(wow) Words Of Wonders Level 2740 Answers – I was long-term Ziopharm Oncology (ZIOP) from 2009 to April 2013. I believed that palifosfamide improved the disease-free survival of patients with sarcoma, approved the drug and could use the ZIOP results to register a solid, game-changing line. oncology treatment with limited support from Intrexon (XON). After the failure of paliphosphamide, like many, I threw in the towel. I couldn't wait almost four more years until Ziopharm turned into a “late stage” cancer team. I recently wrote an article about CorMedix (CRMD), comparing CRMD's pricing to ZIOP's. In this article I mostly criticized ZIOP without being specific and got a lot of comments from Ziopharm fanatics about how wrong it is. Since then I've done more diving and found some interesting information that I don't think most people know. I will review key data from a recent investor presentation posted on the Ziopharm website:
Ziopharm claims that this increased infiltration of CD8+ T cells is indicative of a “substantial immune response”. What I won't tell you is that IL-12 is a very potent inducer of the cytokine interferon gamma (IFNg). IFNg strongly induces three chemokines CXCL9, CXCL10 and CXCL11. All 3 of these chemokines are very effective in attracting T cells and other lymphocytes. Spend a few minutes clicking on the Wikipedia link for an advanced and easy-to-understand overview of this method. According to this biology is established;
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When you induce high levels of intratumoral IL-12, you will experience greater T-cell infiltration. Ziopharm showed this infiltration of T cells as a weather forecast that when it rains, the pavement is wet.
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The question then arises are these CD8 T cells specific for the tumor antigen and will this high density of lymphocytes have any effect? To answer this, a basic understanding of T cell biology is required. Normal T cells express a T cell receptor that has the best specificity for the peptide antigen in the context of the MHC molecule. A CD8 T cell can be stimulated to kill by this TCR that it recognizes through a specific MHC/peptide complex. However, mice only have 20 specialized cells, so finding cells specialized for a particular antigen is actually more difficult than finding a needle in a haystack. These types of odds are now using the liquid formula Ziopharm IL 12. It is very likely that these T cells are recruited to the tumor by IL-12/IFNg/CXCL9-11, a tumor-specific antigen. They may create an inflammatory state that may have some benefit, but it is likely that most tumor cells are killed in a TCR-dependent manner by CD8 T cells.
In addition, it has recently been shown that tumor-specific CD8 cells are already present in the tumor and PD-1 inhibitory molecules. This may explain the success of monoclonal antibodies such as nivolumab or lambrolizumab, which target the PD-1 pathway. By blocking this pathway, Bristol-Myers Squibb ( BMY ) and Merck ( MRK ) remove inhibitory signals from specialized T cells, allowing them to work and kill tumor cells that express the antigens they recognize. The effect of IL-12 on these PD-1+ specific CD8 T cells is not clear in humans, but there is some evidence in mice that IL-12 increases PD-1 ligand expression;
Individual histograms in the top 2 rows show clear upregulation of PD-L1 and PD-L2 induced by IL-12 stimulation. Here is another paper showing an IL-12-induced increase in PD-L1 that appears to be dependent on IFNg production. II. I'll let the reader decide whether this mouse data is applicable to humans.
Convince IL-12-stimulated activator binding can turn a death sentence into 100 survival. All appropriate controls are present. What Ziopharm doesn't tell you is that II-XII is also a potent activator of NK cells, a type of lymphocyte that specializes in killing cells that appear to be “non-self” in a non-antigen-specific manner . Here is a quote from a review of the GL261 model that includes two decades of research:
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Note that GL261 is “moderately sensitive to activated NK cells” and the authors describe tumor cells as “modest antibodies”. That's what
When you stimulate an abundance of NK cells with IL-12, you achieve rapid and effective tumor rejection. This is in no way similar to the human condition and merely demonstrates tumor immunogenicity, an inherent weakness of the GL261 model. If human tumors were moderately immune and susceptible to activated NK cells, there would be no cancer.
Finally, for the sake of fairness and equity, I will highlight the only other data slide in the presentation that deals with the efficacy of IL-12;
The leaflet doesn't list the symptoms, but I think it's melanoma given in this December 2013 press release. The gap is very short on details (time of tests, duration of treatment, patient characteristics, etc.), but it looks like a tumor has shrunk by 50%. This is what you want to see in a melanoma diagnosis, but there are many questions about the type of immune response these tumors produce. I don't even know exactly what is happening, but one likely explanation is that this response is NK cell mediated and represents the elimination of more “non-self” cells, similar to those seen in the mouse model. This will leave tumor cells that can inhibit NK cell-mediated killing and become more like me. If these indications are true, the tumor may improve after treatment, which appears to be less adaptive to the immune system.
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These Ziopharm inspirations are inspirations like the Sirens of Greek mythology. They are all nice and polished, but beneath these little slips slips the information about the multiple rocks that have sunk many a ship. Clearly, Ziopharm must demonstrate that its II-12 Rheoswitch therapy activates specific CD8 T cells that can perform antigen-specific analysis of tumor cells. While I can't fault Ziopharm for not addressing these complex antibody issues at investment meetings, I believe investors need to understand that Ziopharm can shift the paradigm and change oncology yet. All data included in the investor presentation
Open: author long CRMD. This article is written by the author himself and expresses his opinion. The author receives no compensation (except from Quest Alpha). The author has no affiliation with any company whose parts are mentioned in this article.
Additional disclosure: The author has no financial interest in ZIOP, and this article is based solely on publicly available opinions and information.
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Disclosure: The author has no positions listed in the stock and does not plan to initiate any positions in the next 72 hours. This article is written by the author himself and expresses his opinion. The author receives no compensation (except from Quest Alpha). The author has no affiliation with any company whose parts are mentioned in this article.
Additional Disclosure: I am an employee of Amgen, but the views and opinions expressed in this article are my own and not those of Amgen.
If you have a blocker on the other side, you will be blocked from proceeding. Turn off the blocker and reset. Maitres du Temps Chapter Three in white gold. (larger version) There are 6 and 12 panels that slide the watch and clear the day/night indicators and the second zone; Moon phase indicator at 4.30, day at 2 and minutes at 8. Like all watches designed and made by the famous independent members of ACHI – this one is the brainchild of Kari Vutilainen and Andreas Strehler – if you ask. price…
An image like this takes an incredible amount of work: I've already talked about the mechanics of turning sound into images in this three-part series (starting here). To be honest, I was planning to shoot the setup and some b-volume for another post, but it's just that I'm always so busy with photography that I don't have time. But I will talk about the amount of work that goes on behind the scenes.
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It's about an hour and a half of lighting the first shot, a few minutes of tweaking, and then you're good to go. But before this, also, for about half an hour there is a cleaning and sprinkling every hour; I love you
