Avid Bioservices Inc (CDMO)

[freethemice]

The road ahead: Bavi, chemo, and immune modulation.
In the last decade it has become obvious that myeloid-derived suppressor cells (MDSC) play an
important role in immune suppression induced by cancer tumors. Only more recently has it
been shown by Thorpe's group that bavituximab can reduce the amount of MDSC and also
switch macrophages from M2 to M1 phenotype. See Thorpe's keynote address, "Targeting Tumor
Vasculature and Reactivating Tumor Immunity with Bavituximab", at the Barcelona antibody
conference on May 26, 2011, and last year's AACR meeting poster for abstract #3651.
Several papers have been published in the last few years which show that some chemo drugs also
reduce the amount of MDSC and can affect such a switch in macrophages.
The interesting thing is that these are drugs that are currently in clinical trials with bavituximab.
The drugs and cancers are: docetaxel and second-line NSCLC, gemcitabine and pancreatic cancer, sorafenib and HCC.
Here are three papers which support these ideas:
Docetaxel: Kodumudi et al, Clinical Cancer Research, 16(18), 4583-4594 (2010).
A Novel Chemoimmunomodulating Property of Docetaxel: Suppression of Myeloid-Derived Suppressor Cells in Tumor Bearers.
http://clincancerres.aacrjournals.org/content/16/18/4583.abstract

Gemcitabine: Sinha et al, The Journal of Immunology, 179(2), 977-83, (2007).
Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response.
http://www.jimmunol.org/content/179/2/977.long

Here is an interesting figure from this paper


Sorafenib: Cao et al, Laboratory Investigation, 91, 598-608 (2011).
Kinase inhibitor Sorafenib modulates immunosuppressive cell populations in a murine liver cancer model.
http://www.nature.com/labinvest/journal/v91/n4/abs/labinvest2010205a.html

That these three drugs have also become the "gold standards" for the respective cancers is probably
due to their immune modulating activity, in addition to their cytotoxic effects. Now that it has been
shown that the MOA of bavituximab includes these very same immune modulating effects the hope
is that using bavi with these drugs will result in a synergy which goes well beyond the effect of each alone.
Thorpe's group have published a paper showing this in mice with pancreatic cancer:
Beck et al, International Journal of Cancer,118, 2639-2643 (2006).
Combination of a monoclonal anti-phosphatidylserine antibody with gemcitabine strongly inhibits the growth and metastasis of orthotopic pancreatic tumors in mice.
http://onlinelibrary.wiley.com/doi/10.1002/ijc.21684/full

and for docetaxel with breast cancer: Huang et al, Cancer Research, 65 (10), 4408-4416 (2005).
A monoclonal antibody that binds anionic phospholipids on tumor blood vessels enhances the antitumor effect of docetaxel on human breast tumors in mice.

Last year at the AACR meeting they presented the poster for abstract # 3643, on bavi and sorafenib in HCC,
which shows such a synergistic effect. See my post #73697, and this year's AACR meeting abstract # 5591.
The beauty of this is that these chemo drugs are indeed the "gold standards", so if using Bavi with
them increases survival, without increasing toxicity, then acceptance would seem to follow.