Abstract
Based on recent clinical success of tumor immunotherapies that block immune suppressive mechanisms to restore T cell function, there is a profound interest in the clinical development of T cell targeted therapies. We have produced a trastuzumab-based HER2 T cell dependent bispecific antibody (HER2-TDB) that conditionally activates T cells resulting in lysis of HER2 expressing cancer cells at low picomolar concentrations. Due to its unique mechanism of action, which is unrelated to HER2 signaling or sensitivity to chemotherapeutic agents, HER2-TDB can eliminate cells refractory to currently approved HER2 therapies. The potent anti-tumor activity of HER2-TDB was demonstrated using four model systems including MMTV-huHER2 and huCD3 transgenic mice. We demonstrate inhibitory effect of PD-L1 expression on the activity of bispecific T cell recruiting antibodies. This resistance mechanism is reversed by anti-PD-L1 treatment and combination of HER2-TDB with anti-PD-L1 immune therapy resulted in enhanced inhibition of tumor growth, increased response rates and durable responses.
Significance:
This report presents a new immunotherapy for HER2+ breast cancer with an alternative, extremely potent mechanism of action that is effective in cells resistant to current HER2 targeted therapies. Several significant advances are provided to bispecific T cell recruiting antibodies: we characterize a critical resistance mechanism, a potential diagnostic marker, a novel transgenic efficacy model and significantly improve the drug-like properties by using technology based on full length antibodies with natural architecture. Finally we demonstrate the benefit of combining two immune therapies: direct polyclonal recruitment of T cell activity together with inhibiting the T cell suppressive PD-1/PD-L1 signaling results in enhanced and durable long term responses.
Citation Format: Teemu T Junttila, Ji Li, Jennifer Johnston, Maria Hristopoulos, Robyn Clark, Diego Ellerman, Bu-Er Wang, Yijin Li, Mary Mathieu, Guangmin Li, Judy Young, Elizabeth Luis, Gail Lewis Phillips, Eric Stefanich, Cristoph Spiess, Andrew Polson, Bryan Irving, Justin M Scheer, Melissa R Junttila, Mark S Dennis, Robert Kelley, Klara Totpal, Allen Ebens. HER2 T cell dependent bispecific antibody (HER2-TDB) for treatment of HER2 positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S1-07.
Volume 75, Issue 9 Supplement
