How close did I get?
Msg 682 of 10961 at 8/15/2016 7:10:33 PM by
The following message was updated on 8/20/2016 1:56:49 PM.
Why Opdivo Failed and Why PV-10 Will Help
I think I know the critical failure of mono anti-pd-l1 therapy.
Opdivo trial did not scan for PD-L1.....but the Keytruda trial did...Opdivo failed....and now to me it is obvious it would but it would have never occurred to me without the failure of Opdivo.
PD-L1 is known to be expressed in the presence of chemokines....like goose bumps on your arm when a cold chill is encountered. They raise up just like that in the presence of chemokines.
My Theory: The industry thinks certain cancers have pdl1 and others do not...not exactly true I say...I think the industry misses why some have it and some do not. I think they all have the ability to express PD-L1....it's the body's self defense mechanism to auto immune disease. So those cancers that express it were already exposed to chemokines which means the Antigen Presenting Cells and the Dendretic Cells already saw something but have not ramped up to tolerance breaking levels and the anti-pdl1 drugs (Opdivo and Keytruda) are giving the chance for the immune system to go over that threshold before being shut down at the tumor sites by the ligands. I would imagine that the tregs are also there to snuff out the candle of response before making the tumor hot....a false fire safety mechanism....if you don't have enough APC's and DC's maturing and outputting enough chemokines then the CD4+T (iTregs) and CD25+Tregs are there to determine it is a false response and then they snuff out the candle before a false cascade fire is started....preventing autoimmune disease. Reducing Tregs gets to make the fire flash over sooner....thank you Moffitt: http://provectuspharmaceuticalsinc.blogspot.com/2016/03/pv-10-at-aacr-2016-t-cell-mediated.html?m=1 http://www.bloodjournal.org/content/112/5/1557?sso-checked=true http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path=9247 http://www.onclive.com/peer-exchange/advances-in-melanoma/hot-versus-cold-tumors-predictive-markers-in-melanoma
To make all tumors respond to anti-pdl1 drugs they first have to have the primer starter fire....the bigger the better. Hot enough to overcome the Treg threshold. That means the immune system sees the not me tumor and produces the chemokines which causes all cells to raise up the ligands which then the anti-pdl1 drugs would give the immune system that window to keep the fire going and get bigger and make the tumor hot....breaking tolerance. They need PV-10 first.
To put it simply: Those cancers who express PD-L1 are already smoldering with immune system reaction....smoldering.....luke warm tumor. The anti-pdl1 drugs are giving the immune system a chance to start a fire. Those tumors that do not express pdL1 have no smoldering immune reaction...they are completely not seen....cold tumors...thus the immunotherapy will not work. A primer such as PV-10 is providing a blow torch to start a fire or make the smoldering ember catch fire. Down regulating Tregs is keeping the fire department away.
CD8+T cells are activated by APC and DC cells That being said: It's all in this paper tying it all together: http://www.sitcancer.org/meetings/am10/presentations/index.php?filename=Gajewski_AM10_secure.pdf
I was not the first to say it...since I finished my first version of this thesis I discovered that Dr. Tom Gajewski saw it before me as mentioned by Dr. Jeffrey Weber. So thus I take my hat off, bow, and step aside. He was the first to say cold tumors will not express pdl1 because the CD8+T cells have not be activated and infiltrating into the tumor where they produce chemokines. I believe that Dr. Gajewski along with Dr. Weber are on the very front of the correct path to understanding how to combat cancer. As the other investigators of PV-10 continue their work, I predict those efforts to validate Dr. Gajewski's insights.
I believe those tumors that do express PD-L1 means that CD8+T cells have infiltrated the tumor. The CD8+T cells produced the chemokines that stimulated the PD-L1 but the CD8+T cells may have recruited Tregs as well...causing the tumor to smolder but not catch fire. That is why Opdivo and Keytruda needs help. This may also explain why bystander effect for PV-10 is not higher than 50%...PV-10 ablation causes the immune system to respond but also causes PD-L1 to express and also brings in TRegs to the environment. Thus the combo with PV-10 and Keytruda now underway should block the PD-L1 ligands. Results of this trial should be forthwith as soon as December of this year. Those results should be the same if Opdivo is used in combination with PV-10 instead. Moffitt demonstrated that down regulating TRegs is important too and I see a human trial version incorporating the combination of either Keytruda or Opdivo with PV-10 and a Treg inhibitor for CD4+T (iTreg) and CD25+Treg sometime in the future to extend what Moffitt has already done with their ckeckpoint inhibitor/PV-10 chemo ablation/Treg down regulator combination murine trial.
PV-10 chemo ablation is not affected by PD-L1 expression or Treg infiltration into the tumor micro environment. PV-10 chemo ablation has no known cancer defense. But Checkpoint Inhibitors such as Opdivo and Keytruda along with Treg down regulation when used in conjunction of PV-10 chemo ablation should help increase bystander effect for a more robust systemic response.