78% (7/9 pts); ORR (PR+CR) of 56% (5/9 pts). Two pts (22%; 2/9) achieved a complete response (CR). To date, 8 pts are alive, and the duration of response ranges from 2\xa0mo to over 12\xa0mo. 7 pts remain on study to date. Conclusions This first in human clinical trial of combination chemoradiation, cytokine fusion protein, checkpoint inhibitor, and NK cell therapy demonstrated a safe and tolerable immunotherapy protocol. Early efficacy data is encouraging with a 78% disease control rate, 56% ORR and 22% (2/9) CR in pts with metastatic TNBC, 2nd-line or greater. Clinical trial identification NCT03387085. Legal entity responsible for the study NantKwest, Inc. Funding NantKwest, Inc. Disclosure P. Soon-Shiong: Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: NantCell; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: NantKwest; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: NantHealth; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: NantBio; Shareholder / Stockholder / Stock options: Celgene. S. Rabizadeh: Leadership role, Officer / Board of Directors: NantBio; Leadership role, Officer / Board of Directors: NantCell. J.H. Lee: Leadership role, Officer / Board of Directors: NantKwest; Leadership role, Officer / Board of Directors: NantCell. L. Sender: Leadership role, Officer / Board of Directors: NantKwest. F. Jones: Leadership role, Full / Part-time employment: NantCell; Leadership role, Officer / Board of Directors: Etubics. K. Niazi: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NantBio. T. Seery: Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer. A. Rock: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: NantCell. All other authors have declared no conflicts of interest.