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yes, for the non responders it will be, and it will also be a change in therapy. According to the American Cancer Society:
"Immunotherapy is treatment that uses certain parts of a person’s immune system to fight diseases such as cancer. This can be done in a couple of ways:
• Stimulating your own immune system to work harder or smarter to attack cancer cells
• Giving you immune system components, such as man-made immune system proteins
In the last few decades immunotherapy has become an important part of treating some types of cancer. Newer types of immune treatments are now being studied, and they’ll impact how we treat cancer in the future.
Immunotherapy includes treatments that work in different ways. Some boost the body’s immune system in a very general way. Others help train the immune system to attack cancer cells specifically.
Immunotherapy works better for some types of cancer than for others. It’s used by itself for some of these cancers, but for others it seems to work better when used with other types of treatment."
The definition tells you what the ImmunoPulse platform is aiming for and what DR. Pierce has been working on for many years. I doubt he will start being wrong now. Notice that immunotherapy seems to work better when combined.
this is the link
"Carter underwent surgery for the liver tumor, and was treated with radiation therapy as well as four doses of pembrolizumab, which is sold by Merck as Keytruda."
Soon there won't be the need for radiation, instead EP IL-12 will help Keytruda do the job.
The abstract, IL-15 Augments Antibody-Dependent Cell-Mediated Cytotoxicity of Anticancer Monoclonal Antibodies, will be presented by the Senior Investigator of Head, Cytokine Immunology and Immunotherapy Section at the Center for Cancer Research for the National Cancer Institute, who will have a keynote presentation at PEGS Boston on April 2016. Dr. Waldmann will be speaking on a recent study sponsored by the NCI that focused on Cytokine IL-15, the interleukin Oncosec will soon introduce to the ImmunoPulse platform.
In clinical trials IL-15 increased the number of activated NK cells and monocytes in patients with metastatic malignancy. In a preclinical syngeneic tumor model IL-15 dramatically increased the ADCC efficacy of rituximab in the treatment of the human CD20 expressing murine EL4 leukemia model. IL-15 also augmented efficacy of the combination of anti-CTLA-4 and anti-PD-L1 anti-checkpoint antibodies. These studies support the use of IL-15 in combination with anticancer monoclonal antibodies.
IF data is good: a condition or supposition.
Which means let's not draw to conclusions until data arrives, but in the meantime understand the end results.
What else would you say when there is a study trial underway, which just began and will answer all your inquiries with interim results in 2016.
No it does not, which is a good thing because the adverse events are pretty high and that is exactly what the ImmunoPulse platform will try to help out with, along with better results. I thought I had explained that when I wrote:
A growing number of clinical trials and the results already available underline the strong potential of DNA electroporation which combines both safety and efficiency Immunopulse platform is working on dealing with the adverse events while trying to improve on the amount of responders.
Low-Dose Ipilimumab/Pembrolizumab reduces toxicity in advanced melanoma.
http://www.cancernetwork.com/smr-2015/low-dose-ipilimumab-pembrolizumab-reduces-toxicity-advanced-melanoma
In conclusion, “The combination of pembrolizumab and low-dose ipilimumab is tolerable, and provided an ORR that is comparable to that previously reported for nivolumab and full-dose ipilimumab.” Efficacy, safety, and biomarkers will be further analyzed in a full expansion cohort of 153 patients. However, let’s keep in mind that both combinations of ipilimumab with nivolumab or with ipilimumab have a high rate of AEs.
In Oncosec's combination trial with ImmunoPulse IL-12, pembrolizumab will be administered at 200mg flat dose every 3 weeks, which means that unless every patient weights an average of 100kg, pembrolizumab will be given at higher rates than the ones being used with the ipilimumab/pembrolizumab combination . And if in fact it lessens drastically the adverse events, while improving results with that slight increase in dosage and incorporation of IL-12, there will be no hesitation in moving forward and using the ImmunoPulse platform in a combination that might already be approved using pembrolizumab.
Nivolumab in combination with ipilimumab FDA accelerated approaval’s regardless of adverse reactions.
Among the 140 patients with BRAF V600 wild-type or mutation-positive melanoma who received at least one dose of nivolumab or ipilimumab, serious adverse reactions (62% vs. 39%), adverse reactions leading to permanent discontinuation (43% vs. 11%) or dose delay (47% vs. 22%), and grade 3 or 4 adverse reactions (69% vs. 43%) all occurred more frequently in patients receiving the combination (n= 94) compared with those receiving single-agent ipilimumab (n=46). The most frequent serious adverse reactions in patients receiving the combination were colitis (17%), diarrhea (9%), pyrexia (6%), and pneumonitis (5%). Additional clinically significant immune-mediated adverse reactions included pneumonitis, hepatitis, endocrinopathies, nephritis/renal dysfunction, and rash.
Common adverse reactions (greater than or equal to 20%) in patients receiving nivolumab plus ipilimumab were rash, pruritus, headache, vomiting, and colitis. The most frequent grade 3 and 4 laboratory abnormalities occurring in at least 5% of patients receiving the combination were increased ALT, increased AST, increased lipase, increased amylase, hyponatremia, and lymphopenia.
A growing number of clinical trials and the results already available underline the strong potential of DNA electroporation which combines both safety and efficiency. Immunopulse platform is working on dealing with the adverse events while trying to improve on the amount of responders.
The 16th Multidisciplinary Management of Cancers: A Case-based Approach.
Tumor Board Cases will be presented by faculty, with discussion by a panel of surgical, radiation and medical oncologists from Stanford, UCSF, UC Davis and the practice community. On Friday, March 18, dr. Melinda Telli will present at the Breast Tumor Cases panel and on Sunday, March 20, dr. Adil Daud will present at the Cutaneous Malignancies Tumor Board Cases panel.
At the conclusion of the activity, participants should be able to:
1. Develop multidisciplinary treatment strategies based on national clinical practice guidelines in oncology in order to improve quality of care for cancer patients.
2. Counsel patients on pharmacological and psychiatric strategies to manage pain.
3. Discuss relevant clinical trials with cancer patients and refer appropriately.
4. Appropriately refer cancer patients to palliative care.
PerkinElmer and Oncosec will have a Patient-Selection Biomarker in Immunotherapy.
Cell-based therapy is currently at the forefront of tissue engineering strategies and is expected to dominate the field in the future. A recent study from the University of Hong Kong was aimed to optimize electroporation parameters for the transfection of human dental pulp stem cells, with cellular viability taken into account. Other chemical transfection agents were used for comparison, and their transfection efficiency and relevant cell viability were assessed.
The study compared the transfection of dental pulp stem cells (DPSCs) to a positive control using the commonly utilized chemical transfection reagents Lipofectamine 2000 and FuGene 6. From the results, they were able to obtain a higher transfection efficiency and cell viability with electroporation conditions compared to controls. The highest transfection efficiency (63.81±4.72%) was achieved with 100V, 20msec, one-pulse square-wave condition. Among the chemical transfection groups, FuGene 6 showed the highest cell viability at all tested transfection ratios, while Lipofectamine 2000 showed the highest transfection efficiency (19.23±3.19%) using 1:1 DNA
An increase in various chondrogenic markers was also found when studying mRNA expression in transfected cells. In conclusion, the results of the study demonstrated optimal electroporation and chemical transfection reagent conditions for human DPSCs, and, subsequently, provided proof of concept for expression of a functional gene using those conditions.
Now what does it have to with PerkinElmer you might ask. FuGene 6 Transfection Reagent has been commercially available since 1997 and since that time, its popularity has increased due to its ease of use, minimal to no cytotoxicity, and the high level of transfection in many different cell lines. It is used by PerkinElmer with their Alpha assays involving tagged recombinant proteins, which are transfected into cells. The approach is a preferred one due to the high protein expression levels achieved in transfected cells, and the availability of good anti-tag antibodies.
Many different technologies are available to transfect the expression vectors into cells (Calcium Phosphate, Electroporation, Ballistic Particles, DEAE Dextran, Cationic Matrix, and Lipofection). The lipofection protocol is a relatively simple method that has been used for high throughput screening. FuGENE6 has been observed to work best in the presence of serum and resulting in little or no toxicity. Only until recently results have proven that Electroporation has an advantage over other technologies, and PerkinElmer would probably prefer to use it with their assays.
“The analytical needs of both UCLA and OncoSec are well aligned with our unique technical capabilities,” said Brian Kim, President, Life Sciences & Technology, PerkinElmer. “This project complements our focus on enabling research to reveal the intricacies of immuno-oncologic interactions. Through this work with UCLA and OncoSec, we think we can make a meaningful contribution toward assisting researchers in improving outcomes for patients.”
It is your right as a shareholder to ask such questions, and if propaganda is given, that is information that especially of a biased or misleading nature, it can be held against the company. I am just trying to help you out with your inquiry.
Hmmmmm, I would think that it is because Merck is sponsoring Keytruda to UCSF and not to Oncosec, but in return, a positive result will benefit Oncosec more than Merck.
Don't take my word for it, call Oncosec and ask yourself, then let us know their response.
Merck does not have a role on the content of the lecture other than the fact that Keytruda is given for free to the doctor who is presenting the lecture. In it he mentions the combination trial which he is in charge of. In case you missed it, I had also mentioned that in the spring of 2015, Vindico Medical Education hosted a number of leading melanoma experts as part of a 2-day international symposium to discuss important advances in Immunotherapy. The monograph, "Updates in Melanoma 2015: Entering a New Therapeutic Era", was created and represents an overview of some of the presentations, focusing on the most recent data on immunotherapy, targeted and intralesional therapies, as well as approaches of combining and sequencing immunotherapeutic and targeted agents. The monograph is what Merck has sponsored in the educational lectures through Vindico.
There is an accredited lecture that is being sponsored by Merck, for medical oncologists, surgical oncologists, dermatologists, oncology nurses, nurse practitioners, physician assistants and other healthcare professionals involved in the treatment of patients with melanoma.
http://www.melanomacme.com/targeted-therapy/2015/09_september/plasmid-il12-electroporation-in-melanoma/cme-information
In the spring of 2015, Vindico Medical Education hosted a number of leading melanoma experts as part of a 2-day international symposium to discuss these important advances. The monograph, "Updates in Melanoma 2015: Entering a New Therapeutic Era", was created and represents an overview of some of the presentations, focusing on the most recent data on immunotherapy, targeted and intralesional therapies, as well as approaches of combining and sequencing immunotherapeutic and targeted agents.
This is what it says about EP IL-12:
Interleukin (IL)-12 is a proinflammatory cytokine that mediates communication between and proliferation of dendritic cells, macrophages, effector T-cells, and natural killer (NK) cells.13 Immunological effects of IL-12 include interferon gamma upregulation, dose-dependent lymphopenia, augmented NK cell cytotoxicity, enhanced T-cell proliferation, and promotion of tumor infiltration with CD8+ T-cells. However, systemic IL-12 produces unacceptable and possibly fatal toxicity. Delivery of concentrated IL-12 intratumorally is based on electroporation, which uses high-intensity electric fields to increase plasma membrane permeability transiently, facilitating transfer of agents into cells. Melanoma tumors are injected with IL-12 plasmid DNA with electroporation-induced incorporation of the DNA into the tumor cells, which then express IL-12. The resulting local proinflammatory process may elicit a successful targeted anti-tumor immune response both locally and systemically.
Overall, preliminary data from intratumoral electroporation of IL-12 demonstrate monotherapy activity in advanced cutaneous and in-transit melanoma, which was safe and well tolerated across multiple treatment cycles. Synergism with other therapies is anticipated, and combination studies are expected to open soon.
IL-12 is a key mediator of communication between DC/Macrophages, Effector T-Cells and NK Cells
Expressing IL-12 will help confine the immune cells and bring the cells in with IL-12 in order to take the breaks off to get an effective immune response. The problem is that it is extremely toxin. However, EP IL-12 helps to get part one of the part two immune response.
“You get inflammation of the tumor, immune cell infiltrating, you get cytokine elaboration and that might be what you really need to synergize with the PD-1 antibody or another immune checkpoint inhibitor.“
And once combined with Teff checkpoints inhibitors like anti-PD1, part two of the immune response will take place by helping the non-responders.
"Other methods of improving response to checkpoint inhibitor therapies could include increasing the T-cell infiltration of tumors through immune-activating antibodies, oncolytic viruses, macrophage inhibitors or targeted therapies", doctor Ribas said.
This is exactly what Dr. Pierce has been saying for years and why he wanted to experiment with EP IL-12. It seems he has been on the right track.
Melanoma CME has a lecture on IL-12 Electroporation supported by a grant from Merck.
LECTURE
•Plasmid IL-12 Electroporation in Melanoma
•
Provider Statement: This continuing medical education activity is provided by Vindico Medical Education.
Support Statement: This activity is supported by an educational grant from Merck and Co., Inc.
Target Audience: The intended audience for the activities is medical oncologists, surgical oncologists, dermatologists, oncology nurses, nurse practitioners, physician assistants and other healthcare professionals involved in the treatment of patients with melanoma.
Learning Objectives: Upon successful completion of this educational activity, participants should be better able to assess the value of plasmid IL-12 electroporation in treating patients with advanced melanoma.
Faculty:
Alain Algazi, MD
Assistant Professor
UCSF Melanoma Oncology
UCSF Helen Diller Family
Comprehensive Cancer Center
San Francisco, California
Accreditation:
Vindico Medical Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
nice hammer to end the month, let the better days begin.
Comparing Oncosec to such a company without any reasoning or logic doesn't deserve a response, but I will give out an advice. Putting money on a company that is on OTC,without any understanding, is concidered gambling, which can only lead to shattered emotions and an empty wallet.
The two companies are on a different league, AMBS did a reverse of 150-1 in order to up list to the Nasdaq, but they are still on OTC and dropped significally ever since. That alone should be a hint. I dont know much about AMBS, but why even have such a company on a watchlist is beyond me.
You probably do not know this, but any article published by SA has to be pre approved, including its disclaimer.
The disclaimer in SA of not receiving compensation is more for the benefit of the company mentioned in the article, rather than for Seeking Alfa, since they take care of their end side by including the sentence of writing the article alone while expressing his own opinions. If Oncosec was to advertise in such a way, by law they would have to inform that in the disclaimer.
I don’t think anyone that knows the company ever thought that it is all about the monotherapy. Once Oncosec began its process for registration of trade mark ImmunoPulse™ IL-12, it became obvious that it is only about the platform.
I understand why, nothing is guaranteed and your trust is not with the company. But just as you are here to make money, so was the company H.C. Wainwright when they acted as placement agents for the offering. Oncosec has been a client of them from the beginning and they know the company better than you and I. So I figure they would only accept a payment that is reachable in a reasonable timeframe.
It doesn't but it adds to the rest of Oncosec's story. If that's the only thing that you found ubsurd, than it is a pretty good estimate in my part. These are business people that take part on this sort of deals.
Everyone knows at what price the business plan of combination with Keytruda for non-responders began and the time when eventually interim results get neared, anticipating for the price to get back there again. In the meantime, why not read about where Oncosec has come from and where it might get to, if the ImmunoPulse platform works out.
Keeping that in mind, let’s take a look at Oncosec’s past history when it comes to offerings. From its annual reports, it can be analyzed that when the company is in need for financing, the price will most likely find itself to be above $5. It would not make sense for them to give a lower discount than that, when comparing to their past offerings, and after having advanced their science with much higher projections of its possible future market.
On June 2015, Oncosec closed a direct offering, in which 2,469,091 shares were purchased at the price of $5.50 per share. Along with some Placement Agent Warrants exercisable on December 8, 2015 at a price of $6.88 per share which will expire on May 12, 2019. This is actually a placement fee that almost guarantees an investor at this point that the price will be well above sometime in the near future.
On June 2014, there was an offering for 1,126,761 shares at $18
On September 2013, there was an offering for 2,389,600 shares at $5
On December 2012, there was an offering for 1,440,000 shares at $5
On March 2012, there was a public offering of 1,550,000 shares at $5
In addition, from Oncosec’s most recent annual report, the company has a total of 1,771,647 shares in outstanding warrants with exercise prices ranging from $5.20 to $24.00. These warrants expire at various times between March 2016 and June 2019.
With all that is mentioned on the 10-Q’s, anything below $5 can be considered a bargain for right now, and the fact that Oncosec recently did a reverse split that closed at $5.30 in order to join the Nasdaq, erases any doubt of another one happening anytime within the next four years.
If you are going to be informed from a business perspective, one will have to consider the annual reports. In it there is a lot of information that can better give a sense of what the price will be in a future capital raise. In addition, Institutions will be buying regardless of a raise, else why would they open small positions. As for a reverse split sometime in the future, I have not yet ran into a company that has done two reverses within a 4 year period. The reason why I mention four years has to do with what is inside of the 10-Q's.
I will explain all this on my next post.
We are all somewhat uninformed at some point, but that is the reason why people come to Ihub and hopefully follow up on some good research.
How so?
I certainly understand the frustration of dealIng with the past year and a half of nothing but negative months, while looking at the share price significantly drop. I also understand why it becomes comical when some might seem blinded when they speak of the company with the hopes to finally see an improvement in their investment, but still can't show anything in return.
Setting all that aside, I can not deny the fact that ever since Dr. Pierce became part of Oncosec, the company has done a good job at finally progressing with their science. There has been numerous meaningful collaborations with scientific institutions that are now willing to work with a method that for more than 20 years had only been applied in preclinical testing. Both electroporation and the use of IL-12 have a very long history with mice and at some point had even been forgotten. So we can not deny the amount of positive ground work covered by Oncosec in this past year and a half.
Now I am not saying that Oncosec has found a magical potion to cure cancer, but they might have figured out a method to deliver such potion safely into humans. The opening of cells to cure them makes a lot of sense to me, even more so than pro-creating stem cells in tubes. For example, just recently researchers at Cambridge University are claiming a stem cell research breakthrough that would allow a baby to be created from the skin cells from two adults, no matter their gender. But that's another conversation.
If you have not noticed, for a few months now the highest ask price for a share of Oncosec ranges from $16 to $30 and the lowest starts at $3.58
As an investor and owner of shares you become a dealer. The dealer sales at whatever price they choose, and some savvy investors have a pretty high asking price that they will not remove until the bid reaches their price.
where is the link? can you prove that? But I can proof to you the small amount of purchases that they have made in the past couple of months. They will buy a lot more at lower prices. The stock market is manipulated in every sense of the word, for those that are new to investing on it.
The drop in share price can easily be explained, with the simple question of who doesn't like a discount? The one good thing Oncosec has now with their investors is their transparancy at keeping every one updated on their schedule. There are no surprises and everyone knows their time table, which they have been late with rather than early. Therefore, why would any major investment company increase on their small present positions now, when they need the money to be elsewhere. In the mean time, they can wait for a greater discount with a lower share price. Notice how they all jumped in at a price above $5 to comply with the requirements, but the idea is for them to buy a greater share amount at a much lower price. That time will be when interim results of the combination trial get near.
Institutes know Oncosec has a good chance at completing their objectives, else why bother with a company that just a few months ago was a long shot that belonged on the OTC market. If someone constantly awaits for the proof of a link or a news release showing how true the science is, that person will never invest in any company. Because by that time they will always find the price to be too high.
you wanted references, just read the interview. I can only conclude opinions from his public words and his actions, but I do not have any access to his private conversations or his thinking.
you are right about that, I never said it was a verbatim reference. You would need to use some common sense to connect the dots as to the reason of him leaving the company and why he has chosen Oncosec as a follow up to his work.
It is not a waste of time or money, nor is it a competition for Oncosec with the recent collaboration of Incyte and Merck. Incyte's IDO1 is an immunosuppressive enzyme that has been shown to induce regulatory T cell generation and activation, and allow tumors to escape immune surveillance. It is being tested in 15 different trials at the moment with some as combinations. Keytruda is an antibody that blocks the interaction between PD-1 and its ligands PD-L1. According to preclinical evidence it has suggested that the combination of these two agents may lead to an enhanced anti-tumor immune response compared with either agent alone. If successful, this can only benefit immunotherapy, which in return can help out Oncosec's ImmunoPulse cocktail, if in part they are successful.
I found scientific explanations as to why in the long run, all these elements of immunological checkpoints IDO and cytokines like IL-12 need to work together with the induction of PD-L1 expression on tumor cells to hopefully finally defeat cancer. The problem will be the toxicity of its nature when all combined. Which is where the ImmunoPulse platform can be utilized.
To better explain, I will continue referencing Dr. Pierce's interview in which he explains his vision of immunotherapy.
"The future is in combination immunotherapies –
I predict they’ll become the backbone in many indications. We just need to figure out how to use current targeted agents and chemotherapies judiciously. Immunotherapies are not innocuous. PD-1’s safety profile is pretty good, but when we combine therapies, we’ll have to be sensitive to synergistic immunotoxicity. That’s a benefit of a multimodal therapeutic paradigm that includes intratumoral therapy – we can harness treatment efficacy without systemic exposure and toxicity.
I think the most important question we need to answer in immuno-oncology now is: how do you make PD-1 non-responders into responders? That’s our current strategy at OncoSec, and our primary candidate is intratumoral delivery of IL-12. Some of the luminaries in the literature today are beginning to talk about intratumoral therapy. I think we’ll see these therapies come of age in the next decade; Amgen’s T-VEC, a virus that encodes GMCSF,
has met with some success, but there are many different ways you can approach it and I think others will follow suit. I also think we’ll come back to DNA damage and repair. Tumors depend on their ability to mutate but this can be their Achilles heel; they become dependent on DNA checkpoints, unlike normal cells, so we have a therapeutic leverage point. I think we’ll see a resurgence of this as a field to explore."
The Link: Changing the Nature of the Game
Sitting Down With… Robert Pierce
(from an interview given by The Pathologist in 2014)
What was the story of PD-1?
The PD-1 program came to DNAX when we acquired Organon, who had planned to move forward in human development without “companion” mouse studies. This was a bold approach. Although it was clear from the literature that anti-PD-1 was a strong candidate molecule for immuno-oncology, Schering-Plough were more conservative and tasked us with building the mouse surrogate program. When Merck and Schering-Plough merged,the PD-1 program was "deprioritized" until Bristol-Myers Squibb published their candidate’s Phase I data.
Then it was like Lazarus – raised from the dead! It’s amazing that Merck still got first approval in the US. I think they benefited from going after ipilimumab-refractory melanoma patients as their main indication; that triggered the breakthrough therapy designation. It’s exciting that we have such a good idea of who responds to anti-PD-1 and who doesn’t. That’s critical to why PD-1 development is going so fast – in large part, we understand the mechanism of action.
My first ah-ha! moment came when I saw tumors IHC-stained with PD-1 and PDL1. Patients who respond to anti-PD-1 have cytotoxic T cells in their tumors; you only need immunology 101 to say, “Wow! The T cell coming in is generating a cytokine which upregulates PD-L1 to shut off the T cells.” It’s a homeostatic mechanism we evolved – every immune reaction contains its own brakes, and tumors hijack them. It took a long time to convince the scientific community that immunotherapy would work – over 100 years of chasing Dr Coley’s vision of harnessing immune responses to treat tumors. If you think about where we are with anti-PD-1 today, where might we be if this transformation had happened earlier? What new treatment strategies hold most potential?
serious? again with that, I understand. But if I give it to you, will you promise me that you will not doubt me again?
I don't think that will be necessary and wont help, but if you want maybe you get lucky. Remember when Dr. Pierce told Merck to continue with the anti PD-1 program and they actually put it on the back burner? Only for years later to become the hottest thing in Immunotherapy. Those were his words.
Being informative. You asked a few questions and hopefully I answered some of them. After all this is a hub for Oncosec investors, and you seem like one. You always have a question or a diverted statement, which is good, it keeps the information flowing. Just don't turn your head when the other person says something that you disagree with.
More proof you ask for, but I can only give you proof of what the science has.
The following is from the article “Macrophage IL-10 Blocks CD8+ T Cell-Dependent Responses to Chemotherapy by Suppressing IL-12 Expression in Intratumoral Dendritic Cells”
“Therapeutics targeting the CSF-1/CSF-1 receptor pathway are currently being evaluated clinically in multiple cancer types, either as monotherapy or in combination with standard-of-care chemotherapy. However, mechanisms by which the CSF-1/CSF-1 receptor pathway and macrophages sustain tumor growth and/or repress response to cytotoxic therapy are unclear. Herein we report that macrophages infiltrating mammary carcinomas are the significant source of IL-10, which in turn suppresses intratumoral dendritic cell production of IL-12 and thereby limits cytotoxic T cell responses during chemotherapy. These data reveal a role for the interaction between tumor macrophages and dendritic cells in mediating response to therapy, identify a CSF-1/IL-10/IL-12 cytokine axis for targetable intervention, and reveal possible risk stratification biomarkers for patient selection.” Page#1.
“Blocking IL-10R has not been used extensively as an approach for anticancer therapy but has been reported to induce tumor regression in combination with CpG oligonucleotides in various subcutaneous tumor models, ostensibly through macrophage/DC activation and increased expression of IL-12.” Page#11.
http://pharmacology.ucsd.edu/graduate/courseinfo/BIOM275-WI15-Courssens-Ruffell%20et%20al%20Cancer%20Cell%202014%20+%20supp.pdf
Some of the important information that has been covered in all of the articles referenced today has been:
CD8 T cells are critical for the control of viral infections. * Multiple cytokines influence every stage of the anti-viral CD8 T cell response. * Inflammation and certain chain cytokines enhance effector responses. * Different classes of chain cytokines promote immunological memory. * Immunosuppressive cytokines limit CD8 T cell responses and favor viral persistence.
If you notice from the previous diagram of Medscape, the blocking of IL-10R can be achieved by raising the levels of IL-12 directly within the cells and in return reduce the high amounts of IL-10. That’s the idea of ImmunoPulse IL-12 for making the tumor recognizable in order for CD8 T cells to do their job.
“IL-10 signaling to T cells reduces their proliferation and effector activity, including the production of effector cytokines such as IFN?. IL-10 can also indirectly inhibit T cell responses by decreasing the antigen presenting capacity of macrophages and DCs and reducing their expression of proinflammatory cytokines which amplify effector responses (Pestka et al., 2004; Wilson and Brooks, 2010). IL-10 deficient mice acutely infected with LCMV have greater numbers of virus-specific CD4 and CD8 T cells at the peak of the response ( Brooks et al., 2010 ), highlighting the role of this cytokine in restricting immune responses.”
However, the biological effects of IL-12 on CD8 T cell differentiation directly signal to the responding cells and act in conjunction with antigenic and costimulatory signals to promote the development and expansion of short-lived effector cells. CD8 T cells lacking the IL-12 inflammatory cytokine receptor are defective in the formation of short-lived cells. While the induction of IL-12 following infection boosts the expansion of highly cytolytic short-lived effector cells, curtailing the inflammatory conditions surrounding CD8 T cells still permits the formation of long-lived memory populations that operate to confer protection against re-exposure to the infection. Hence, there is the need to reduce the levels of IL-10.
"Anti-viral CD8 T cells and the cytokines that they love"
https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S0042682212004539?returnurl=http:%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0042682212004539%3Fshowall%3Dtrue&referrer=http:%2F%2Fwww.google.com%2Furl%3Fsa%3Dt%26rct%3Dj%26q%3D%26esrc%3Ds%26source%3Dweb%26cd%3D1%26ved%3D0CCIQFjAAahUKEwjwnt7d_NTIAhWCHD4KHZFAB9U%26url%3Dhttp%253A%252F%252Fwww.sciencedirect.com%252Fscience%252Farticle%252Fpii%252FS0042682212004539%26usg%3DAFQjCNHyJC93-oYmvDnPiY_9Q2GV2reT0w
Keep an open mind with the fact that in April 2011, Plexxikon was acquired by the Japanese pharmaceutical company Daiichi Sankyo for $805 million with an additional $130 m in potential milestone payments. There is very little to no reason for such big company not having a clue of the science that is needed. They probably approached Oncosec, but I know you will need the link. When I find it, if there is one, you will get it.
One can read from the information I previously posted as reference, that Tumor-Associated Macrophages (TAMs) are one of the major constituents of tumor stroma in many solid tumors and there is compelling preclinical and clinical evidence that macrophages promote cancer initiation and malignant progression. Therefore, these cells represent potential targets for therapeutic benefit. In addition to pro-inflammatory activity, in some instances, TAMs can play critical roles in antigen presentation and sustaining Th1 and cytotoxic T-cell responses through the production of IL-12. Unfortunately, in most clinically apparent tumors, there is little evidence of a large population of TAMs with macrophages programming. However, therapeutics, which can enhance these functional activities of macrophages (M1, M2) are a promising treatment strategy. Hence the need by Dr. Pierce to regulate Interleukin 12, which you can read more of the subject in the article “Positive Regulatory Role of IL-12 in Macrophages and Modulation by IFN-g1” which is published in The Journal of Immunology. http://www.jimmunol.org/content/167/1/221.full.pdf
Now, going back to my original post, which I can now take time to reference, https://blogs.shu.edu/cancer/2015/05/13/csf-1-inhibitor-plx3397-keytruda-anti-pd1-for-multiple-cancers/
One can see from the Medscape graph how low IL-12 relates to M2 macrophages by further reinforcing the M2 phenotype while suppressing CD8 + T cells, resulting in an overall immune-permissive environment for tumor growth and spread. Looking at the graph it shows why the need to regulate IL-12, since IL-12 is an interleukin that is naturally produced by macrophages. However, when a tumor is growing the Immune system does not recognize the need for IL-12 and in return drops their level due to the damaging loop that is taking place.
Dr. Pierce knows this and more, else, he would be talking out of his elbow when it comes to non-responders. And so would be Dr. Nghiem and Dr. Bhatia who only a few days ago at 2015 European Cancer Congress said “We believe this approach warrants further exploration in MCC, perhaps in combination with emerging systemic therapies, such as anti-PD-1/PD-L1 agents,” when referring to ImmunoPulse of IL-12 and Merkel Cell carcinoma.