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This is what I like to see - finally, a US patent application for gene delivery optimization. From what I’ve observed in early data, especially with Merkel Cell Carcinoma, some solid cancer tumors are more challenging to electroporate than others. This ought to help quite a bit with transfection and expression of encoded proteins like IL-12.
https://patentscope.wipo.int/search/en/detail.jsf?docId=US241445002&tab=NATIONALBIBLIO&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=FP%3A%28Oncosec%29&recNum=1&maxRec=31
I immerse myself in journal publications to keep myself current.
To keep this post relevant to Oncosec, I've included several publications that ought to be relevant to their new multigene construct. I think "Spark", their new multigene product, will demonstrate improvements to IL-12 transfection efficiency, downregulation of PD-1 checkpoints on T cells, better trafficking of T cells to the tumor microenvironment, and improved T cell activation.
If the "licensing" model is correct for anti-PD-1 therapy, then direct, protracted and adequate expression of IL-12 in the TME will lead to significantly lowered PD-1 on T cells. I am pretty confident that rescuing exhausted T cells is possible without anti-PD-1 checkpoint inhibitors. It can be accomplished through adequate expression of local IL-12 through the upregulation of T-bet (induced by interferon gamma).
Of course, IL-12 also triggers interferon gamma production. This improves MHC I and II cancer antigen presentation. We should be seeing improvements in interferon gamma levels and antigen presentation following local administration of Spark.
Very few people I gather actually understand the implications of this first multigene product and how simple improvements to IL-12 production (through a new plasmid construct) will have major downstream effects, including downregulation of immune checkpoints.
Here are some published data to back up what I'm saying and to let everyone know that I'm not just pulling this from you know where...
IL-12 Effect on PD-1 Expression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720703/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342548/
http://cancerres.aacrjournals.org/content/76/21/6266
http://www.jimmunol.org/content/186/5/3093
http://www.mdpi.com/2072-6694/10/12/498/pdf
https://www.nature.com/articles/s41434-018-0044-5
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003208
https://www.ncbi.nlm.nih.gov/pubmed/30552459
https://jitc.biomedcentral.com/articles/10.1186/2051-1426-2-S3-P10
https://www.cell.com/immunity/fulltext/S1074-7613(18)30439-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1074761318304394%3Fshowall%3Dtrue
IL-12 Upregulates T-bet Via STAT4-Interferon gamma-STAT1 Pathway
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003208
https://www.ncbi.nlm.nih.gov/pubmed/17114419
https://www.ncbi.nlm.nih.gov/pubmed/16220539
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774174/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768040/
https://www.sciencedirect.com/science/article/pii/S1074761312004177
https://www.sciencedirect.com/science/article/pii/S0954611106005075
http://www.medsci.org/v14p0977.htm
https://iai.asm.org/content/75/4/1738
https://www.ncbi.nlm.nih.gov/pubmed/12893768
http://www.bioscirep.org/content/38/3/BSR20171420
https://journals.lww.com/transplantjournal/Fulltext/2011/01150/Treatment_With_Interleukin_12_23p40_Antibody.6.aspx
http://rbmb.net/article-1-115-en.pdf
T-bet Regulates PD-1 Expression on T Cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112830/
https://www.nature.com/articles/ni.2046
http://cancerres.aacrjournals.org/content/79/4_Supplement/P4-06-22
http://www.jimmunol.org/content/jimmunol/196/6/2431.full.pdf
https://www.cell.com/immunity/pdf/S1074-7613(16)30005-X.pdf
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004251
http://tcr.amegroups.com/article/view/20796
https://jvi.asm.org/content/90/19/8934
https://www.cellmolbiol.org/index.php/CMB/article/view/2455
https://www.hindawi.com/journals/jir/2016/8941260/
CXCL9 Recruits T Cells to the Tumor Microenvironment
http://www.jimmunol.org/content/196/1_Supplement/212.1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4305179/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885704/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119981/
https://www.nature.com/articles/bjc2016172
https://www.tandfonline.com/doi/full/10.4161/onci.25752
https://www.researchgate.net/figure/CXCL9-and-CXCL10-promote-the-migration-of-antigen-specific-T-cells-in-the-absence-of-Type_fig3_316358401
http://ascopubs.org/doi/abs/10.1200/jco.2015.33.3_suppl.627
Membrane-Bound anti-CD3 Provides Signal 1 for T Cell Activation
http://www.jimmunol.org/content/jimmunol/163/7/3948.full.pdf
https://www.nrcresearchpress.com/doi/10.1139/O07-013#.XI7tP63My9s
https://www.ncbi.nlm.nih.gov/pubmed/10694815
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502409/
Imagine you’re Merck or BMS. Sales of your anti-PD-1 drugs (Keytruda and Opdivo) exceed $8b and $5b, respectively, each year. And sales are growing rapidly yoy. Imagine what would happen to your share price if a company like Oncosec achieves the unthinkable: priming in situ immune responses for solid tumors while simultaneously negating the need for anti-PD-1 therapy.
The problem with Oncosec’s current IRES-based plasmid construct and electroporation voltage parameters is that transfection is not optimal, nor is IL-12 expression. If you don’t see adequate IL-12 levels being expressed intratumorally, odds are pretty good that you also won’t observe elevated levels of interferon gamma (and subsequent expression of STAT 1 genes); you won’t observe high T-bet levels, but higher Eomes and more T cell exhaustion; greater Treg ratios; poor tumor antigen presentation; and fewer chemokines that draw T cells into the TME.
I think “Spark”, the new multigene product, will undoubtedly resolve these issues and effectively reduce or completely eliminate the need for anti-PD-1 agents.
Oncosec has demonstrated that their p2a-linked plasmid construct is able to downregulate PD-1 checkpoint molecules without any checkpoint inhibitor. The protracted intratumoral IL-12 concentration that is produced by the cancer cells triggers the release of T-bet by the tumor infiltrating lymphocytes. There is an inverse relationship between T-bet and PD-1 molecules: the more T-bet you have the less PD-1 is expressed on T cells.
This observation has been confirmed in other studies as well.
IL-12 is the third activation signal for T cells. It not only leads to interferon gamma release, but it downregulates PD-1, CTLA-4, TIM3, etc.
I think this first multigene product, which encodes an anti-CD3 antibody, will improve T cell activation, contribute to in situ expansion of T cells, and lead to the downregulation of checkpoints without a single checkpoint inhibitor needed.
I think it’s a combination of patent protection (many applications not issued yet); people misinterpreting data required to support approval (I suspect conditional approvals requiring confirmatory trials aren’t on peoples’ minds); a failure by investors to understand IO and what is required to activate T cells, how to overcome immune checkpoints without actually using checkpoint inhibitors, how to improve cancer antigen presentation in situ, and what’s required to upregulate MHC Class I and II; and a complete misread in how versatile Oncosec’s multigene platform can be.
It is now crystal clear that checkpoint inhibitors are only part of the solution for solid cancers. To improve efficacy you need to use combination therapies. But systemic administration would be far too toxic. Oncosec’s approach takes advantage of a tumor’s full repertoire of cancer antigens by priming T cells in the TME - that is an enormous advantage! And it is arguably the safest method to administer combination therapies. DNA-encoded genes that get expressed as cytokines, antibodies, antigens etc following electroporation of plasmids aren’t transiently produced like mRNA or what’s observed with systemic administrations of checkpoint inhibitors; they are manufactured by cells in a protracted manner. This slows down the retreat of antigen presentation and chemokines, delays Treg infiltration while CD8 cells accumulate intratumorally, and armors T cells by downregulating checkpoint molecules like PD-1, CTLA-4, etc. for an extended period of time.
Please elaborate...
Funny how no one is catching on yet that Oncosec will be presenting data on the efficacy of an encoded monoclonal antibody (anti-CD3).
Getting anti-PD1 - which is another monoclonal antibody - nonresponders to respond in many solid tumor cancers is going to require combinations. But the problem with systemic administration are the toxicities. That is why intratumoral administration is going to be essential moving forward with combinations. Oncosec’s platform is flexible and they are demonstrating the ability to encode multiple genes on single plasmids. And they just might have an applicator that can reach even visceral lesions in a very direct fashion.
Also, recent IL-12 studies are showing how the cytokine provides the ‘license’ required to downregulate PD1 (and other checkpoints) on immune cells following anti-PD1 therapy. That, my friends, should be enough to value this company in the billions already if it is true. In other words, why use an anti-PD1 if you can simply downregulate PD1 molecules directly with IL-12. I think the p2a-linked plasmid structure is capable of accomplishing such a feat.
This company has the potential to be disruptive, no doubt about it.
He has a history of glossing over the details, not necessarily biased.
Several points not discussed by the author:
1. Oncosec’s enrolled patient population consists of confirmed anti-PD-1 non-responders in the PISCES trial.
2. The PISCES trial has independent reviewers who confirm or deny response data.
3. The duration of responses for the TAVO/pembrolizumab combo have been remarkable. No other combo under investigation comes close! There are many recurrences in the Idera trial data set. The biggest problem, in my opinion, is that an anti-PD-1 isn’t being used in the Idera trial.
4. TAVO/pembro combo has consistently shown deepening responses over time, i.e. partial responders converting to complete responders.
Also, I think 20% response rate is actually quite reasonable in this patient population. Response durations should also factor in to a provisional approval that requires a confirmatory phase III trial.
The ISR is pretty favorable for claim 1.
I have looked at the expression data for this first construct and genetic sequence and it looks like a significant improvement in IL-12 expression over the current IRES plasmid used in TAVO trials. In addition, the first claim includes encoded flt3l, which I strongly believe will expand mature dendritic cell populations intratumorally and improve signal 2 (co-stimulation) by increasing CD80 and CD86 on APCs, thus helping to overcome CTLA-4 on Tregs.
This PIM sequence also includes a common cancer antigen, NY-ESO-1. While the antigen by itself will facilitate vaccination against the antigen found in cancer cells, I think it will accomplish a couple additional things. First, because it is expressed with flt3l, it will help dendritic cells reach maturation, expand, and improve T cell activation intratumorally. This activation of CD4 and CD8 T cells, receiving the third signal through local IL-12 production, will contribute to increased interferon gamma. Once you improve interferon gamma levels intratumorally, usually you observe improvements in MHC I and II expression. This ultimately facilitates recognition of the cancer cells.
Second, the addition of the NY-ESO-1 to the plasmid construct helps with monitoring the immune response.
In other words, this PIM product helps to achieve signals 1-3 for T cell activation, and should improve MHC I and II expression intratumorally.
There are no products or platforms currently being tested, at least to my knowledge, that achieve all of these things. This would be a protracted intratumoral effect. Moreover, the electroporation procedure will inevitably release additional neoantigens intratumorally, thus serving as a highly personalized in situ vaccine strategy.
These TNBC patients received a single cycle of EP encoded IL-12. The trial was not designed to test overall responses. It was intended to investigate immune responses, safety and bio distribution of IL-12. If a patient goes off protocol and immediately on to an anti-PD-1, then there might be interesting tidbits. But, my point is that this small trial was in no way intended to report response rates. In my opinion, the TIL data are far more important anyhow.
These patients received just a single cycle of TAVO per protocol, not a full regimen. There may be others - like the two who went straight to pembro and responded - who went off protocol, but I wouldn't count on it. The point of OMS140 was to view immunologic responses with a single cycle. I don't think they will look at BORR for OMS140.
The current TAVO plasmid construct containing just IL-12, along with the unimproved electroporation device, have their limitations. That doesn’t mean that the current TAVO IL-12 plasmid construct and EP device won’t work for some patients; it just means that there are opportunities for improvement on the plasmid construct, the encoded genes and transfection efficiency. The Merkel Cell trial data show that IL-12 expression using the first gen EP device and plasmid construct is not always good, perhaps due to tumor tissue heterogeneity and/or voltage parameters. I think adequate IL-12 expression was observed in something like 75% of those patients. That begs the question regarding transfection efficiency in the melanoma trials. However, observing 20%-30% durable responses in refractory anti-pd-1 patients with advanced melanoma is superior to anything else currently reported in clinical trials including Dynavax’s SD101. The TAVO plus pembro combo has demonstrated great PFS, DOR and safety as well.
The intratumoral administration of encoded IL-12 is a rational approach when combined with electroporation. The electroporation procedure by itself contributes to tumor antigen release. This is extremely important for adaptive immunity. Expressed IL-12 that originates from the encoded plasmid activates NK cells, which then start producing IFNg, CCL5 (a chemokine that attracts dendritic cells), FLT3 ligand and other chemokines. The FLT3 ligand then expands the dendritic cell population, thus improving antigen presentation to CD4 and CD8 T cells. Unfortunately, Tregs with their CTLA-4 can control antigen presentation and priming by outcompeting CD80 and CD86 on dendritic cells. This is why adequate IL-12 expression is so important intratumorally. If transfection is poor, then you won’t see much improvement in NK cell activation and expansion, and antigen presentation/priming will be insignificant. To overcome this priming hurdle, I believe several things can be accomplished without dramatically modifying the company’s electroporation platform:
1. Make improvements to the EP device and voltage parameters - check.
2. Improve the plasmid construct to ensure greater transfection - check.
3. Encode FLT3 ligand with IL-12 to overwhelm CTLA-4 on Tregs with high densities of dendritic cells - unknown if this is being actively pursued in the next product although preclinical work demonstrates that they have thought of it; or
4. Encode anti-CTLA-4 with IL-12 to eliminate the immune suppressive effects caused by CTLA-4 - no evidence of Oncosec pursuing this approach.
5. Encode anti-PD-L1 with IL-12 and FLT3 ligand (or anti-CTLA-4) - intratumoral administration of anti-PD-L1 affimers has been mentioned, but it is unknown whether or not this is really in the cards.
Tregs by themselves aren’t necessarily predictive of response. I think we need to specifically focus on their CTLA-4 expression and densities in locations where T cell activation/priming occurs, e.g. intratumoral, draining lymph nodes, and spleen. It is the CTLA-4 on Tregs, not exhausted CD8 T cells, that are preventing most of the priming of effector cells. They are hijacking CD80 and CD86 on conventional dendritic cells, thus preventing co-stimulation with CD28 on T cells.
I think this can be overcome in several ways. First, intratumoral electroporated IL-12 with FLT3 ligand or the combination with highly focused radiotherapy of the primary tumor. The goal would be to expose all tumor antigens to a large pool of antigen presenting cells. This would help to overwhelm CTLA-4 expression on Tregs and allow more priming of effector T cells.
Second, you could also administer antiCTLA-4 therapy intratumorally or in lymphatic tissue where the Tregs do their hijacking. I think it would still be essential to get the tumor antigens released, therefore electroporation or targeted radiotherapy would be necessary. Adding IL-12 and FLT3L would probably result in dramatic immune responses and successful tumor regression.
There is zero doubt in my mind that Tregs need to be addressed in anti-pd-1 refractory patients. You simply won’t get priming if CD80 and CD86 are missing from dendritic cells. Antigen presentation also requires the machinery (dendritic cells) and availability of tumor specific antigens. And you won’t get tumor antigens released unless the cancer cells die. That is why electroporation or highly targeted radiotherapy is going to be key.
Tregs help to protect our internal organs from autoimmunity. They help to maintain homeostasis. But imagine cancer cells developing in that immunosuppressive environment... you don’t have much of a chance to develop adaptive immunity. I first thought about the role of Tregs when my wife developed ovarian clear cell carcinoma at 39 years old. We were pregnant at the time. She had endometriosis apparently for quite a long time. Chronic inflammation can damage cells. Your body’s inflammatory processes retreat during pregnancy and you begin to observe higher frequencies of Tregs. In the context of this new immunosuppressive environment, my wife’s cancer cells spread and her lesions grew adjacent to the endometriosis. Tregs were in control protecting our baby from autoimmunity in the uterus while simultaneously facilitating cancer growth. My wife ultimately had her lesions and one ovary removed and has been in remission following chemotherapy.
I don’t think there is a point of no return with the right combination of immunotherapy. It comes down to maximizing tumor antigen presentation and preventing CTLA-4 hijacking of the antigen presentation machinery. Once that is achieved, then you will witness effector T cell activation and sustained local and abscopal responses. The problem with so many companies developing combo drugs is that they aren’t really focusing on the priming phase in the immunity cycle.
No, Dr. Daud's assessment regarding clinically meaningful responses in this patient population appears to be spot on. Success has a benchmark, and it is below 20%. Both Oncosec and DVAX are leading this race toward rescuing refractory anti-pd-1 patients. This is not an all comers or treatment naive patient population. It is a subset of advanced melanoma patients who have essentially no options remaining after failure on pembro or nivo.
Based on prior observations, the reported PISCES patients will more than likely see deepening responses over time. Just my opinion.
The stats sound about right. Very similar responses were observed in the predicted nonresponder trial for actual anti-pd-1 failures (20%). As Dr. Daud pointed out, this patient population has essentially no other options after failure on anti-pd-1. We know that approximately 10% observe some responses on chemo after anti-pd-1 failures, but those responses are rarely durable. It also sounds like these patients had very few CD8-positive T cells at baseline, just like those patients who progressed in the predicted nonresponder trial.
Even though 20% doesn't sound like much, I think the company is making a sound decision to continue pursuing the approval in anti-pd-1 refractory advanced melanoma patients. Again, these patients have no options after failure on anti-pd-1 treatment.
The market's reaction is puzzling. This isn't a treatment naive or all-comers trial, and I don't think approval odds have changed much. Of course we would all love to see higher response rates, but it really isn't necessary (for approval purposes) to achieve 50% BORR or whatever in these anti-pd-1 refractory patients. Unfortunately, some individuals misinterpreted the earlier trial's data and lumped all patients with prior checkpoint inhibitor therapies together to arrive at a high BORR. Some basic analysis would have resulted in the discovery that only 2/10 patients in the trial were actual anti-pd-1 failures who responded.
I am also anticipating responses somewhere around 30% for the preliminary analysis. DVAX's BORR at 21.4% is probably the most promising at the moment for actual nonresponders (to anti-pd-1) with advanced melanoma. We'll see what tomorrow brings.
The phase 1 TNBC study was also only designed to detect immunological responses after a single cycle of treatment on TAVO. The fact that 2/2 patients who went straight on to anti-pd-1 treatment immediately after TAVO responded is very, very intriguing given that only 5% of TNBC patients ever respond to anti-pd-1 therapy.
Right, since this is an ATM deal. I'm not certain how the market will value success in the PISCES P2b trial considering we don't have any pricing estimates at this point from the company. I remember numbers being thrown around in the past, but who really knows. We have some idea how many advanced melanoma patients in the US fail anti-pd-1 treatments each year (somewhere around 10,000). And then there's Australia.
One could look at success in the PISCES trial as an indicator of what's possible in other solid tumor cancers as well. This may also impact the company's valuation. There is such an enormous unmet need for advanced solid cancers. In the US, for example, I believe there are approximately 40k-50k new cases of TNBC diagnosed each year and only around 5% respond to anti-pd-1 therapy. Would Oncosec's current TNBC trial be factored in to the company's valuation given hypothetical success in the PISCES P2b trial? We already have a glimpse of what happens when anti-pd-1 treatments follow a single treatment cycle of ImmunoPulse IL-12 in TNBC - responses in both patients who went straight to anti-pd-1 treatment. There is mounting evidence now that the ImmunoPulse platform works across multiple solid cancers.
Very smart move in my opinion. Dilutive? Yes. But the percentage will ultimately depend on market valuation. How valuable is a product that may rescue anti-pd-1 nonresponders in advanced metastatic melanoma and perhaps triple negative breast cancer? Only approximately 5% of advanced TNBC patients observe responses to anti-pd-1 treatments. Both are significant unmet needs, no doubt about it. There are basically no other options for these patients once they fail anti-pd-1 treatments. This reminds me of the early days with checkpoint inhibitors - the momentum will grow pretty quick in my opinion.
Some summarized thoughts on Oncosec's IL-12 TAVO program, IL-12 in general and Oncosec's electroporation platform.
Electroporation using empty vectors - that's correct, not encoding anything - results in the release of tumor-associated antigens in the tumor microenvironment (TME). These antigens get picked up by antigen presenting cells, e.g., dendritic cells, which then present to naive t cells to initiate priming. Sometimes this priming occurs locally in the TME, in the spleen, and in tumor draining lymph nodes. Mature antigen-loaded dendritic cells release interleukin 12. This might account for some of the transient immune responses observed in preclinical models using empty vectors. IL-12 concentrations are simply too low to contribute to much of a significant adaptive immune response when electroporating an empty vector, but the point is that electroporation by itself triggers the release of antigens in the TME.
The production of IL-12 that is encoded on Oncosec's plasmid constructs produces a protracted release of the cytokine in the TME. When the IL-12 is adequately expressed intratumorally, it appears to trigger the activation and expansion of natural killer (NK) cells. This activation results in the production of CCL5, FLT3 ligand, interferon gamma and additional chemokines. CCL5 attracts dendritic cells, thus improving tumor antigen presentation locally. Through cross talk - observations have been made elsewhere that show clustering of NK cells and dendritic cells - more IL-12 is released in the immediate proximity of NK cells, thus leading to more CCL5, interferon gamma, FLT3 ligand, and chemokines. It's essentially a positive feedback loop. The release of FLT3 ligand, a well known growth factor for dendritic cells, results in the expansion of antigen presentation machinery.
As IL-12 helps to activate and expand the NK cell population, after some time passes and IL-12 is at lower concentrations, a portion of these cells start upregulating PD-1 on their surface. At the point from which they exhibit an exhausted phenotype, an intratumoral administration of anti-PD-1 or its ligand would help to rescue the innate cells along with their release of CCL5, interferon gamma, FLT3 ligand, etc. It's possible that Oncosec has already thought of this if you look at the collaboration between them and Avacta to develop intratumorally delivered encoded affimers, specifically anti-PD-L1.
In the context of IL-12, more T cells take on an effector phenotype and their exhaustion, despite being challenged, is delayed. In addition, perhaps through the expression of BLIMP-1 and T-bet following IL-12 exposure, CD8 T cells lose their propensity to upregulate PD-1. These activated effector T cells relocate throughout the body to "kill" tumor cells containing matching antigens. This is essentially the abscopal effect that we observe where untreated lesions are reduced or eliminated over time. Some of these cells become exhausted due to chronic antigen stimulation whereas others become memory effector cells. Assuming adequate levels of IL-12 are expressed intratumorally and in the context of naive T cells, we should be observing sustained responses in untreated lesions. This might negate the need for systemic delivery of an anti-PD-1 agent like pembrolizumab or nivolumab due to the sustained low level of PD-1 surface expression on effector T cells. I think the key would be to maximize and sustain IL-12 delivery in the context of naive T cells to ensure expression of BLIMP-1 and T-bet. This would likely lead to low levels of PD-1 surface expression on CD8 T cells (owing to the knockout of NFATC1) in untreated TMEs. We have observed these effector T cells in both the spleen and untreated tumors of mice as well as humans now. Sufficient intratumoral levels of IL-12, again, contribute to NK cell activation and expansion, consequently leading to improvements in antigen presentation, vis-a-vis FLT3 ligand expression originating from NK cells. If there is an adequate level of dendritic cell-derived IL-12 expression in lymphatic tissue - remember, FLT3 ligand expands dendritic cell populations which then mobilize to lymphatic tissue - you should observe improvements in T-bet and BLIMP-1 expression, fewer exhausted CD8 T cells and higher percentages of effector T cells in the periphery.
T-regs, which constitutively express CTLA-4, appear to hijack CD80 and CD86 on antigen presenting cells. This results in handicapped co-stimulation with CD28 on T cells. As a result, effector cells cannot proliferate. To overcome this obstacle, one solution could be to simply expand dendritic cells through intratumoral delivery of encoded FLT3 ligand on multigene plasmid constructs. This would essentially improve the ratio of dendritic cells to T-regs without requiring a CTLA-4 antibody. The dendritic cells would numerically overwhelm CTLA-4.
A p2a-linked multigene plasmid construct containing encoded IL-12 and FLT3 ligand, when electroporated intratumorally in low voltage conditions, could be a nail in the coffin for many solid tumor cancers including those that are advanced. The electroporation procedure by itself potentially exposes ALL tumor antigens. This provides the key ingredients for in-situ vaccination and adaptive long term immunity. The approach wouldn't require adaptive T cell transfer/expansion ex vivo, nor would it require biopsies or personalized/engineered vaccines that could be cost prohibitive, dangerous, slow to manufacture and ineffective against all tumor antigens. Oncosec's electroporated IL-12 TAVO approach is a single off-the-shelf product, the most personalized medicine I can imagine for solid tumors. The p2a-linked plasmid construct in low voltage conditions might even eliminate or reduce the need for systemic administration of checkpoint inhibitors, specifically anti-PD-1 if it results in sustained low levels of PD-1 expression on effector cells in the periphery.
Right, they could have stopped the trial early due to futility and focus energy and limited resources elsewhere, e.g. developing their next generation plasmid construct with the p2a-linked design. They do appear to be confident right now in what they are observing.
Companies that don't have much faith in their advanced clinical program(s) tend to focus on their early development programs. None of that seems to be the case with Oncosec. In fact, it perturbs me that they haven't accelerated their next generation plasmid design or discuss it much, because I think its potential is enormous. But anyway, the bottom line is that they are behaving in a manner that shows a lot of confidence in IL-12 TAVO.
I would be extremely surprised to see 50% responses in this patient population, although several patient characteristics could skew the data and result in such a high percentage:
1. Age - older patients tend to have fewer Tregs.
2. Tumor sizes.
3. The number of TIL at baseline for the combo. Remember, the predicted non-responder trial intentionally selected patients who were immunologically frozen, i.e. very few CD8 positive T cells with an exhausted phenotype.
I have not yet observed any combination with an anti-PD-1 that results in anything close to 30% in anti-PD-1 nonresponders in advanced metastatic melanoma, or any solid tumor cancers for that matter.
From my own experience, a poster presentation typically holds more information and data than an oral one. You aren't restricted to time parameters that limit the amount of content. If you uphold a high standard for scientific integrity and desire to impress the professionals in your field, it is always best to show the details that could get lost in an oral presentation. Just my thoughts.
Given the slightly less restrictive enrollment criteria in the PISCES trial, i.e. the subjects don't have to be so immunologically frozen, I tend to think the responses will be slightly better than the "predicted non-responder" trial.
Also, keep in mind, the independent central review is blinded! I imagine the response data will be looked upon more favorably knowing there is this additional unbiased review.
This is, I believe, an update to the monotherapy data - announced a few weeks ago.
This publication is quite interesting for a multitude of reasons, but this is the main one:
It is the first time - quite unexpectedly from what I gather - that the abscopal effect generated by intratumoral administration of encoded IL-12 genes noticeably lacked exhaustion markers in tumor infiltrating lymphocytes found in untreated tumors. Typically this only happens during acute situations. If the new p2a-linked plasmid construct coupled with modified electroporation parameters has something to do with the significant improvements in intratumoral IL-12 expression and armoring of effector cells, then this is definitely a big deal. Obviously, just like everything else in immunology, the observations would need to translate into humans. But if it does, it could potentially negate the need for systemic anti-pd-1 agents!
Characterization of Abscopal Effects of Intratumoral Electroporation-Mediated IL-12 Gene Therapy
Anandaroop Mukhopadhyay, Jocelyn Wright, Shawna Shirley, David A. Canton, Christoph Burkart, Richard J. Connolly, Jean S. Campbell & Robert H. Pierce
Gene Therapy (2018)
https://www.nature.com/articles/s41434-018-0044-5
Abstract:
The biomarker data are essential for TAVO's development. When you look at the IL-12 monotherapy data, it is interesting that Natural Killer cells, the innate immune response, is more immediately responsive to intratumoral administration of EP TAVO than adaptive immunity. The adaptive immune response, I believe, takes time to reach critical density in the TME.
I would like to know more about the FOXP3 densities and proximities to CD8 observed. In case you haven't noticed, I am a firm believer that CTLA-4 on the FOXP3 Tregs are preventing T cell activation.
Would TAVO be more successful if it could be expressed more productively in the TME or TDL? Is tissue heterogeneity preventing adequate expression of IL-12? Would improvements to the plasmid construct lead to better expression, thus improvements in NK cell activation/expansion and FLT3L production? If so, then a program solely focused on improving IL-12 expression would make complete sense.
The slide you are referencing is exclusive to those patients who observed responses to the TAVO+Pembro combination; it omits patients who were previously treated with an anti-pd-1 agent and failed the TAVO+Pembro combo. I believe a total of 10 patients were actual anti-pd-1 failures prior to the TAVO+Pembro combo. This suggests a response rate of 20%. I wouldn't lump prior anti-ctla-4 monotherapy and Tvec failures just because they are immunotherapies - they have completely different immunological mechanics. Moreover, PISCES is exclusive to anti-pd-1 failures.
Something we have to remember though with the patient population in OMS-I102... these patients were immunologically cold at baseline, meaning relatively few CD8 T cells. Not all anti-pd-1 non-responders will be so frozen, immunologically speaking, at baseline. In other words, the odds of response success in the PISCES trial should be better than the OMS-I102 predicted non-responder trial.
Thanks for your post Danger.
I don't think Oncosec will abandon the EP IT pIL-12 "TAVO" program; it definitely appears to work well in some patients in combination with an anti-PD-1 agent. The problem: it's not yet clear which patients will benefit most from the combination who have failed prior anti-PD-1 treatment - this, I think, is where Dr. Lo's analyses will be very useful moving forward. It's clear that at least some anti-PD-1 nonresponders will respond to the combination of TAVO and pembrolizumab in metastatic melanoma, but which patients? Patient-specific immune and genetic data are slowly becoming appreciated and utilized in cancer immunotherapy and California research institutions are really taking it seriously.
None of this means the PISCES trial won't be successful, it simply means future trial designs will benefit from data gathered in the PISCES trial.
I'm simply concerned that nobody is aware of the preclinical progress the company has made; it isn't exactly advertised anywhere on the company website or in presentations. The information is buried. It bothers me so much because I absolutely believe their multigene product that contains both encoded FLT3 ligand and improved IL-12 signals (p2a-linked) will be completely disruptive. But why would the company intentionally conceal their preclinical progress?
That guy hasn't gone anywhere. I'm being cautious given the slightly different patient population (i.e. all anti-pd-1 non-responders) we're dealing with in the PISCES trial. I wasn't exactly impressed with the responses in the OMS-I102 Trial for actual anti-pd-1 nonresponders; however, patient selection was based on exhausted CD8 T cell levels and those patients who progressed had little to no detectable levels of these TILs. I don't think the PISCES trial will have so many patients with such low levels of CD8 T cells at baseline, but you just never know.
With that said, I am still very impressed with the PFS and DOR data as well as the depth of response (nearly every patient who responded eventually experienced a complete response). That is quite impressive.
I've been re-reviewing the available data from Oncosec's trials to better understand why some patients are responding to EP pIL-12 in combination with anti-pd-1 agents and others are not. I'm beginning to think that innate immunity (i.e. activation of NK cells) is the most critical immediate effect with EP pIL-12. These NK cells, once activated, "communicate" (through FLT3L) with dendritic cells. If these NK cells aren't already present or are insufficiently activated by IL-12, you probably won't observe an expansion in the number of antigen presenting cells, e.g. dendritic cells, due to insufficient FLT3L expression. Without adequate antigen presentation, CTLA-4 on Tregs can control downstream CTL activation (CD8 T cells, for example). Obviously, the ultimate goal is to generate sufficient numbers of tumor antigen-specific CTL in the tumor microenvironment, but the path to get there requires sufficient antigen presentation. If IL-12 can't do it alone in some patients, then the next best thing would be to bypass NK cell activation and directly produce FLT3L intratumorally or in tumor draining lymph nodes to expand the population of dendritic cells where they are needed most. In my opinion, this would diminish or eliminate local immune suppression caused by CTLA-4 on Tregs.
I believe ONCS is heading down that road - encoding both FLT3L and IL-12 on a single plasmid - with their first multigene product. Unfortunately, that still hasn't been clarified by the company.
The company has a lot confidence in TAVO - no discussion of preclinical work or details on the next product candidates. The pipeline is primarily TAVO plus anti-pd-1 in a few indications. What happens if TAVO isn't as effective as they think in the PISCES trial? Would that bode well for a company with no other product candidates?
I hope the company isn't putting all its eggs in one basket. The preclinical work and patent progress seems to have really stalled out.
They actually used a Lonza 4d system for their electroporation.
I can see the obvious utility of this "breakthrough" in autoimmune diseases. Its use in cancer immunotherapy will be limited to blood cancers and a few solid cancers that don't typically observe many mutations.
To take advantage of solid tumors' full antigenic repertoire, the T cells must be primed and expanded in-situ. No question about it. Programming T cells to recognize specific cancer antigens ex vivo doesn't make sense for cancers that have many different types of mutations. Antigen presentation needs to be maximized where T cells are activated. Doing so in-situ eliminates many steps: tumor sampling, T cell sampling, programming/engineering, T cell expansion, and reintroduction.
This has got to be the most interesting journal article I have seen in quite some time:
https://www.nature.com/articles/s41591-018-0085-8
Published: 25 June 2018, Nature Medicine (2018)
A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments
Kevin C. Barry, Joy Hsu, Miranda L. Broz, Francisco J. Cueto, Mikhail Binnewies, Alexis J. Combes, Amanda E. Nelson, Kimberly Loo, Raj Kumar, Michael D. Rosenblum, Michael D. Alvarado, Denise M. Wolf, Dusan Bogunovic, Nina Bhardwaj, Adil I. Daud, Patrick K. Ha, William R. Ryan, Joshua L. Pollack, Bushra Samad, Saurabh Asthana, Vincent Chan & Matthew F. Krummel
Abstract:
Effector T cell activation occurs in tumor draining lymph nodes. Primary lung cancer could indeed be treated through electroporation if the local lymphatic tissue were targeted. This would likely be the safest and most feasible approach for electroporated plasmid treatments in primary lung cancer.
Obviously I don't know if they would attempt to treat lung cancer patients at this point, but in theory they could.
Great, thanks Wait.
I continue to believe in this company's disruptive potential. In my opinion, there is nothing discouraging in the company's filings, its finances, its data, its researchers, its clinical investigators, its patent applications, its leadership, or its partners.
I would certainly like to learn more about their multigene products, but I'm sure information will be delivered on that front this year. The PIIM construct that includes encoded flt3-ligand and antigen is truly ingenious; this is one way to overwhelm Tregs with mature dendritic cells and allow priming to occur through the expansion of dendritic cell populations. It is essentially a diversion.
The convergence of their key technologies and approaches - tissue adaptive electroporation, deep tissue applicator, intratumoral-administered treatments, multigene plasmid constructs, and improved gene expression - should facilitate cancer antigen-specific immune responses across multiple solid tumor cancers. They may even have the capacity to directly treat most visceral lesions locally using their technology.
The key to anti-PD-1 drug success is having adequate numbers of cancer antigen-specific CD8 T cells intratumorally. And cancer patients won't achieve adequate thresholds if there are too many Tregs preventing immune responses during the priming phase. I am not a medical doctor, but I spend exorbitant amounts of time researching immunotherapy; it has become an obsession. Sometimes, spectators can see more than the players on the field. Medical doctors are the skilled players, but they don't always have an opportunity to scan the entire field at any given moment. And immuno oncology is a rapidly evolving game. If there is one thing I am absolutely sure about, it is that intratumoral Tregs and Tregs in TDLs are preventing immune responses in so many of these patients who are failing anti-PD-1 therapies. Immune privileged sites and organs that require substantial immune tolerance, are locations where cancer, if found, cannot be easily eliminated by anti-PD-1 monotherapy.
http://clincancerres.aacrjournals.org/content/early/2018/06/05/1078-0432.CCR-18-1116.full-text.pdf
Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations
Curtis H. Kugel III, Stephen M. Douglass, Marie R. Webster, Amanpreet Kaur, Qin Liu, Xiangfan Yin, Sarah A. Weiss, Farbod Darvishian, Rami N. Al-Rohil, Abibatou Ndoye, Reeti Behera, Gretchen M. Alicea, Brett L. Ecker, Mitchell Fane, Michael J. Allegrezza, Nikolaos Svoronos, Vinit Kumar, Daniel Y. Wang, Rajasekharan Somasundaram, Siwen Hu-Lieskovan, Alpaslan Ozgun, Meenhard Herlyn, Jose R. Conejo-Garcia, Dmitry Gabrilovich, Erica L. Stone, Theodore S. Nowicki, Jeffrey Sosman, Rajat Rai, Matteo S. Carlino, Georgina V. Long, Richard Marais, Antoni Ribas, Zeynep Eroglu, Michael A. Davies, Bastian Schilling, Dirk Schadendorf, Wei Xu, Ravi K. Amaravadi, Alexander M. Menzies, Jennifer L. McQuade, Douglas B. Johnson, Iman Osman and Ashani T. Weeraratna
Thanks for sharing. There are many things I am looking forward to this year, and this is one of them.