Is THIS the reason adding herceptin to chemo only improves OS by 40%?
 

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

Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?
 

I don't understand this?? Can you break it down ??

Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?
 

Sadly me neither, thank you Lani.

Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?
 

hyaluronan is like glue in the space between cells and surrounds her2+ breast cancer cells in about 60% of her2+ tumors

translation of the rest:

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)--this is the area outside the tumor but adjacent to the tumor which serves as a home for the tumor, who we will compare to a fugitive mass murderer. The tumor(fugitive mass murderer) asks the microenvironment--mom, dad, grandma grandpa for food, warmth, blankets, drink and entertainment.

Mom, dad, grandpa and grandma besides sheltering and feeding the mass murderer/tumor also like the company of the tumor (mass murderer) and pass on wisdom, information on the location of the FBI/police, binoculars to look for lurking police/FBI outdoors, disguises and hope and other things that help it cope.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.( It is a sticky, glue-like stuff leet's say it is a hedge-high moat or wall of supersticky cotton candy). In this study, we describe that a physical barrier associated with high levels of HA (HAhigh) in the TME restricts antibody and immune cell ( police and FBI who come to take away the fugitive mass murderer) 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 (those responsible for cancers of the mouth and other areas of the head and neck) are HAhigh, and hypothesized that HAhigh tumors may be refractory to MAb--monoclonal antibody) therapy.(monoclonal antibodies are smart-bombs, such as herceptin--if herceptin cannot get to the cancer cell because of the cotton candy moat it cannot stick to its her2 receptor or invite in killing immune cells like NK cells.) We found that the pericellular matrix(cottoncandy moat or hedge) produced by HAhigh tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC)--the process by which those killer cells kill the her2+ cells) in vitro.

Depletion of HA(cotton candy) by PEGPH20, a pegylated recombinant human PH20 hyaluronidase(enzyme that eats hyaluronon or cotton candy), 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(herceptin) and NK cells(the cells attracted to come kill the her2+ breast cancer cells after being summoned by the herceptin"hey, guess what I found, a lovely her2+ breast cancer cell to kill and eat!" or alternatively, an FBI agent who is happy to have had
in informant call in but is frustrated because he cannot see thee location and whether the serial murderer is unarmed because the sticky cotton candy hedge obscures the murderer so the FBI agent cannot swoop in and "take him out!"), and that PEGPH20 treatment in combination with anti-cancer MAbs may be an effective adjunctive therapy for HAhigh tumors (both, acting together, serve to 1) act as an informant as to where the murderer is and 2) takes down the cotton candy hedge/moat so the FBI can come in for the kill)

I continue to believe you could utilize my chocolate, cherry and whipped cream system to fathom the information without my help. It might take a bit of practice, though.

Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?
 

Love this Lani!!

Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?
 

That is a great analogy! Do pathologists always know what your tumor is made of?? Like all I know about mine is her2+++ and ER+ 55 on the last biopsy.

Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?
 

That was hilarious, Lani.

I know it's more work for you (and I'm grateful), and I'm also well aware that it's possible to understand study results with a little help from Dr. Google, but I wouldn't have missed that for anything.

Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?
 

linn65--they only look for what is requested by the doctor ordering the pathology examination with report and only with the means requested

eg, if IHC (immunohistochemistry) is requested and only ER PR and her2 are checked of, those are the only stains utilized and those the only items reported

if FISH is ordered(or ordered only if her2 2 and above) for her2, that is reported

As regards "cotton candy" it has only now been reported to be potentially so important. If these findings are corroborated by others we may see the test for "cotton candy" added to the list to be checked off for tests the pathologist should run and maybe it will become standard of care to add a monoclonal antibody to "cotton candy" to herceptin to the treatment of those whose her2+ tumors that have enough of it

Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?
 

Lani,
Bispecific MABs with anti-hyraluonic acid on the leg opposite the HER+ leg might work. I know they are doing this for T-Cell attractants to make the MAbs easier to pick up for recirculating white cells. I think I will ask someone to think about it. Someone that could actually try this concept pretty quickly.
Paul

Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?
 

Interesting. They would need to attach the PEGPH20 enzyme to the Her2 antibody rather than an antibody, which might be easier - provided some of the her2 antibody could get to the receptor. An antibody to the cotton candy would probably affect to much normal tissue.

First up, it would be good to have a simple test to detect the HAhigh tumours in the first place. I don't think this would be too hard to do.

Aussie Girl

Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?
 

This is cool.

Lani, your "translation" is priceless.

Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?
 

Lani,
Thanks for posting this and bringing to my awareness and for the breakdown or analogy of it all! I didn't have pCR of my tumor site(did of my lymph nodes) so I am thinking I have the HAhigh(cotton candy). Is there anything at this point that I could do? I don't even think they tested my tissue at the time of my mastectomy as to if it was her2+ or what?? They just said there was a 4 mm IDC area found in the tissue and I had neoadjuvent therapy so that's what scares me. I didn't have further chemo after mastectomy...

Re: Is THIS the reason adding herceptin to chemo only improves OS by 40%?