[Lani]

I had assumed that de novo resistance to herceptin (initial p95 truncated receptors, presence of complex mucin which prevented herceptin from approaching the receptor, inadequate immune system response capability etc) and acquired resistance to herceptin (selecting out the clones with more her3+, with other driving or downstream active pathways, etc) were the reasons that OS was only improved 40%, but perhaps , as was proposed at SABCS, herceptin works mainly not by blocking the her2 receptor or preventing formation of dimers of her2 and other her2,her3,egfr or her4 receptors, but rather because of ADCC. Here it appears that tumor-associated hyaluronan (the same substance temporarily degraded to allow subcutaneous herceptin to gain access to the body) in 60% of cases her2 ihc 3+ early breast cancers may not provide access of the NK immune cells to the tumor by "gumming up the matrix" thus preventing ADCC from taking place.

This article presents the intriguing possibility of combining anti-hyaluronan monoclonal antibodies with antiher2 antibodies to provide effective treatment in that other 60% of tumors where herceptin can't get to "where the money is"

Hopefully the new mAbs don't cost an arm and a leg. They will need to be targeted as hyaluronan has a lot of different important functions in a lot of different normal tissues. Seems quite "doable" though.

Mol Cancer Ther. 2014 Dec 15. pii: molcanther.0580.2014. [Epub ahead of print]
Tumor-associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy.
Singha NC1, Nekoroski T1, Zhao C1, Symons R1, Jiang P1, Frost GI2, Huang Z1, Shepard HM3.
Author information
Abstract
Despite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (MAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME). Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies. In this study, we describe that a physical barrier associated with high levels of HA (HAhigh) in the TME restricts antibody and immune cell access to tumors, suggesting a novel mechanism of in vivo resistance to MAb therapy. We determined that ~60% of HER23+ primary breast tumors and ~40% of EGFR+ head and neck squamous cell carcinomas are HAhigh, and hypothesized that HAhigh tumors may be refractory to MAb therapy. We found that the pericellular matrix produced by HAhigh tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Depletion of HA by PEGPH20, a pegylated recombinant human PH20 hyaluronidase, resulted in increased NK cell access to HAhigh tumor cells, and greatly enhanced trastuzumab- or cetuximab-dependent ADCC in vitro. Furthermore, PEGPH20 treatment enhanced trastuzumab and NK cell access to HAhigh tumors, resulting in enhanced trastuzumab- and NK cell-mediated tumor growth inhibition in vivo. These results suggest that HAhigh matrix in vivo may form a barrier inhibiting access of both MAb and NK cells, and that PEGPH20 treatment in combination with anti-cancer MAbs may be an effective adjunctive therapy for HAhigh tumors.
Copyright © 2014, American Association for Cancer Research.
PMID: 25512619 [P