Abstract P2-11-12: Novel protocol combining metronomic nant-paclitaxel with HER2-targeted natural killer cells (innate immunotherapy) for HER2-positive metastatic breast cancer
Authors: Rabizadeh S , Simon B , Klingemann H , Sims D , Weiss R , Soon-Shiong P 
Published: May 2016

Background. Natural killer (NK) cells are an important effector cell type for adoptive cancer immunotherapy. Phase 1 clinical trials in patients with advanced cancers demonstrated the safety of unmodified, activated NK-92 cells (aNK), with no evidence of cytokine storm from 18 infusions delivered over 6 months; clinical responses were observed in a subset of patients. Like T cells, NK cells can be engineered to express chimeric antigen receptors (CARs) to enhance their antitumor activity. A stable clonal HER2-specific NK-92 cell line (HER2.taNK) mediated selective and sequential killing of HER2-expressing MDA-MB-453 cells in vitro (Schönfeld. MolTher. 2015;23:330-338). In addition, HER2.taNK cells were enriched in MDA-MB-453/EGFP xenografts and reduced the number of pulmonary metastasis in a renal cell carcinoma model, suggesting that HER2.taNK cells are a promising clinical candidate for use in adoptive cancer immunotherapy. Metronomic (low-dose, continuous) chemotherapy can be more effective than high-dose therapy in patients with advanced breast cancer (Montagna. Canc. Treat. Rev. 2014;40:922-950). Here we evaluate HER2.taNK cells in combination with metronomic nant-paclitaxel (lyophilized polymeric micellar formulation of paclitaxel) in a mouse model of HER2-positive breast cancer to determine the feasibility of a human clinical trial of HER2.taNK in combination with metronomic nant-paclitaxel.

Methods. HER2.taNK cells were generated as described previously (Schönfeld. MolTher. 2015;23:330-338). MDA-MB-453 cells were implanted into the mammary fat pads of female nude mice. When tumors reached 100 mm3, mice were divided into 6 groups of 5 mice and dosed (IV) with saline (10 mL/kg, qd x 15), nant-paclitaxel (2.5-4 mg/kg q2d x 15), γ-irradiated (5 Gy) HER2.taNK cells (1 x 107 cells, days 1, 3, 5, and 8), or nant-paclitaxel + γ-irradiated (5 Gy) HER2.taNK cells–γ-irradiation is a potential safety measure for clinical application and prevents HER2.taNK cell replication while preserving antitumor activity. Tumor size and animal weights were measured every other day post-implantation.

Results: Results obtained 20 days post-treatment are shown in the table. Nant-paclitaxel alone and HER2.taNK alone significantly inhibited tumor growth. The combination of nant-paclitaxel + HER2.taNK led to significant tumor regressions (p&lt;0.05).

Treatment Dose T/C (%) P-ValueSalinenant-paclitaxel5 mg/kg-26.7 P &lt; 0.05 (vs saline) HER2.taNK1 x 107 cells-22.2 P &lt; 0.05 (vs saline)nant-paclitaxel +5 mg/kg +-60.0P &lt; 0.05 (vs nant-paclitaxel)HER2.taNK1 x 107 cellsP &lt; 0.05 (vs HER2.taNK)

Conclusions: Single agent nant-paclitaxel and HER2.taNK were similarly effective at inhibiting tumor growth in this mouse model of HER2+ breast cancer. The combination of nant-paclitaxel + HER2.taNK appeared to be synergistic resulting in tumor regressions and significantly better efficacy vs each agent alone. This study illustrates the potential for combining metronomic low-dose chemotherapy with NK-based immunotherapy in a clinical trial of patients with metastatic breast cancer.

Citation Format: Rabizadeh S, Simon B, Klingemann H, Sims D, Weiss R, Soon-Shiong P. Novel protocol combining metronomic nant-paclitaxel with HER2-targeted natural killer cells (innate immunotherapy) for HER2-positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-12.