Abstract P5-04-02: Safety and efficacy from first-in-human immunotherapy combining NK and T cell activation with off-the-shelf high-affinity CD16 NK cell line (haNK) in patients with 2nd-line or greater metastatic triple-negative breast cancer (TNBC)
Authors: Kistler Mira , Nangia Chaitali , To Christina , Sender Lennie , Lee John , Jones Frank , Jafari Omid , Seery Tara , Rabizadeh Shahrooz , Niazi Kayvan , Rock Amy , Soon-Shiong Patrick 
Published: March 2020

Abstract
TNBC is an aggressive subtype of breast cancer 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.
We instituted this first in human immunotherapy protocol consisting of low-dose metronomic chemoradiation therapy, combined with a novel IgG1 Fc-engineered IL-15-complexed protein (N803), adenoviral and yeast tumor-associated antigen vaccines (MUC1, brachyury, CEA), followed by off-the-shelf high-affinity NK cells (haNK), and a PD-L1 checkpoint inhibitor. 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 assessment is ongoing.
Nine pts have been treated to date in an outpatient setting. All pts had at least 1 grade ≥3 TRAE, primarily chemotherapy-related neutropenia or anemia. Grade ≥3 haNK-related AEs (fever and fatigue) were observed in 2 subjects. No SAEs were attributed to investigational agents. 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, median follow up time is 301 days. 7 pts are alive, and the duration of response ranges from 2 mo to over 12 mo. In pts with CR or PR, peripheral blood (PB) analysis showed &gt;13x increase in TCR diversity at 2 mo after initial treatment with increasing overall diversity thereafter; conversely, in pts with SD, PB TCR diversity increased &lt;2x or decreased. Four patients remain on study.
This first in human clinical trial of combination chemoradiation, cytokine fusion protein, NK cell therapy, and a checkpoint inhibitor 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.
Citation Format: Mira Kistler, Chaitali Nangia, Christina To, Lennie Sender, John Lee, Frank Jones, Omid Jafari, Tara Seery, Shahrooz Rabizadeh, Kayvan Niazi, Amy Rock, Patrick Soon-Shiong. Safety and efficacy from first-in-human immunotherapy combining NK and T cell activation with off-the-shelf high-affinity CD16 NK cell line (haNK) in patients with 2nd-line or greater metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-02.