Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Yes, it would be a proof of concept for a platform that could theoretically be an easy plug and play based on biomarkers. The various gene combinations would be virtually limitless, cheaper and easier to produce, safer because the proteins aren't expressed systemically, and more effective when expressed intratumorally. Achieving in-situ vaccination locally allows for an abscopal effect that seeks and destroys distant cancer cells/tumors expressing matching antigens. Systemic anti-PD-1 would still need to be employed due to the exhausted t-cell phenotypes present in mets, but that too could be accomplished through intramuscular electroporation of a plasmid encoding the PD-1 antibody.
We know IL-12 will continue to be the backbone of any multigene product, but imagine if they can demonstrate the successful expression of multiple genes simultaneously and intratumorally. There are probably hundreds of companies, both small and mega cap, designing individual recombinant proteins, to be used mostly in combinations with recombinant checkpoint inhibitors. Oncosec may be able to combine any of these protein targets into a single plasmid product, which would otherwise be highly toxic when delivered systemically as a recombinant protein package.
Oncosec's multigene constructs would be too disruptive to ignore. Next month's presentation is not just about a single new product being tested in mice; it will be more about the proof of concept for a technological innovation that will disrupt the way immunotherapies are administered and produced.
Those institutional numbers will probably change very soon - I think the multigene construct(s) may turn out to be a major technological disruption. This all assumes the genes transfer and the proteins become expressed well intratumorally.
I simply cannot imagine seeing major biotech companies producing recombinant proteins, including checkpoint inhibitors and other antibodies, just standing there watching a company with a cheaper, safer, and more effective IO platform just steamroll them. Oncosec may have the means to safely deliver a product that allows a patient's own body to produce a suite of therapeutic proteins that drive immunity in the presence of tumor specific antigens. Moreover, I think they have the potential to also encode checkpoint inhibitors on these multigene plasmids. And if that is indeed the case, this little company will be valued in the billions real quick.
Infinity Pharmaceuticals also just announced a Late-breaking presentation at SITC and they are up over 75% with a market valuation over $150M. The company's value has increased $65M on the news.
I am quite surprised to see this as a late-breaking abstract at SITC.
https://www.sitcancer.org/2017/abstracts/titles/late-breaking
Oncolytic Viruses and Intratumoral Therapies
P524
Jon, this is exactly the one to watch in my opinion. I want to see what the multigene construct(s) will contain. There is one particular antibody that I hope is encoded on the plasmid - anti-CTLA-4. That antibody delivered intratumorally will allow CD28 on t cells to bind with their ligands on antigen presenting cells, e.g.dendritic cells. That will drive a tumor antigen specific immune response. CTLA-4 outcompetes CD28 for the same ligands on APC; therefore by blocking that checkpoint in the presence of APC, you allow CD28 to do its job of stimulating an immune response.
This would probably be required in advance of a systemic PD-1 checkpoint inhibitor.
I haven't yet discovered any company encoding multiple genes on plasmids that are delivered INTRATUMORALLY. This by itself is a big deal because there is mounting evidence that in situ vaccinations, i.e. local delivery, can lead to abscopal effects. Adding in an encoded checkpoint inhibitor like an anti-CTLA-4 antibody to an intratumorally delivered plasmid vehicle would potentially be worth billions of dollars.
Thanks for your feedback on the topic of ONCS's pipeline. If they are able to demonstrate responses in an anti-PD-1 nonresponder group, and they are able to treat visceral tumors through their proprietary EP device, then metastic melanoma is only the tip of the iceberg. In the meantime, the share price may continue its downward trend until there are more data.
At this point, I am simply not convinced that they are actually able to convert anti-PD-1 nonresponders into responders using the current IL-12 DNA construct and electroporation device. The 33% BORR advertised is for all checkpoint inhibitor nonresponders, not just anti-PD-1 nonresponders. That is, they aren't going for anti-CTLA-4 nonresponders in the PISCES trial. This is the biggest issue I have with the company right now. I don't feel comfortable with the existing data to give me much confidence in the PISCES trial.
With all this said, the P2A-linked data, TRACE-enabled device, and multigene constructs give me a lot of faith in the company's future. I also truly like the company's leadership. I think ONCS's intratumoral gene expression platform is the best approach to eliminating solid tumors. I think there is so much locked up value in this early stage work that it has become frustrating for me to see the company languish around a $20M valuation. I have invested literally thousands of hours researching cellular biology and combing through peer reviewed data and I gotta tell ya, as soon as ONCS figures out the right combinations of encoded proteins to drive immunity, things will change very quickly. I think anti-CTLA-4 needs to be encoded on a plasmid delivered and expressed intratumorally with P2A-linked IL-12 and a co-stimulator. That is in my unprofessional opinion, but it is an informed one.
I agree there are many applications and countless combinations of encoded genes. There is enormous potential here. But what are the multigene products and for what indication(s)? They avoid these discussions. Right now, the only known product candidate is EP IL-12 used alone - which by the way doesn't make sense as a monotherapy - and in combination with an anti-PD-1 monoclonal antibody. That is it. What are the other product agents? No one knows and that doesn't bode well for share price.
Yeah, you and others are certainly right in that respect. The company simply doesn't discuss or list any product candidates other than EP IL-12.
I'm afraid so. They have been talking about additional intratumoral DNA constructs for quite some time, but there simply hasn't been anything definitive. Why have they stalled out? What proteins will be expressed for these other agents and what are the indications? No one knows much of anything about their preclinical pipeline. They have been so laser focused on the PISCES phase 2 trial that they have lost sight of investor perception. NO INVESTOR IS GOING TO RISK MUCH MONEY ON A POSSIBLE ONE TRICK PONY. They need to simultaneously advance their preclinical pipeline - right now, it doesn't appear to exist. And Punit goes to these conferences just glossing over the early stage work. Is there a pipeline or not?
Not a bad article. You know, there is one thing that continues to bug me about the company - they essentially have no pipeline. Any prospective investor looking at this company takes a quick glance at their product pipeline and sees essentially nothing - there are no new listed gene products other than the IL-12 combination in melanoma. What happens if the PISCES trial data aren't as good as hoped? Why take the risk if that is all they got?
Now I realize they are actively pursuing multigene constructs, but they STILL have not announced what the next product(s) would be; it has been all general information about possible combinations, nothing concrete. No investor wants to take the risk if they have no real pipeline. They need to solidify these other products.
This looks interesting to say the least (in case you missed it).
https://wc2017.electroporation.net/event/program#track-36
This is what I have been patiently waiting to see - actual preclinical data on a multigene construct delivered intratumorally. This presentation will be delivered at SITC in November. Can't wait to see which proteins are encoded in the construct.
https://www.sitcancer.org/2017/abstracts/titles/oncolytic-viruses-intratumoral-therapies
SITC 2017 Abstract Titles – Oncolytic Viruses and Intratumoral Therapies
I think T-Vec has a hard time dealing with visceral lesions, even in combination. I wasn't too impressed with their monotherapy data, but their most recent combo trial results were okay for metastatic melanoma. T-Vec is able to prime tumors for checkpoint inhibitors in all comers, which is probably why they have seen decent results, i.e. 62% responses (n=21). These results, however, are comparable to many other combination treatments with checkpoint inhibitors in all comers; these aren't anti-pd-1 failures, so it's difficult to compare these results with Oncosec's.
ESMO 2017 Congress Highlights
http://www.sitcancer.org/aboutsitc/media-room/meeting-highlights/2017/esmo#e6
Tumor LAG-3 expression is associated with response to combination LAG-3/PD-1 pathway inhibition in patients with melanoma that has progressed on prior anti–PD-1/PD-L1 therapy (LBA18)
I think you have it correct, Pazzo. Merck has had substantial involvement in the design - it is a collaboration regardless of Merck's total investment right now.
There seems to be a lot of stuff going on behind the scenes with their preclinical work. At first glance, there appears to be virtually no pipeline, but patent filings and a few key presentations tell a different story.
Few people understand the basics of immunotherapy, and far fewer understand how a multigene plasmid product encoding multiple proteins can lead to a personalized cancer vaccine with built in encoded checkpoint inhibitors. I think their new multigene construct platform may seriously disrupt things.
These data are for patients in a first line setting - no prior therapies. Oncosec is going for anti-PD-1 failures in a second/third line setting, ie patients who are progressing following anti-PD-1 treatment.
It is worth noting that that the Epac/Keytruda combo has relatively fewer complete responders compared to interim data presented earlier this year.
http://www.businesswire.com/news/home/20170830006308/en/New-Data-Epacadostat-Combination-KEYTRUDA®-pembrolizumab-Demonstrate
ORR: 30/54 (56%)
CR: 8/54 (15%)
PR: 2/54 (41%)
In advanced melanoma, all treatment naive.
Adoptive transfer of T cells is so darn expensive because it requires sampling, engineering, and expansion of the immune cells. This obviously works for blood cancers.
Another alternative for solid tumors, probably a MUCH cheaper route, is to identify the neoantigens on the tumors, select from a library of encoded antigens that are already p2a-linked with encoded immune stimulatory agents (e.g. IL-12) on plasmids, electroporate the plasmid in the tumor, and let the body manufacture the T-cells. This would have to be combined with checkpoint inhibitors.
Even better in my opinion, direct the body to stimulate an in situ vaccination. Find a way to expose the tumor's unique antigens in the presence of professional antigen presenting cells. Let the body do the hard work - just find the correct combination of encoded proteins that will stimulate the immunity after electroporation. Again, checkpoint inhibitors will still have to be used.
(WO2016154473) METHOD FOR THE TREATMENT OF MALIGNANCIES
Pub. No.: WO/2016/154473 International Application No.: PCT/US2016/024079
Publication Date: 29.09.2016 International Filing Date: 24.03.2016
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016154473&recNum=4&maxRec=13&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=FP%3A%28oncosec%29&tab=PCT+Biblio
You know, I was thinking...
Individual checkpoint inhibitor therapies, e.g., Yervoy, Keytruda, Opdivo, etc. individually cost nearly $150,000 per year per patient. These drugs serve as the foundation to most immuno oncology regimens. Combining checkpoint inhibitors to improve efficacy comes with toxicities and obviously higher costs.
If indeed a high proportion of pre-existing partially exhausted TIL correspond with equal efficacy when comparing a monotherapy (anti-pd1) to a combination therapy (anti-CTLA4 and anti-pd1), then it seems apparent that you can achieve desired efficacies with anti-pd1 monotherapies - and potentially save a lot of money - as long as those exhausted TIL phenotypes are elevated. If ONCS is capable of achieving such a goal - i.e. getting to the point where they can increase the exhausted TIL phenotypes - then they may considerably reduce costs by negating the need for combination checkpoint inhibitor therapies. They essentially create the right TME conditions for monotherapy anti-pd1 drugs, for example. Can ONCS electroporate their product for under $150K/per year/per person to demonstrate savings?
Then of course we have the possibility that ONCS may start developing their own gene-encoded checkpoint inhibitors that could be delivered (via electroporation) systemically (e.g. anti-pd1) and intramurally (e.g. anti-CTLA4). It's right there in their patent application claims - this could lead to a significant disruption in the checkpoint inhibitor market and lead to massive savings in health care if they actually do it.
This is a great read - nothing beats understanding fundamental cellular biology.
If anyone knows anything about checkpoint inhibitors it is this guy, James Allison.
https://www.sciencedaily.com/releases/2017/08/170810124952.htm
Checkpoint inhibitors fire up different types of T cells to attack tumors
How do you turn a $20M company into one worth $20B??
Demonstrate that you can encode checkpoint inhibitors on plasmids and that you can successfully deliver and express them intratumorally and systemically (via muscle) through a gene electrotransfer method, i.e. electroporation.
A new granted patent...
(US20170216585) METHOD AND DEVICE FOR TREATING MICROSCOPIC RESIDUAL TUMORS REMAINING IN TISSUES FOLLOWING SURGICAL RESECTION
https://patentscope.wipo.int/search/en/detail.jsf?docId=US201368932&recNum=1&maxRec=12&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=FP%3A%28Oncosec%29&tab=NationalBiblio
At today's closing SP that would be close to 33% dilution, assuming an average 1.07 ATM offering price.
I think most of us saw this coming a while ago with last year's registration filing. I am a bit surprised it didn't happen sooner.
Forgot to mention, according to one of the company's presentations (I forget which one) the next product will be a P2A-linked multigene construct using low voltage.
I think it will be a combination of encoded IL-12, an adjuvant with tumor-specific antigen, an expression promotor, and a co-stimulatory molecule.
Based on existing data, the P2A link leads to statistically significant changes in protein expressions. This is quite a big deal if you're trying to elevate Interleukin 12 expression and resulting interferon gamma and PDL1 levels. Nonresponders consistently show low levels of both.
Low voltage leads to vast improvements in transfection rates.
I am basing all of this on presentations and patents filings.
Hey Wait, yes, Jean Campbell described some of the patent application's elements last fall, but didn't describe the formulated compositions in any detail.
Here is what I think is interesting about this application:
1. They are trying to maximize protein expression intratumorally by combining various encoded genes on a single plasmid.
2. They now include tumor associated antigens fused to adjuvants on the same plasmid. This will hypothetically allow for improvements in CD8 tcell activation and thus lead to stronger immune responses against tumor targets. Adaptive immune responses require recognition of non-self tumor antigens, i.e. neoantigens, to drive immunity. Having a tumor antigen fused to something like heat shock protein 96 will theoretically improve presentation to dendritic cells, which in turn present to t-cells for activation. They can also now evaluate the immune response by analyzing lymphocytes for the presence of the encoded antigens.
3. Being able to encode various proteins on a single plasmid is one of the first steps towards developing personalized immunotherapies. This is a possible plug and play in the making. Once you figure out the tumor profile of the patient, you can theoretically tailor the plasmid to contain specific antigens unique to the patient. This won't negate the need for checkpoint inhibitor treatments, but it will certainly drive the tumor infiltrating lymphocytes that need to exist before checkpoint inhibitor therapy. Having the expression promoters and fused adjuvants on the same plasmid should contribute to adequate immunity. Adequate protein expression has always been a challenge for electrogene transfer, but combining GENESIS with TRACE, encoded adjuvants, promoters, cytokines and tumor associated antigens is really loading the deck, and they are able to do it right where it's needed most - intratumorally. This will lead to a systemic immune response through the release of tumor specific antigens, i.e. neoantigens.
4. They seem to leave the door open to cassettes that contain RNA sequences. RNA doesn't need to make it to a cell nucleus to express a protein. See Moderna Therapeutics on the possible implications for this.
A new patent application was just published.
See https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017106795&recNum=1&maxRec=11&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=FP%3A%28Oncosec%29&tab=PCT+Biblio
PLASMID CONSTRUCTS FOR HETEROLOGOUS PROTEIN EXPRESSION AND METHODS OF USE
Sorry I didn't catch your highlight, Chickpea - I haven't been keeping up with everyone's posts here.
Clinically relevant protein expression is going to be key, and if they can demonstrate sufficient expression levels then things will radically change for the company. I know I have said this many times before and I know you get it, Chickpea, to allow the body to successfully manufacture its own proteins either locally or systemically will make current antibody production methods obsolete; they could end up disrupting a massive market.
This is really interesting, I had missed it ...
I don't think any IDO inhibitors are ineffective, because there are quite a few trial results - all early stage - that in general show benefits to adding an IDO inhibitor to anti-PD-1 treatments. In Newlink's case, it might simply be the types of solid tumors they are attempting to treat with Roche, e.g. non small cell lung cancer, triple negative breast cancer, that aren't responding too well, because they lack immunogenicity.
The Newlink IDO inhibitor combination data with Merck's Keytruda in metastatic melanoma was actually very similar to various Epacadostat and anti-PD-1 combinations in the same indication. I think the Newlink combo data demonstrated a 52% ORR with a CR of 10% in their anti-PD-1 naive patients.
If anything, I think TLR9 agonists are going to be competitive with intratumoral IL-12, because one downstream effect of these agonists is elevated production of interleukin 12. Successes in intratumoral TLR9 agonist treatments will likely translate into successes for intratumoral Il-12 electrogene transfer and vice versa. The mechanisms of action are similar, but TLR-9 agonist treatments are arguably more indirect, because they require intermediary steps to ultimately get to the production of interleukin 12. For TLR-9 agonists, they primarily rely on dendritic cells to produce the needed effect.
A 5% complete response rate in advanced melanoma all comers according to the Epac combination data... not impressive. A 63% BORR sounds good, but when you realize that these patients are mostly just partial responders, then you know that they will be seeking a better solution.
Incyte's Epac is an improvement, but it really doesn't get the job done. T-vec is even worse.
Hey everyone I found this quite interesting and relevant...
http://www.marketwired.com/press-release/dynavax-presents-updated-data-sd-101-combination-with-keytrudar-pembrolizumab-highlighting-2219983.htm
It looks like TLR9 and Keytruda are very effective in combination when treating all-comers, but can't achieve more than 17% ORR in anti-PD-1 nonresponders. Just keep this in perspective when ONCS data start to roll in. DVAX is up 20% on this news. They are taking the fight directly to the tumor, which is exactly where the PD-1 upregulation needs to occur and where tumor antigens are recognized to stimulate immune responses.
I cannot think of anything more compelling than the use of your own body's cells to manufacture the biological drugs that will eliminate cancer and prevent/treat diseases.
Thanks for sharing Chickpea. Nothing is more direct in engaging interferon gamma production and recruiting professional antigen presenting cells than il-12.
Thanks, Ahab, will do.
While digging deeper into the company's patent applications and connections with one particular institution, I am convinced that they are pursuing in-situ production of antibodies, including checkpoint inhibitors, through encoded polycistronic vectors. Oncosec has the capacity to be a major disruptor.
Imagine your cells as a factory that can produce any encoded antibody when the genetic material is adequately transfected...
That all sounds very reasonable and a capital raise makes sense considering their cash runway is less than a year out.
Here are a few additional thoughts to consider that may drag the company out of this free fall before any dilution.
1. Immunotherapy companies in general see a boost in share price during ASCO; this is a time for releasing major breakthroughs and simply being in the immune oncology space has its benefits.
2. Oncosec may indeed be presenting at ASCO. Accepted late-breaking abstracts are released after the start of the conference.
3. The company's market cap is somewhere close to cash on hand with zero debt. The market, therefore, has placed no value in its pipeline. How long is that going to last?
4. We now know that they have at least two TAP agreements in place. Even if the fee structure is negligible per agreement, the company is still seeing revenues. If they secure more agreements then those negligible fee revenues could add up and reduce the amount of dilutive funding. We still don't know how much they are charging and they may have secured more agreements. They aren't announcing every TAP agreement, just the first one.
5. They are radio silent on their preclinical development. Who knows what they have in the works in terms of gene combinations. The gene expression improvements provided by bicistronic constructs and tissue sensing gene delivery technology would theoretically amplify the interferon gamma signature in the tumor microenvironment. This would lead to improvements in the upregulation of PD-1 and PD-L1 phenotypes, thus setting the stage for better responses to checkpoint inhibitors like Opdivo and Pembrolizumab.
6. Patent applications are painting a possible pipeline picture where checkpoint inhibitors are encoded on plasmids with or separate from immune stimulatory agents. The implications for a product that contains DNA-encoded antibodies for use in immune oncology cannot be overstated.