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Msg  6519 of 6584  at  5/21/2022 2:04:07 AM  by

leave_the_gun


Science and thoughts by Vorlon.


 Checkpoint inhibitors only work on about 20% of treated patients. That does not mean complete responses….just that they get some level of ORR in one out of five patients treated. Thus big pharma drive for combos with checkpoint inhibitors to drive up ORR past 20%.

For checkpoint inhibitors such as Keytruda and Opdivo to work there needs to a PDL1 ligand expression on the cell surface of tumors for those anti-PD1 drugs to work. For PDL1 ligand expression to happen there must be IFNy circulating in the blood. For IFNy to be circulating in the blood there needs to be active targeting mature CD8+T cells cloning themselves
to go out and attack targets. For this to happen there needs to be first Antigen Presenting Cells/Dendritic Cells discovering a non normal MHC I/II antigen on the tumor surface and presenting that discovered target to the CD8+T cells in the lymph nodes. Active mature CD8+T cells make IFNy.

A tumor can be hot or warm if there is APC/DC presenting to CD8+T activity. The tumor is called cold if the APC/DC cells never recognize bad cancer MHC I/II antigens on the surface of the tumors.  In this case the tumor is running under the radar and is not discovered by the immune system. In a cold tumor no amount of checkpoint inhibitors will cause the tumor/cancer to be discovered by the rest of the immune system. The only purpose for the anti-PD1 drugs is to block/lock up on the CD8+T the PD1 receptors from the PDL1 ligands on cell surfaces.

When a APC/DC discovers something amiss on a cell…specifically in this case a bad/cancer MHC I/II antigen, it migrates back to the central points of the lymph nodes  and there reaches out in the blood stream and grabs an immature killer CD8+T cell and presents thr CD8+T cells with that target antigen. From there it recruits a helper CD4+T cell for confirmation of the antigen target for a two key activation to launch a very dangerous to all cells a killer CD8+T cascade. CD8+T cells convert to mature and active. They release IFNy…a chemokine..,that alerts all cells in the body that CD8+T cells just matured and went active to killer mode. All cells …including cancer…because they were once normal cells…express self defense finger like PDL1 ligands reaching up from their cell surface …whose sole purpose is to bind with killer CD8+T PD1 cell surface receptors, when they get too close, and shut them down. It’s a body wise, all cell, self defense against an active immune system designed to prevent autoimmune disease.

Thus the logic of checkpoint inhibitor drugs… to block cancers PDL1 expression from shutting down killer CD8+T’s who has their name on its kill list. This is all predicated on the assumption that the APC/DC cells saw a target first. If they did…the tumor is hot. If the antigens could not be distinguished from normal ones the tumor is cold…and therefore checkpoint inhibitors drugs such as Keytruda and Opdivo do diddly in cold tumors.

Thus the search far and wide for combo drugs with checkpoint inhibitors to cause a tumor to become hot…and they are failing. Why?

One drug tried IL-12 to stimulate APC/DC production…but without antigen targets to present to CD8+T cells. Ziopharm abandoned this after negative results. Others try their drugs to interfere with the normal cascade of the immune system to promote an up-regulation or down regulation at points to promote effects without addressing the beginning of the normal immune cascade. They don’t address the normal flow of the immune reaction.  This is almost all of other drugs trying to combo with big pharma checkpoint inhibitors. Just about all failed in this route.

Then comes specific antigen targeting through TCR drugs….targeting specific cancer antigens.  The thoughts on this has merit. However it is limited to the lack of heterogeneity of single or dual antigen targeting. This is failing in solid tumors. Why? Because solid tumors have different layers of hypoxia. The deeper in the tumor the greater the lack of a available oxygen. This causes endoplasmic reticulum stress that turns certain genes on and others off to deal with surviving in low oxygen environments. Result? Different layers of solid tumors have different antigens. Thus TCR drugs work really good in blood cancers where there is no cancer mutations…but perform  poorly in solid tumors…..though they are all attempting to increase multiple antigen targeting in their drugs.

But what is the Pareto analysis solution to this problem? Kill the whole tumor… tumor death releases HMGB1, caspases, autolysis, autophagy…causing  cell death and tumor necrosis…and thus releases all cancer antigens no matter what mutation depth…to be surveilled by the very start of the immune cascade by the APC/DC cells. An elegant and simple primer of the start of the immune system by a drug that does this…PV-10.

Therefore the logic of PV-10 injection into a solid tumor to cause first autolysis per destruction of lysosomes… releasing acidic hydrolyses followed by autophagy and apoptosis. From there the cell wall breaks apart and allows greater separation of self vs non self MHC I/II antigens so that the APC/DC cells can then differentiate normal vs all cancer antigens. No TCR science needed.

This mgt has sought a simpler route to addressing cancer therapy. Tumor destruction first. Checkpoints inhibitors added later. But mgt is holding on to some new science not yet addressed in the industry. How Rose Bengal taking orally affects interleukin paths. This is very new science yet to be fully developed. Science yet to be addressed by the industry. However our mgt sees the implications.

Now to the billion dollar question…what does all this mean to us long shareholders?  Many of you expected mgt to do things to raise the share price… but I don’t think raising share price without big news was their intent. Increasing the strength of the IP was. Doing this through independent research…allowing said research to explore all things RB first…applying for patents on this research first…and at the same time allowing P1 trials to conclude naturally.

Taking to industry experts: if there is evidence of metabolic complete response in Uveal Mets to the liver you have then proved turning the coldest of all tumors hot.  By extension you just proved the logic of PV-10 being a great primer to make checkpoint inhibitor drugs more effective….increasing their probable ORR past 20%.  Which is what big pharma is keeping an eye out for.

Now many may say where is big pharma? Why have they not stepped up by now? I answer why would they? They have combined with hundreds of drugs and mostly ended up with combo failures. Not all…but most. Those combos they entertained that showed efficacy is still not that great. Our results are too early in combos. As of this date we are proving monotherapy efficacy of tumor destruction by intralesional injection of PV-10.  While initially per RECIST measuring there were progressions of certain lesions….overtime many of those progressed lesions ended up regressing per the meta analysis of all all melanoma studies in Australia. Resulting in medians not yet reached after years. This is big.

First Summation: In my opinion mgt was not trying up to now to increase SP….there was no way to do so without a BP nod or a FDA/TGA approval.  What they seemed to be doing was being the research arm of BP (per mgt at a annual meeting) exploring things  not thought of by a company doing things not expected. In our situation timing is everything….and finally I think the timing is coming to decisions how the rest of this plays out shortly. We needed first to throw away all the crap bad designed trials and protocols. Replace them with more sound trials…each of those proving a different part of the halogenated xanthene science. Cold tumors to hot, naive vs prior checkpoint therapy, immune cascade products…HMGB1, STING, caspases, autophagy, autolysis, necrosis, interleukin inhibition, NK and NKT innate immune up regulation, APC/DC/CD8+T/CD4+T up regulation, Treg down regulation. This science had to be explored first.

We needed to answer all the science questions first…before moving on things to monetize the company. Otherwise you leave possible money on the table….and you never leave possibly money on the table when it’s based on research first.

Second Summation:

The final science point in our drug is efficacy of causing a Uveal met to the liver to a metastatic complete response per PET scan using PERCIST measuring and not RECIST measuring….a recently more important measuring technique to determine a tumor to be metabolically dead. Results coming up at ASCO.

Third summation:

I think mgt is summing up their science first push. Next should be any early TGA/FDA push for advancing this early not so early science, and if they get a nod from one or the other or both to indicate a next step…that may give a better timeline to BP on how to address our research and IP vs what they tried to do without our new data and discoveries.

Evidence? Nov/Dec 2021 the meta analysis of all things PV-10 in hundreds of patients in Australia dealing with intransit met melanoma. Why publish? The only sane logic …data summation for TGA. Then add per company plan A…FDA/TGA  advancement.

And here we are.


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