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I am not sure whether or not they will report on more patients than what they did at SITC, but it is possible.
I am looking forward to the immune reponse data. We should be able to see for the first time how the combo treatment is impacting the TIL phenotype percentages. We had seen baseline levels reported at SITC, but no monitoring percentages were shared. Is immunopulse IL-12 elevating the PD-1/CTLA-4 hi TIL phenotype in activated CD8 tcells, thus priming immune cells for pembrolizumab? If so, how significant are those changes, and are the post treatment TIL phenotype levels exceeding that magic 20% threshold?
It looks like new data will be released soon for the current phase 2 pembrolizumab and immunopulse IL-12 trial.
Abstract 78: Immune monitoring outcomes of patients with stage III/IV melanoma treated with a combination of pembrolizumab and intratumoral plasmid interleukin 12 (pIL-12)
First Author: Alain Algazi
http://immunosym.org/abstracts
This is an interesting combination plug-and-play approach using patient-specific neoantigens with checkpoint inhibitors.
Another plug-and-play could be obtaining the tumor neoantigens through sampling, characterizing them through bioinformatics, and using a plug-and-play electrogene transfer method (electroporation) with other genetic constructs (e.g. IL-12) on plasmids delivered intratumorally.
Alternatively, you can create an in-situ vaccine targeting tumor neoantigens that won't require tumor sampling. What you need is a mechanism to get tumor cells to expose their neoantigens (e.g. through tumor cell death), professional antigen presenting cells (vis-a-vis IL-12) e.g. dendritic cells, co-stimulatory molecules (e.g. OX40L) for t-cell clonality, and upregulation of checkpoints like PD-1 and CTLA-4 on activated CD8 "killer" t-cells and tumor cells (vis-a-vis interferon gamma production by IL-12). All of these pathways can be triggered by the expression of DNA constructs delivered intratumorally through electroporation. This sets the stage for checkpoint inhibitors like anti-PD-1 and anti-CTLA-4 drugs. Robert Pierce is all over this streamlined in-situ vaccine approach.
Great to hear! With the ever-changing immuno oncology landscape, we need someone with eyes on the field, not just on the ball.
The material found in the report is supported by clinical data and market research - nothing distorted, plain and simple.
However, I agree that LifeSci Capital is paid by the company to promote the business.
If one looks at the Daud et al (2016) study in Journal of Clinical Investigation 2016;126(9):3447–3452. doi:10.1172/JCI87324, one can see that the non-responders from both study populations are primarily above a 5% PD-1hi CTLA4hi CD8+ TIL level - in fact 83% of those non-responders are above that level.
https://www.jci.org/articles/view/87324
Yet, in the interim phase 2 data reported at SITC by Oncosec, we see that 5/6 patients (83%) who were actual non-responders to anti-pd-1 therapy are below that 5% PD-1hi CTLA4hi CD8+ TIL level. The relative proportion of anti-pd-1 non-responders below that 5% level seems to be quite anomalous. Therefore, I am fairly confident that greater enrollment of actual anti-pd-1 non-responders in the combination phase 2 trial will demonstrate relatively higher numbers of non-responders with greater than 5% PD-1hi CTLA4hi CD8+ TIL baseline levels. This might translate into higher response rates.
http://content.stockpr.com/oncosec/files/docs/161117_IAD+Presentation.pdf
I couldn't be more confident despite the drop in the SP.
Thanks for sharing.
I do like the fact that PD and company are mindful of futility and are following data rather than their tails. Their decisions really do seem to be data driven, with slight tweaks here and there instead of committing to fruitless endeavors seen with so many other biotech companies. I applaud Oncosec on their simultaneous flexibility and progress.
Dr. Bannon, here is one example in preclinical studies where electroporation used alone in two models (melanoma and colon) demonstrates some effect on the percentage of antigen-specific CD8 t-cell expansion and tumor infiltrating lymphocyte relative counts. The active arm by comparison is a DNA-encoded GP96lg and FC-OX40l plasmid, therefore not IL-12.
http://oncosec.com/wp-content/uploads/2015/09/2016_AACR_Suresh.Final_.pdf
You'll notice that fold changes and TIL counts change from baseline and are higher versus no electroporation. EP alone, like you mentioned, does have some in-situ vaccination potential, but it probably isn't clinically significant by itself.
I think the key differentiating factor with EP intratumoral IL-12 expression is its ability to promote an increase in professional antigen presenting cells (e.g. dendritic cells) in the tumor microenvironment (TME), thus increasing antigen-specific CD8 TIL, essentially a patient-specific in-situ vaccine; and its generation of interferon gamma genes in the TME, which induces pd-1/pd-l1 and ctla-4 upregulation on tumor and immune cells, thus priming checkpoint inhibitor use. The electroporation by itself most certainly kills some of the tumor cells and, like you said, any dead tumor cells will release neoantigens. These released neoantigens would then be recognized by the professional APC generated by interferon gamma signaling.
I think the fact that IL-12 is increasing professional APC in the TME suggests to me that both induced (via electroporation) and natural tumor cell death is met with so many TME-local dendritic cells that it would be hard for a tumor to escape recognition when neoantigens are released.
I like how PD thinks - drive growth through innovation, not by inflating drug prices every year - time to cap that shiznit. Whether or not we like Trump, it sure sounds like biopharma is not going to be spared by him.
. @brentlsaunders agree w/ comments u made today on your thoughts on Drug Pricing & how @Allergan is committed to drug affordability @Citi
— Punit Dhillon (@PunitDhillon) December 8, 2016
What I am most curious about is the change in TIL numbers, specifically the exhausted phenotypes, following combo treatment. I hope they present these data in the coming year for the current phase 2 metastatic melanoma trial. Moreover, it would be interesting to see if the responder/non-responder data align with the UCSF biomarker studies. These are data we did not see at SITC.
I think the anti-pd-1 non-responder approach is in fact a great way for the company to garner some much-needed attention. Truly, what options do metastic melanoma patients have if they fail anti-pd-1 monotherapy, currently the gold standard for this indication?
I am encouraged by what I have seen so far with their melanoma results. The response durations and level of responses, i.e. complete responders, suggests to me that the treatment is definitely priming patients for checkpoint inhibitor use and they are essentially creating clinically effective in-situ vaccines as demonstrated by response durations. You simply do not see these types of responses in monotherapy anti-pd-1 data. And, you don't see as many complete responses even in combination treatments among all-comers.
An important topic in immuno-oncology research right now is personalized therapies.
Some researchers are approaching personalized therapies through the identification of tumor associated antigens, i.e. neoantigens, that allow tumor cells to be recognized by the immune system. For some, the question is which prediction software will be most precise in identifying the tumor cell antigens found in each patient's tumors. For example, see Parker Institute for Cancer Immunotherapy and Cancer Research Institute Launch Collaboration on Cancer Neoantigens
at http://www.cancerresearch.org/news/2016/pici-and-cri-launch-collaboration-on-cancer-neoantigens#sthash.Hl7W8YCT.dpuf
This approach requires sampling individual tumors' DNA to identify neoantigens. I think once they nail down the best predictive software, this could hypothetically lead to a "plug-and-play" administration of matching antigens, that is a personalized vaccine. This "plug-and-play" approach to personalized therapies was mentioned by RP last month. If you know each individual's tumor neoantigens, and you can create a personalized vaccine, do you administer the vaccine intratumorally or systemically? In my non-professional opinion, it would make more sense to send the vaccine directly to where it needs to be applied - the tumor from which the neoantigens originate.
Now what happens when you have matching antigens already prepared in the form of DNA plasmids, which you could combine and deliver via electro transfer soon after identifying each individual's tumor neoantigens? Vaccines have a reputation for eliciting mediocre immune responses without adjuvants. So, you combine the DNA plasmid vaccine with DNA constructs of IL-12 and other agents to optimize CD8 tcell activation in the tumor microenvironment where the neoantigens originated. In case you missed it, last month Jean Campbell also discussed how the next gene product is going to use a polycistronic cassette that may incorporate personalized antigens (neo-antigens).
You can take an in-situ approach as well that takes advantage of antigen chaperones like Heat Biologics GP96-lg in the form of DNA plasmids. This too is a personalized therapy that allows neoantigens to be transported by antigen presenting cells, e.g. dendritic cells, leading to CD8 t-cell activation. The GP96-lg "chaperones" individual tumor cells' antigens to the antigen presenting cells. Once again combine this with DNA plasmids expressing synergistic molecules like IL-12 and OX40L.
Therefore, there are two distinct intratumoral vaccine approaches that could be maximized by Oncosec's Genesis. There are quite frankly no gene electro transfer devices other than Oncosec's that conforms to tissue conditions for optimal delivery of DNA plasmids; it can be used with any tumor type. And, at least in my opinion, there is no better way to deliver a targeted(ex vivo developed) personalized vaccine than to do it directly in the tumor from which the neoantigens were removed.
In situ Vaccination: Potential Mechanism(s) of Action and Biomarker Development
Robert Pierce, M.D., Scientific Director, Immunopathology Core, Fred Hutchinson Cancer Research Center
Biomarkers and Immuno-Oncology World Congress 2017
http://www.biomarkerworldcongress.com/Personalized-Immunotherapy/
I think this is his new role at Fred Hutchinson:
Overview
IMMUNO-ONCOLOGY POSITION AT THE FRED HUTCHINSON CANCER RESEARCH CENTER
The sky is literally the limit with the new Genesys electroporation device in my opinion. The device could be used in any tissue, i.e. muscle, tumors, visceral organs, skin, etc.; this implies both local and systemic applications.
The ComPACT vaccine appears to demonstrate vast improvements over ImPACT in terms of immunomodulation. This small dataset illustrates some correlation between immune stimulation and response with an anti-pd-1. With that said, I think the co-stimulatory molecule in the ComPACT vaccine would lead to better immune responses and improvements in ORR and durations.
I think more researchers are beginning to realize that PD-L1 tumor cell expression is strongly correlated with interferon-gamma levels.
How do we increase interferon-gamma levels in the tumor microenvironment to elevate the PD-L1 tumor cells' expression so that anti-PD-L1/anti-PD-1 drugs work? Well, one direct way is through the release of IL-12 in the TME. The trick, so it seems, is to get these patients over that 30% PD-1-positive CD8 TIL threshold when concurrently using anti-PD-1 drugs. Interferon gamma helps to drive t-cell activation and antigen presentation, thus the reason for increases in exhausted TIL phenotypes following electroporated intratumoral IL-12 DNA plasmid administration. If the patients land in the 20%-30% PD-1-positive CD8 TIL zone, then it is really a ratio game between immune suppressing and activated (i.e. cytotoxic CD8 t-cell) TIL. Anything over that 30% threshold when used in combination with an anti-PD-1 drug will likely lead to a response.
There are many articles out there that demonstrate correlations between PD-L1 tumor expression and interferon-gamma signatures. Here are a few...
Scandinavian Journal of Immunology
Volume 80, Issue 1, Version of Record online: 20 JUN 2014
W. Xu, H. Jiang, J. Gao & Y. Zhao
Department of Radiation Oncology, Beijing Military
General Hospital, Dongcheng, Beijing, China
http://onlinelibrary.wiley.com/doi/10.1111/sji.12177/pdf
Exactly, they might be able to match the RFS and PFS with BCG at one year, but to reach statistical significance requires nothing short of perfection.
I think long term PFS and RFS will be better with the combo arms, but that doesn't resolve the immediate failure.
Different vaccine, same concept, but with a checkpoint inhibitor included. I have seen someone on here post about the phase I lung cancer trial observing 25% complete response rate - there is absolutely no evidence in the abstract that those responses were complete regressions.
I think to compete against BCG in NMIBC it would likely take several years to really observe statistically significant differences between the arms. BCG trials have observed 1-yr recurrence free rates in the 80%-83% range, so it would have been very difficult to improve statistically upon those rates with HTBX's vaccine at one year out. The differences, in my opinion, would be observed several years after surgical removal when the different arms' would be challenged by new cancer cells.
I don't see any indication in the abstract that these responses were "complete" responses. Where are you getting this from?
To have a one-year runway, it would seem prudent to find funding now considering they only have enough to get through Q3 2017.
I don't know if we are necessarily at a bottom. I remember thinking HTBX was at a bottom when it had a MC of $20M, then it dropped all the way down to something like $9M, primarily due to the threat of dilution.
I don't honestly foresee any near-term milestones either, but I imagine dilution is most certainly in the cards.
Plug-and-play is the concept of today.
Individualized therapies will require knowledge of one's tumor-specific (neo)antigens. First, identify an individual's tumor antigens. Next, select from a full repertoire of DNA-encoded antigens to accompany immune-stimulating DNA-encoded agents (IL-12, professional APC, TLR agonists, etc.) on a single plasmid delivered intratumorally via smart electroporation. Lastly or concurrently apply DNA-encoded checkpoint inhibitors intratumorally via smart electroporation.
Just sayin'.
lol but but but, company progress is contingent upon patents.
If patent applications are nothing more than creative writing, then lets just liquidate them all.
Lol, here's what's missing in that list:
1. An EP device that uses feedback data to conform to tissue types.
2. DNA-encoded checkpoint inhibitors plus immune-stimulatory agents.
3. INTRATUMORAL application with the above, not just muscle or skin.
Best of luck.
The link you provided relates to work injecting DNA-encoded mAb plasmids IN MUSCLE.
There are no other companies that have IP related to INTRATUMORAL ELECTROPORATION OF DNA-ENCODED CHECKPOINT INHIBITORS AND IMMUNE-STIMULATORY AGENTS, NOR ARE THERE ANY OTHER COMPANIES WITH EP DEVICE IP THAT RELATES TO TISSUE CONDITION FEEDBACK.
So why would someone want to electroporate DNA-encoded checkpoint inhibitors intratumorally?
1. Safety - systemic applications of combined CTLA-4, PD-1/PD-L1 and any other checkpoint inhibitor combinations thereof leads to high toxicities, i.e. grade 3/4 in the majority of treated patients. Combinations lead to greater efficacies versus any checkpoint inhibitor used alone; however these combinations lead to very high toxicities.
2. Efficacy - the checkpoints that you really want to eliminate are found in tumor microenvironments (TME), NOT THROUGHOUT THE BODY! Once intratumoral EP DNA-encoded IL-12 or any other cytokine ramps up the interferon gamma in the TME, you get up-regulation of antibodies, especially PD-1/PD-L1, CTLA-4 and TIM3, on tumor cells and immune cells specifically in the TME. That is, when you elevate the TME interferon gamma signature, you see more tumor infiltrating lymphocytes and tumor cells with up-regulated antibodies. This not only increases the total number of tumor fighting immune cells (antigen-specific TIL), but it also increases the number of checkpoints, SPECIFICALLY IN THE TME. Electroporating DNA-encoded checkpoint inhibitors intratumorally allows local tumor cells to express the checkpoint inhibitors (e.g., anti-PD-1/PD-L1, anti-CTLA-4, etc.) right where they are needed most - in the TME. Moreover, these checkpoint inhibitors would be expressed over an extended period of time in the TME. Durable expression should also lead to quicker response times and quicker release of tumor-specific antigens, thus speeding up immune activation and improving abscopal effects.
3. Efficiency - DNA-encoded checkpoint inhibitor plasmids delivered intratumorally is a far more efficient means of delivery than a systemic approach. DNA-encoded plasmids allow cells to do the work that would be accomplished ex-vivo, in labs.
This would be a worldwide patent.
Checkpoint targets could include the following:
CTLA-4, PD-1, PD-L1, LAG-3, TIM3, KIR, BTLA, A2aR, HVEM
Others will follow, stay tuned...
These are worldwide patent application publications.
Published applications...
https://google.com/patents/WO2016112359A1?cl=en
Method for the treatment of malignancies
WO 2016112359 A1
https://www.google.ch/patents/WO2016161201A2?cl=en&dq=Systems+and+methods+for+improved+tissue-sensing+based+electroporation++WO+2016161201+A2&hl=en&sa=X&ved=0ahUKEwiZ5KbU877QAhVExGMKHWmeCNwQ6AEIHTAA
Systems and methods for improved tissue-sensing based electroporation
WO 2016161201 A2
Thanks, that's an informative article.
There is only one company that seems to be addressing immune activation/escape and checkpoint inhibition directly in TME, i.e. Oncosec. AND, they appear to have a device that can work with any tissue type, including tumors, rather than just muscle or skin. I literally cannot find any single company that is accomplishing these three things, and believe me I have been searching.
Now, with that said, ONCS still needs to publish preclinical data and get their patents issued.
It is also my understanding that the new TRACE and Helix combination can be applied to any tissue condition, therefore, systemically as well, i.e. in muscle or skin.
Perhaps the most distinguishing feature of ONCS's new EP device is its ability to be applied to any type of tumor - that is, every tumor is unique. Ichor and Inovio's EP devices can only be applied to muscle or skin. In other words, Ichor's and Inovio's approaches are systemic applications, and not intended for intratumoral electroporation.
I really think ONCS needs to nail down these EP device patents for valuation and licensing reasons.
Their immune stimulating platform appears very solid, especially their proposed multigene product addressing multiple biological pathways, and I think incorporation of EP DNA-encoded antibodies with the new EP technology will be revolutionary if applied in the TME. But they absolutely must get those additional patents issued before they license any technology. They are a fledgling company working very diligently, and I'm confident that they will get those patents issued, it's simply a matter of time in my opinion.
It looks like the bulk of their EP technology patent applications are at the pre-publication (application) stage, i.e. less than 18 months out from the filing dates. Obviously, these applications can't be viewed by any of us until they are published - they are currently confidential.
There are a couple relevant issued patents, but it appears as though the most important technology improvements might still be in their infancy.
Yes, that was definitely my impression last week as well, although it's not clear to me if the patents have been granted yet on the EP/applicator devices. I would have to research this a bit.
I think their vaccine platforms will accomplish more in maintenance settings, such as with NMIBC.
Stimulatory molecules really appear to make a difference as well.
Efficiency, robust and lasting expression at the site of the checkpoints, safety, and reliability are all reasons for electroporating monoclonal antibody-encoded DNA plasmids, ie checkpoint inhibitors, rather than having them administered systemically. Checkpoint inhibitor combinations administered systemically lead to high toxicity rates.
Perhaps the key differentiating features are these:
1) Electroporating devices - I think what sets ONCS apart is their new real time and adaptive technology that theoretically works with any tumor type anywhere in the body. Each pulse duration is optimized based on feedback data. Their helical needle seems to offer improvements in terms of surface area coverage as well. If all of this is indeed true, then there should be improvements on efficiencies and efficacies.
2) ONCS's proposed multigene product, to be used with their new EP technology, should address a greater suite of biological pathways in the tumor microenvironment. I think the proposed multigene product will demonstrate improvements in terms of the number of antigen-specific and pd-1-positive tumor infiltrating lymphocytes, and will likely allow more tumor cells to upregulate pdl1; this would allow for a more robust response once the EP mAbs are expressed. I don't see Inovio pursuing such an aggressive immune response platform. Inovio is using EP DNA encoded constructs for IL-12, antigens, and various mAbs, but they don't appear to be generating TLR, additional chemokines, antigen chaperones, APC, or co-stimulatory molecules.
Inovio is accomplishing great things in my opinion, but the subtle differences between the companies might be enough to differentiate the better choice in terms of cancer applications. Also, they don't seem to be pursuing the same disease indications thus far.
One additional point - ONCS still needs to produce preclinical data for the combination of their multigene product, the new EP device, and EP DNA encoded mAb constructs.