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Gene electrotransfer:
Genetic material (DNA) is trafficked to a cell nucleus after electroporation where the DNA is converted into RNA (transcription) and then the RNA is converted into, for example, functional proteins or molecules(translation). These proteins and molecules are the products that become EXPRESSED TO FUNCTION OUTSIDE THE CELL.
Electroporated genetic constructs of cytokines, antigens, toll-like receptors, antigen chaperones, co-stimulatory molecules, chemokines, and monoclonal antibodies can all go through this same "manufacturing" process.
And yes, you can have tumor cells express the phenotypes for encoded monoclonal antibodies like anti-pd-1, anti-ctla-4, anti-tim-3, etc. Efficiency, robust and lasting expression, safety, and reliability are all reasons for electroporating monoclonal antibody-encoded DNA plasmids, ie checkpoint inhibitors, in tumors. This is where you find the antigen-specific tumor infiltrating lymphocytes (TIL)that up-regulate pd-1 on their cell surface in the presence of interferon gamma, owing to the IL-12. Guess what else then gets up-regulated? Yep, pdl1 on tumor cells. When you have both the pdl1 (ligands) on tumor cells and the pd-1 on antigen specific TIL up-regulated you get a stalemate. That is when you unleash the checkpoint inhibitors to allow the TIL to do their job of killing tumor cells.
Btw, all of these DNA encoded elements, ie, chemokines, TLR agonists, co-stimulatory molecules, professional APC, and IL-12, for the new multigene product were described by Jean Campbell yesterday. All of these genes would be encoded in a single product.
Listen carefully to Kevin Hollevoet and Jean Campbell's presentations.
Imagine sustained expression of anti-pd1, anti-pdl1, anti-ctla-4, anti-tim-3, - virtually any monoclonal antibody - in tumor microenvironments...
Now imagine those antibodies being delivered by ONCS's new electroporation device, which as we learned now has several pending patent applications.
Prime an immune response using electroporated and DNA-encoded chemokines, TLR agonists, Co-stimulatory molecules, professional antigen presenting cells, and IL-12 prior to delivery of DNA encoded antibodies. Guess what happens when you successfully express all of those therapeutic agents in tumor microenvironments...
I read a report somewhere that checkpoint inhibitors may collectively exceed $50B in peak sales by 2025.
I think this is what PD was referring to when he kept mentioning value creation.
Like I also suspected, the mAb expression is sustained over a long period of time is situ.
Folks, do you all realize what is going on between ONCS and Ku Leuven's antibody gene transfer program?! The collaboration is literally going to leapfrog conventional systemic checkpoint inhibitors like Keytruda, Opdivo, Yervoy, etc. Pay close attention to today's presentation. Oncosec will provide the new smart electroporation technology as a delivery vehicle for DNA encoded mAbs, in any tissue type including tumors! This is the local delivery of monoclonal antibody DNA that I was talking about recently.
This is an enormous development!!
Mark this post, because you will all one day want to remember this moment of enlightenment.
I had to listen to today's presentation a couple times before I realized what was going on.THIS IS AN INSANELY HUGE DEVELOPMENT.
Yeah, my guess is still a phase 2 registration trial.
Probably folks like you and me...
Hi Twiz, a registration study is designed to sufficiently answer specific efficacy and safety questions. These trials are typically large enough to test for statistical significance and they serve as the basis for new drug applications. The FDA evaluates a NDA to determine whether or not a drug should be approved. A registration study, therefore, is the last trial prior to approval or a denial, ie, a complete response letter. Most registration studies are phase 3 trials, but not always.
You can have a phase 2 trial serve as a registration study, but typically you would be required to follow it up with a confirmatory trial after the drug gets approved, assuming it gets approved. In other words, the drug could be marketed while it goes through the confirmatory trial.
Technology Access Program... looking forward to hearing how this works.
Sorry, meant to say recurrences, not regressions.
The abstract provides just a glimpse. In this case, the composite RFS and carcinoma in-situ RFS suggests to me that HTBX's vaccine is likely not inferior to BCG, otherwise the percentages would be lower. The two immunotherapies appear to be synergistic and the addition of HTBX's immunotherapy to BCG is likely improving regression free survivals in a patient population that observes up to 90% regressions over 5 year periods.
Here is the abstract being presented in a couple weeks(highlighted text is mine)...
http://suonet.org/meetings/upcoming-meetings/2016-suo-annual-meeting/online-program-viewer.aspx
TOP-LINE RESULTS FROM VESIGENURTACEL-L (HS-410) IN COMBINATION WITH BCG FROM A RANDOMIZED, BLINDED PHASE 2 TRIAL IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC)
Gary Steinberg MD¹, Neal D. Shore MD², Lawrence Karsh MD³, James L. Bailen MD4, Trinity J. Bivalacqua MD PhD5, Karim Chamie MD6, James Cochran MD7, Richard David MD8, Robert Grubb MD?, Wael Harb MD¹°, Jeffrey Holzbeierlein MD¹¹, Ashish M. Kamat MD¹², Vijay Kasturi MD¹³, Edouard J. Trabulsi MD¹4, Michael Williams MD¹5, Frederick N. Wolk MD8, Michael E. Woods MD¹6, Melissa Price PhD¹7, Brandon Early MS¹7 and Taylor H. Schreiber MD PhD¹7
¹University of Chicago Medical Center, Chicago IL; ²Carolina Urologic Research Center, Myrtle Beach, SC; ³The Urology Center of Colorado, Denver, CO; 4First Urology, Jeffersonville, IN; 5Johns Hopkins University, Baltimore, MD; 6University of California Los Angeles, Los Angeles, CA; 7Urology of North Texas, Dallas, TX; 8Skyline Urology, Torrance, CA; ?Washington University of St. Louis, St. Louis, MO; ¹°Horizon Oncology, Lafayette, IN; ¹¹Kansas University Medical Center, Westwood, KS; ¹²MD Anderson Cancer Center, Houston, TX; ¹³University of Massachusetts Memorial Medical Center, Worcester MA; ¹4Thomas Jefferson University, Philadelphia, PA; ¹5Urology of Virginia, Virginia Beach, VA; ¹6University of North Carolina, Chapel Hill, NC; ¹7Heat Biologics Inc.
Presented by: Gary Steinberg
Introduction and Objectives: Vesigenurtacel-L (HS-410) is a vaccine comprised of an allogeneic cell line, selected for high expression from a series of bladder tumor antigens, which has been transfected with gp96-Ig. Cell-secreted gp96-Ig delivers these cell-derived antigens directly to a recipient's own antigen presenting cells, resulting in highly selective activation of CD8+ cytotoxic T cells. Here we present, for the first time, unblinded primary endpoint data (1-year Recurrence-Free Survival (RFS)) from a randomized Phase 2 trial with vesigenurtacel-L in combination with BCG in NMIBC. Trial ID: NCT02010203
Methods: 78 patients with intermediate- (n=5) or high-risk (n=73) NMIBC who are either BCG-naïve or recurrent, with or without carcinoma in situ (CIS), were enrolled 1:1:1 to one of two doses of vesigenurtacel-L (either 10^6 or 10^7 cells/dose) or placebo in combination with 6 weeks of induction BCG, followed by 6 more weeks of vesigenurtacel-L in the induction phase. Maintenance treatment in combination with BCG continued in patients without evidence of disease for 3 courses of 3-weekly treatments at the following timepoints: 3 months, 6 months, 12 months. Concurrently, 16 patients (1 intermediate risk, 15 high-risk) were enrolled in an open-label monotherapy vesigenurtacel-L arm for patients who will not receive BCG. The primary endpoint is 1-year RFS. Secondary efficacy evaluations include recurrence and progression at various timepoints, and analyses of immunologic response in peripheral blood and tumor.
Results: Vesigenurtacel-L treatment was well tolerated with no vaccine-related SAEs; primary AEs were mild, most commonly transient injection site reactions. AE profiles (number and severity of AEs) were similar across the treatment arms indicating that vesigenurtacel-L does not significantly alter the known safety profile of BCG. Composite RFS across all arms (prior to the unblinding event at 1-year) was 84.6%, with a 6-month complete response rate in CIS patients of 87.5%. Vesigenurtacel-L antigen expression showed prominent overlap with patient tumors. Additionally, IHC may define a responder and non-responder phenotype by baseline levels of TIL and PD-L1.
Conclusions: The combination of vesigenurtacel-L and BCG is well-tolerated with preliminary evidence of synergistic effect and immunologic responses that are consistent with vaccine mechanism of action. Vesigenurtacel-L warrants further investigation as a potential treatment for NMIBC.
Yep!
If the synergies explored in HTBX's preclinical studies using comPACT with anti-pd1s translate similarly in humans, then an electroporated gene version of GP96lg and co-stimulatory molecule like OX40L would facilitate an expansion of neoantigen-specific TIL due to their administration in tumor microenvironments. I am VERY curious what will happen when you combine EP IL-12 DNA with EP comPACT DNA and systemic pembro...
I would be extremely surprised if ONCS doesn't use Heat Biologic's comPACT platform and combines it with EP IL-12 and pembrolizumab. The preclinical data just reported by HTBX at SITC is too huge to ignore in my opinion. The reported antigen-specific t-cell expansion in peripheral blood and spleen, along with the memory precursor cell improvements, is incredible.
Using an EP version of comPACT DNA with IL-12 DNA and pembrolizumab should theoretically lead to neoantigen-specific t-cell expansion, thus potentially increasing PD1/CTLA4-hi-positive TIL necessary for improving responses.
Per the presented preclinical data at SITC, the antigen specific t-cell expansion with combination ComPACT/anti-pd-1 or anti-pdl1 checkpoint inhibitor in peripheral blood and spleen are quite frankly unbelievable! The memory precursors are also increasing dramatically when the combination is used.
These are just selected preclinical data, but the reported immune profiles are simply off the charts.
Thanks for sharing the updated corporate presentation. I have been "in the trenches" for a few days, so I haven't really had the chance to review the presented results until now.
The presented data, albeit preliminary and a small dataset, definitely appear to demonstrate efficacy improvements over what would be expected of monotherapy keytruda, or any monotherapy anti-pd1 treatment for that matter. Although it hasn't been discussed much, I think the individual duration of response data seem to be very intriguing for those patients who have been treated beyond 3-4 months; none of these patients are progressing once they respond. Long term follow up is obviously needed, but response durations thus far indicated are remarkable.
Also, like I said before, the complete responses really stand out for me, and they're occurring in patients with relatively low pd1/ctla4-hi positive TIL baselines.
In terms of the non-responders in this trial, most of whom were previously treated with anti-pd1 therapy, suggests to me that these patients are having a hard time getting their pd1/ctla4-hi positive TIL up in the right territory (>30%-positive TIL) and/or the TIL are landing in that 20%-29% zone where responses are less predictable.
I have also read published studies that describe how tumors can develop adaptive resistance to prolonged anti-pd1 therapies. For example in Koyama, S. et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat. Commun. 7:10501 doi: 10.1038/ncomms10501 (2016), data suggest that there is an upregulation of TIM-3 expression on T-cells following prolonged exposure to pd-1 immune checkpoint inhibitors, noted in lung cancer patients. If this is the case with the non-responders in ONCS's combination phase II metastatic melanoma trial, then it stands to reason that to turn these particular patients into responders ONCS might have to use a combination of checkpoint inhibitors to attack multiple pathways OR use EP IL-12 plasmid DNA plus pembrolizumab in a first line setting. While it is apparent that a certain percentage of these previously treated anti-pd-1 patients are responding, I think the combination therapy may work even better in a first line setting or in combination with additional checkpoint inhibitors in a second line setting. Again, this is just in my non-professional opinion.
Hi Sammy, thanks for sharing. That information clarifies a few things for me. I was wondering if they had enrolled real nonresponders to monotherapy Keytruda.
To have 5 patients responding with TIL percentages less than 20% gives me even more confidence in this combination platform. I will be looking closely at baseline and post-treatment TIL numbers. I am most curious about the baseline TIL for the combination's nonresponders.
I think the most important and insightful data will be shared in a couple days.
For example, what exactly were the pre-treatment TIL percentages in patients who responded or did not respond? Were non-responders' TIL populations very low initially? Are they actually elevating the PD-1 and CTLA-4 TIL phenotypes following EP IL-12 DNA plasmid treatments? At what point in the treatment cycles did some folks respond and what are response durations looking like?
What I think is most interesting about this small dataset is that there were more complete responders than partial responders. This suggests to me that for those patients who respond in the trial population, they are generally responding VERY WELL, so much so that all signs of cancer are gone. If the trial participants were true monotherapy Keytruda non-responders, and the trial size were larger, I think it would be very difficult for competing or synergistic companies to ignore the data. Again, beware this was a small dataset, but interestingly the complete response rates were greater than the partial response rates, thus supporting the retrospective analysis reported earlier this year. That retrospective study also demonstrated more complete responders than partial responders. So why are most patients who respond seeing complete remissions?
This was presented by Inovio at the 19th Annual Meeting of the American Society of Gene and Cell Therapy on May 5:
In Vivo Expression of Plasmid Encoded IgG for PD-1 or LAG3 by Synthetic DNA as a New Tool for Cancer Immunotherapy
https://globenewswire.com/news-release/2016/05/04/836532/0/en/Inovio-Pharmaceuticals-Showcases-its-Broad-Pipeline-of-DNA-based-Immunotherapies-Vaccines-and-dMAbs-at-the-American-Society-of-Gene-Cell-Therapy.html
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This is an example of a company testing electroporated DNA versions of checkpoint inhibitors
Back in April at the AACR, Algazi mentioned potentially expanding the study to include 41 patients with high (>25%) TIL tumors. See slide 17 of that presentation.
Thanks for taking the time to read and respond to my comments. I'm not a medical professional, just someone who is genuinely interested in cancer research, so I appreciate your input.
I tend to think that the use of antigen chaperones (GP96) in the context of an inflamed tumor microenvironment (driven primarily by interferon gamma through IL-12) will allow for improved activation of CD8 t-cells that can target tumor-specific (neo)antigens. The antigen chaperones would actively deliver neoantigens to antigen presenting cells, which should be prolific in the context of an inflamed tumor microenvironment. This, the activation of neoantigen-specific CD8 t-cells, I think would drive the exhausted pd-1/ctla-4-positive TIL phenotype. When a co-stimulatory molecule like OX40L is added to the mix, there should theoretically be a polyclonal expansion of the differentiated CD8 t-cells along with improvements in memory precursor cells.
The exhausted TIL phenotypes (pd-1 and ctla-4) are an apparently essential requirement for checkpoint inhibitor efficacy. If true, then a local expression of checkpoint inhibitors, manufactured over the course of several days by tumor cell machinery vis-a-vis EP genes, should not only release the brakes on blocked TIL, but should also continuously feed TIL and augment tumor cell destruction due to the TIL phenotype expressions present. This could potentially lead to a positive feedback loop in which more neoantigens are released and more inflammatory cytokines are produced in the immediate tumor environment, thus leading to a significant systemic immune response.
Again, there is no indication that the company will go down this road, but the synergy between all of these EP agents is screaming, at least to me.
because, in the first instance it is all conjecture/theory. No actual data to support any of it. Second it is not consistent with our knowledge of how the PD1 inhibitors work as I have discussed many many times. It is fine to have theories, such as the use of tin foil hats to prevent brain cancer, but solid evidence or at least a rational theory would be more convincing
well now we seem to be making some progress as we are no longer talking about electroporating PD1 inhibitors, but instead taking about ep of DNA encoding for PD1 inhibitors. However, no compelling explanation of the reason for doing this has been offered. thanks
If it's not compelling, please explain why not...
Thus far, ONCS nor any other company to my knowledge, has electroporated checkpoint inhibitor (specifically anti-PD1, anti-PDL1, anti-CTLA4, etc) DNA in tumor cells. In a previous post, I mentioned how Inovio is electroporating monoclonal antibody DNA, but they aren't anti-cancer checkpoint inhibitors. I'm curious whether or not a patient's adaptive immune response would improve if one were to electroporate checkpoint inhibitor DNA in non-metastatic solid tumors IN THE CONTEXT OF ELECTROPORATED IL-12, GP96 AND FC-OX40L (I originally left this contextual part out). Would the local administration (within the tumor microenvironment) of EP checkpoint inhibitors improve adaptive immune responses by allowing for a quicker and durable release of tumor-specific antigens (neoantigens) in the context of 1) an inflammed tumor microenvironment (IL-12), 2) antigen chaperones (GP96), and 3) co-stimulatory molecules (OX40L)? All of these agents administered together would theoretically drive a robust immune response that is capable of preventing recurrences, increasing responses, and greatly expanding progression free survival and overall survival.
We all know ONCS has been working with the GP96 and OX40L DNA plasmids in the preclinical setting. I think these agents administered together with IL-12 would greatly improve responses. But I also wonder if EP checkpoint inhibitors would add the "icing on the cake" if they too were to be administered in solid tumors in combination with these other agents.
As for metastatic lesions, I think the EP combination of IL-12/GP96/OX40L/anti-pd-1 (or anti-pdl1) would theoretically drive a significant abscopal effect by increasing the number of tumor infiltrating lymphocytes in non-treated lesions. In such cases where the TIL are "braked" by checkpoints in these distant lesions - which by the way is very likely due to the potential for exhausted phenotype in immune cells - at that point you would administer systemic checkpoint inhibitors. Again, this systemic application would be limited to advanced metastatic lesion situations - the TIL would be there, but they would be stopped by the checkpoints.
I additionally think there could be another use for an IL-12/GP96/OX40L/anti-pd-1 (or anti-pdl1) EP combination in the adjuvant setting, i.e. prior to surgical removal. This would theoretically contribute to an adaptive immune response that prevents recurrences or progression.
My primary question is whether or not the immune response would play out this way when you electroporate checkpoint inhibitor DNA in the tumor cells and in these settings.
Any thoughts?
John, it was indeed mostly a cut and paste, but the truth is that it would be essentially the same information had I reworded it.
More nonsense - who said they were using EP to deliver pd-1 inhibitors? They are an example of a company that is using EP to deliver monoclonal antibodies. PD-1 inhibitors are monoclonal antibodies.
Per your request, here is an example of electroporated DNA that encodes for monoclonal antibodies.
Inovio Deploys DNA-based Monoclonal Antibody Technology in Quest to Cure HIV
PLYMOUTH MEETING, Pa., July 14, 2016 (GLOBE NEWSWIRE)
http://ir.inovio.com/news/news-releases/news-releases-details/2016/Inovio-Deploys-DNA-based-Monoclonal-Antibody-Technology-in-Quest-to-Cure-HIV/default.aspx
Once the DNA is processed by the tumor cells and the monoclonal antibodies are produced, i.e. they exit the tumor cells, at that point they are full-fledged monoclonal antibodies capable of achieving the same role as systemically-delivered monoclonal antibodies (e.g. checkpoint inhibitors). At that point they can initiate contact with pd-1 on the surface of immune cells to block the checkpoint.
This is the same transfection process that ONCS has used to express IL-12, GP96 and FC-OX40L DNA intratumorally. After the cancer cells process the genetic material and "spit out" the product, what you get are functional IL-12, GP96 (antigen chaperones), and FC-OX40L (agonists).
GoodJohn, here is what I'm thinking...
To drive a significant abscopal effect and immune response to cancer tumor cells, you would need recognition of neoantigens. Systemically administered checkpoint inhibitors are ultimately delivered to locations all over the body. This route of administration not only leads to severe toxicities when used in combination with other checkpoint inhibitors, but the effect is non-localized. In theory, or at least in my mind, electroporating checkpoint inhibitors would drive more significant localized tumor regressions in a shorter amount of time than systemic injections. In addition, you would see far fewer severe adverse events versus combination checkpoint inhibitors administered systemically. Electroporating an anti-pd-1, anti-ctla-4, etc monoclonal antibody (checkpoint inhibitor) with IL-12/GP96/OX40L would drive a profound immune response and abscopal effect because greater numbers of neoantigens would initially become exposed in the context of an inflamed tumor microenvironment. Metastatic lesions would then be subject to TIL with tumor specific neoantigens. There would theoretically still be a need for systemic applications of checkpoint inhibitors in some metastatic situations, but the electroporation of the genes would substantially eliminate systemically delivered checkpoint inhibitor use.
Electroporating DNA for checkpoint inhibitors would 1) speed up neoantigen release and presentation to naive t-cells; 2) provide robust and continuous localized expression for perhaps up to a couple weeks; 3) lead to a profound abscopal effect and important innate immunity; and 4) provide a safer alternative to repetitive systemic checkpoint inhibitor use. Of course, the checkpoint inhibitors would work best in the context of an inflamed tumor microenvironment (IL-12) that contains antigen chaperones (GP96) and co-stimulatory agonists (FC-OX40L) that are capable of polyclonal expansion and that are responsible for memory precursor cell production. What this comes down to is complete tumor regression in treated lesions in a relatively short amount of time, and a robust innate immune response that is capable of driving TIL in metastatic lesions.
What is nonsense?
The same argument can be said about checkpoint inhibitors just five years ago - "if anti-pd-1 treatments are effective, why aren't they being used." Now we know they are being tested in nearly every solid tumor type.
I laid out my rationale for electroporating checkpoint inhibitor (monoclonal antibody) DNA. Again, this doesn't mean the company is going to do that, it just seems like a logical next step from my perspective. And, because I know antibodies can be produced via electroporated DNA, it is also theoretically possible to achieve production of checkpoint inhibitors in-situ.
I would have to listen to the call again to try to understand the details of the amended protocol proposal mentioned by Dr. Gargosky.
I would be very pleased to see responses in the 30% range for the phase II combo trial, simply because there are other combination trials with pembrolizumab and other checkpoint inhibitors that reach 58% ORR in metastatic melanoma. While no two trials can be compared against one another, there appears to be consistency in ORR with these combo trials hovering around that 58% mark. In my estimates, this would be nearly-equivalent to a 28%-38% ORR in Oncosec's phase II combo trial with pembro. Dr. Gargosky does indeed appear to be happy with what they are observing, and I'm sure KOLs will be looking at individual case studies to determine the data significance. For example, what are the TIL phenotype profiles prior to treatment? No one understands the significance of the data like the oncologists.
PD-1 checkpoint inhibitors ARE antibodies - they are monoclonal antibodies. Cells process the DNA that is encoded for the antibodies when the genes are electroporated into them.
I'm not sure why you would even ask that question.
Companies electroporating DNA that is encoded for antibodies...
1. Pfizer/Ichor
2. Roche/Inovio
Inclusion criteria:
"Patients must have histological or cytological diagnosis of melanoma with progressive locally advanced or metastatic disease that is not amenable to definitive local therapy with curative intent." When you have "progressed", you are refractory to treatment(s) or your disease is not stable without treatments. Non-responders would fall into this category.
However, the trial allows for "prior chemotherapy or immunotherapy or radiation therapy." This implies that they are enrolling patients who aren't just potential non-responders to anti-pd-1 monotherapy, but they are also potentially enrolling patients who are refractory to chemotherapies, other immunotherapies, or radiation therapies.
I am confident that the TIL phenotype exploratory biomarker developed by the UCSF is truly representative of patients that would be clinical non-responders to monotherapy pd-1 checkpoint inhibitors. But for this trial, they aren't actively recruiting patients who are determined non-responders to monotherapy pd-1 treatment. They have opened the door to patients who MAY be non-responders to immunotherapy in general, but they have also left the door open to non-responders to chemotherapy, non-responders to radiation therapy, and even to treatment-naive patients.
While the protocol calls for "<70% PD-1hiCD8+CTLA4+ in the CD45+ gate based on flow cytometry", they have further refined the requirement to only include patients with <25% PD-1hiCD8+CTLA4+ TIL; these details are left out of the clinical trials inclusion criteria, but it is still technically <70%.
Is this <25% requirement an accurate predictor of patients who would be non-responders on monotherapy pd-1 treatment? From what I can gather from the data presented in the Journal of Clinical Investigation, the two cohorts comprised of 20 patients each - "discovery" and "validation" - clearly shows that no one with a <20% PD-1hiCD8+CTLA4+ TIL profile had responded to anti-pd-1 monotherapy. In addition, everyone with a >30% PD-1hiCD8+CTLA4+ TIL profile did respond to anti-pd-1 monotherapy. Predictability is not significant for patients in the 20%-30%-positive range. This means patients in the 20%-25% (25% is the trial cutoff) range may or may not respond to monotherapy anti-pd-1. It will be interesting to see case studies on the phase II combination patients to know exactly what their biopsied TIL phenotypes show.
The biomarker assay is still very significant, because it informs the registration trial design. Trial investigators appear to be confident in the predictability of the biomarker, and if they see responses in the phase II combination trial, they are likely going to attribute those responses to the EP IL-12. This builds confidence in the product and the feasibility of moving forward with the registration trial.
Say Whaaa?
Antibodies are already being electroporated by companies, just not monoclonal antibodies inhibiting pd-1, ctla-4, etc, at least to my knowledge.
The processed DNA becomes an interleukin (IL-12), antibody (anti-pd-1), antigen chaperone (GP96), co-stimulatory molecule (OX40L), etc.
Would you mind describing the MOA for electroporated IL-12 please?
The expressed genes would be the antibody that interacts with the pd-1 on the cell surface of immune cells; EP provides a localized and continuous expression of the antibody. The alternative would be systemic application. And I just listed the reasons why systemic application is inferior.
There is a reason why electroporation was developed.
Lowe, I could be wrong, but your statement leads me to believe that you are misinterpreting ONCS's electroporated DNA-based therapy.
Yes, the genes go INTO cells, in this case tumor cells, but the genes are then processed and EXPRESSED as interleukins, antibodies, antigen chaperones, etc. The genes don't just stay in the cells as your post implies. The key advantage to electroporation is localized expression and safety mitigation. The expressed genes would then work either directly or indirectly on their targets through multiple pathways.
To drive a significant abscopal effect and immune response to cancer tumor cells, you would need recognition of neoantigens. Systemically administered checkpoint inhibitors are ultimately delivered to locations all over the body. This route of administration not only leads to severe toxicities when used in combination with other checkpoint inhibitors, but the effect is non-localized. In theory, or at least in my mind, electroporating checkpoint inhibitors would drive more significant localized tumor regressions in a shorter amount of time than systemic injections. In addition, you would see far fewer severe adverse events versus combination checkpoint inhibitors administered systemically. Electroporating an anti-pd-1, anti-ctla-4, etc monoclonal antibody (checkpoint inhibitor) with IL-12/GP96/OX40L would drive a profound immune response and abscopal effect because greater numbers of neoantigens would initially become exposed in the context of an inflamed tumor microenvironment. Metastatic lesions would then be subject to TIL with tumor specific neoantigens. There would theoretically still be a need for systemic applications of checkpoint inhibitors in some metastatic situations, but the electroporation of checkpoint inhibitor genes would substantially eliminate systemically delivered checkpoint inhibitors.
Electroporating DNA for checkpoint inhibitors with IL-12, GP96, and OX40L would 1) speed up neoantigen release and presentation to naive t-cells; 2) provide robust and continuous localized expression for perhaps up to a couple weeks; 3) lead to a profound abscopal effect and important innate immunity; and 4) provide a safer alternative to repetitive systemic checkpoint inhibitor use.
These are only my thoughts.
I tend to engage in a lot of thought experiments...
Absolutely no one is talking about electroporating checkpoint inhibitors, as they are administered systemically. For metastatic diseases, this wide administration makes a lot of sense, as tumors are found in more than one place in the body.
But what were to happen if you were to electroporate a combination of genes including IL-12 and GP96/OX40L with checkpoint inhibitor(s)?
In non-metastatic solid tumors, I think complimentary pathways would be triggered to allow complete tumor regressions. This would theoretically benefit patients with both resectable and non-resectable tumors. In patients who would normally have tumors surgically removed, you could build immunity to tumor associated antigens, thus preventing recurrences. You tend to see maintenance chemo therapy in patients with surgically removed tumors;this combination EP approach would replace the chemos and would be performed prior to hypothetical surgical removal. I even think surgery will ultimately become unnecessary in most patients - that is how effective I think a combination EP version of IL-12/GP96/OX40L/checkpoint inhibitors would prove to be. I think non-resectable tumors will be dealt the same death blow, leading to long term immunity and recurrence free outcomes.
I even see a situation where the same EP combination could be used in metastatic cancers. I think an electroporated combination of IL-12, GP96/OX40L, and checkpoint inhibitor(s) would serve to immediately annihilate a solid tumor, and using the OX40L co-stimulatory pathway, you would observe significant polyclonal expansion of activated and tumor specific CD8 tcells. The resulting abscopal effect would then serve to prime metastatic tumors for systemic checkpoint inhibitor use.
I seriously believe checkpoint inhibitor genes can be electroporated and expressed intratumorally with other complimentary genes like those I listed. There would still be a reason to use systemic anti-pd-1, anti-ctla-4, and other checkpoint inhibitors in metastatic disease; however, an electroporated version of those genes would become the more universal application.
Obviously, this is what I would personally pursue, not necessarily what Oncosec is going to do. I see substantial synergy between the combination I just mentioned. I can go into great detail about the pathways for each gene element, but I will save that for another post.
On a personal note, I lost my mother 10 years ago from an ovarian adenocarcinoma that had recurred - she had just celebrated her 45th birthday. She had her tumor surgically removed and went into remission for about a year. Then it came back with a vengeance, spreading to her lymph nodes and ultimately taking her life. The chemotherapies, I believe, destroyed her immune system and prevented any chance of her developing an immunity to cancer antigens.
If we can increase and unleash more tumor infiltrating lymphocytes using an intratumoral electroporation of combination with anti-pd-1, anti-ctla-4, etc checkpoint inhibitors, then we will probably see much greater response rates with improved progression free survival and overall survival in metastatic solid tumors.
If my thought experiment proves to be correct, then Oncosec will be leading a revolution in cancer treatment. There is simply no way I can overstate the significance of achieving an electroporated version of checkpoint inhibitors.
I have been thinking...
What happens when you introduce an electroporated genetic version of a checkpoint inhibitor like anti-pd-1 in a non-metastatic solid tumor?
There is excitement around IDO inhibitors right now (e.g. see Incyte's epacadostat), especially when they are used in combination with other checkpoint inhibitors.
For example, see Questions Remain About Immunotherapy in Melanoma - http://www.curetoday.com/articles/questions-remain-about-immunotherapy-in-melanoma?p=1.
Here is a little bit of what Jason Luke has to say:
"We are very excited about the idea that combination strategies might double down on T-cell inflammation where it is present. Our research suggests that between about 50 percent to 70 percent of patients with advanced melanoma have active inflammation in their tumor microenvironment, which we think is the rationale for why PD-1 antibodies are so effective. Along that same sort of approach is the addition of other tumor microenvironment factors or inhibitors, such as the IDO pathway, which also looks quite exciting."
How do IDO inhibitors differ from other types of immunotherapies?
This again goes to the concept that some patients have an immune infiltrate in their tumor. When that is present, we see that the T cells drive an inflammatory phenotype in which the tumor cells react to the immune cells that are in the tumor microenvironment, upregulating certain molecules—one of them obviously being PD-L1, the important one for PD-1 antibodies."
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The observations that I have made with the ECHO 202 phase 1 trial testing epacadostat with pembrolizumab, suggests to me that an IDO inhibitor combination will ultimately be on par with combination T-vec plus pembrolizumab and yervoy plus opdivo. All of these combinations seem to hover around 58% ORR for metastatic melanoma in all-comer trials; it's actually quite interesting to see the consistent response rates.
Jason Luke's comments confirm my suspicion that tumor cells adapt to immune cell pd-1 phenotype upregulation during inflammation by upregulating their own pd-l1. And what pathway leads to significant inflammation? Yep, interferon gamma, a byproduct of IL-12.
Also, Jason's excitement over IDO inhibitors is something to keep in perspective when we try to extrapolate the upcoming phase II EP IL-12/pembro combination data. Like I have said before, technically speaking, the biomarker that is being used and developed by UCSF investigators is an exploratory biomarker. Despite it not being a validated biomarker, I think it is absolutely predictive of response/non-response in metastatic melanoma; it simply requires more validation from others. If we see responses in the upcoming data release for ONCS's/UCSF's EP IL-12/pembro phase II combination trial - presented as a late-breaking oral poster - it is my opinion that EP IL-12 is significantly driving pd-1/ctla-4-positive TIL phenotype, thus leading to the responses. From a statistical perspective, the likelihood of any responses occurring in the trial due solely to pembrolizumab is almost infinitesimal based on the "discovery" and "validation" cohort data.