Therapeutic efficacy of monoclonal antibodies (MAbs) against solid tumor targets, like trastuzumab (anti-HER2) and cetuximab (anti-EGFR), have been used successfully to treat cancer, despite the many physical barriers impeding their access to the malignant cell surface1. For example, only about 50% of HER23+ patients have a durable response to therapy with trastuzumab2. Extracellular matrix (ECM)-mediated inhibition may be among the mechanisms of resistance to MAb therapy of solid tumors. Aberrant accumulation of hyaluronan (HA), a major component of the ECM in many tumors, is associated with poor prognosis and treatment-resistance in multiple malignancies3-5. We investigated HA-dependent pericellular matrix-mediated inhibition to ADCC in HAhigh human cancer cells in vitro and in vivo. We observed high levels of tumor associated HA (HA3+) in >50% of HER23+ breast adenocarcinoma and ∼40% of EGFR+ head and neck squamous cell carcinoma (HNSCC) primary tumors. Human hyaluronan synthase 2 (HAS2)-overexpressing breast cancer cells formed an HAhigh pericellular matrix, which inhibited both natural killer (NK) cell access to tumor cells and ADCC in vitro. Hyaluronan depletion by PEGPH20, a pegylated recombinant human PH20 hyaluronidase currently in clinical study for pancreatic cancer, increased NK cell access to HAS2-overexpressing breast cancer cells and greatly enhanced trastuzumab- or cetuximab-dependent ADCC. Trastuzumab and NK cell accessibility to HAS2-overexpressing tumors was enhanced following HA-depletion by PEGPH20. In an in vivo ADCC-based efficacy study, PEGPH20 treatment in combination with trastuzumab and NK cells enhanced tumor growth inhibition. This work describes a novel tumor microenvironment (TME)-dependent mechanism of inherent resistance to therapeutic antibody-mediated ADCC in vitro and in vivo, and furthermore shows that ADCC can be enhanced by hyaluronan depletion. These results may help to explain as to why tumors with high levels of HA are more aggressive, and suggest potential benefits of PEGPH20-mediated HA depletion in combination with therapeutic antibodies like trastuzumab or cetuximab in the treatment of HAhigh solid tumors.

References:

1. J. Christiansen, A. K. Rajasekaran, Biological impediments to monoclonal antibody–based cancer immunotherapy. Mol Cancer Ther.3, 1493-1501 (2004).

2. H. M. Shepard, C. M. Brdlik, H. Schreiber, Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family. J. Clin. Invest.118, 3574-3581 (2008).

3. A. Kultti, X. Li, P. Jiang, C. B. Thompson, G. I Frost, H. M. Shepard Therapeutic Targeting of Hyaluronan in the Tumor Stroma. Cancers4, 873-903 (2012).

4. R.K. Jain, Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol.31, 2205-18 (2013).

5. R. K. Boregowda, H. N. Appaiah, M. Siddaiah, S. B. Kumarswamy, S. Sunila, K. N. Thimmaiah, K. Mortha, B. Toole, S. D. Banerjee, Expression of hyaluronan in human tumor progression. J. Carcinog.5, 2 (2006).

Citation Format: Netai C Singha, Tara Nekoroski, Chunmei Zhao, Rebecca Symons, Ping Jiang, Gregory Frost, Zhongdong Huang, H Michael Shepard. Hyaluronan (HA) depletion sensitizes HAhigh tumors to antibody-dependent cell-mediated cytotoxicity [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 P5-04-02.