(wow) Words Of Wonders Level 2723 Answers – I was a ZioPharm Oncology (ZIOP) from 2009 to April 2013. I believe polyphosphamide will improve the disease-free survival of sarcoma patients, the treatment will be approved, and ZIOP will use it. use that money to fund a robust pipeline of game-changing products. Oncology treatment with a little help from Intrexon (XON). After palifosfamide failed, like many, I threw in the towel. I can't wait four years when Zeopharm transforms itself into an “end-of-life” oncology company. Recently, I wrote an article about CorMedix (CRMD), which has a different market cap of CRMD than ZIOP. In this article I will strongly oppose ZIOP without any substance and Ziopharm Longs many comments about how I am wrong. Since then, I've dug deeper and found some interesting information that I think most people have known for a long time. I'll run through the key data slides from the new investors' presentation posted on Zeopharm's site:
Ziopharm says this increase in the recruitment of CD8+ T cells indicates an “optimal immune response.” What they don't tell you is that IL-12 is a powerful inducer of the cytokine interferon gamma (IFNg). IFNg strongly stimulates the three chemokines CXCL9, CXCL10, and CXCL11. All 3 of these chemokines are very efficient at attracting T cells and other lymphocytes. Spend a few minutes reading the Wikipedia links for a high-level, easy-to-understand overview of this technique. Based on this neat biography,
(wow) Words Of Wonders Level 2723 Answers
When you generate high levels of intratumoral IL-12, you increase the influx of T cells. Ziopharm describes this T cell influx as a weather forecaster predicting that it will rain and be humid.
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The question arises, are some of these CD8 T cells specific for tumor antigens, and does this have an effect on this important pool of lymphocytes? To answer this, a thorough understanding of T cell biology is required. Normal T cells express a T cell receptor (TCR) specific for peptide antigens associated with the MHC molecule. The CD8 T cell can be activated to kill when this TCR is primed by a specific MHC/peptide complex it recognizes. In a mouse, there are 20 T cells of a particular type, so finding a specific cell for a specific antigen is more difficult than finding a needle in a haystack. Now use these types of introductory gifts made by Ziopharm IL-12. It is likely that these T cells are recruited to tumors by IL-12 / IFNg / CXCL9-11 for tumor antigens. An inflammatory environment may be created that may be beneficial, but it is unlikely that many tumor cells are killed by CD8 T cells in a TCR-dependent manner.
In addition, it has recently been shown that tumor-reactive CD8 cells are present in the tumor and express the inhibitory molecule PD-1. 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 ) prevent an immune signal from tumor-specific T-cells, which can activate and kill tumor cells. Antigen can be expressed. The effect of IL-12 on PD-1+ tumor-specific CD8 T cells in humans is unclear, but there is evidence in mice that IL-12 significantly increases the expression of PD-1 bindings:
The graphs shown in the top 2 rows show the upregulation of PD-L1 and PD-L2 induced by IL-12 stimulation. Another paper shows that PD-L1 is increased by IL-12, and it depends on the production of IFNg. In other words, IL-12 can produce signals that directly inhibit tumor-specific CD8 T cells. I'll leave it to the reader to decide for himself whether this mouse data applies to humans.
Motivation IL-12 activator ligand can make 100% survival of the death sentence. All controls are in place. What Ziopharm doesn't tell you is that IL-12 is also a powerful activator of NK cells, a type of lymphocyte that specializes in killing cells that are considered “non-self” in a non-antigen-specific manner. Here is an excerpt from a review of the GL261 model spanning two decades of research:
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Note that GL261 causes “sensitivity to activated NK cells” and the authors classify the tumor cells as “moderately immunogenic”. That's really it
When you activate NK cells with IL-12, you get a quick and effective response. This is not the same as in the human condition, and only reflects the immunogenicity of the tumor, which is a weakness of the GL261 model. If a person's cancer is small and sensitive to the activation of NK cells, the cancer will not develop.
Finally, for the sake of fairness and balance, I'll just present some additional data in the movie presentation about the power of IL-12:
The slide doesn't show up, but I believe it's melanoma data related to this December 2013 press release. The slide is very short on details (time of measurement, time of treatment, patient characteristics, etc.), but it appears that some tumors decreased in size by 50%. That's what you want to see in studies of melanoma, but there are a lot of questions about the type of immune response that these tumors make. I don't know what's going on, but a reasonable explanation is that this response is entirely NK cell mediated and represents the elimination of most of the “non-self” tumor cells, seen in mouse models . This leaves behind tumor cells that are resistant to NK cell-mediated killing and are very similar to “self”. If this explanation is correct, the cancer will get better after treatment, because the immune system will not detect it.
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These revelations of the investor Ziopharm are similar to the sounds of the Greek story. It's beautiful and moving, but beneath these tiny slides of data is a complex immunological rock that has sunk many a ship before. Clearly, Ziopharm must demonstrate that their IL-12 Rheoswitch drug activates tumor-specific CD8 T cells capable of antigen-specific lysis of tumor cells. While I can't really blame Zeopharm for not addressing these complex disease issues in business meetings, I think investors should know that Zeopharm is also changing paradigms and transforming oncology . All data is presented in their financial statement
Disclosure: The author is a senior CRMD. This article is written by the author himself and reflects his own views. The author receives no compensation for this (other than Alpha Seeking). The author has no business relationship with any of the companies whose items are mentioned in this article.
Additional disclosure: The author has no funding from ZIOP, and this article is based on publicly available opinions and data.
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Disclosure: The author has no positions in any of the stocks mentioned and has no plans to initiate any positions in the next 72 hours. This article is written by the author himself and reflects his own views. The author receives no compensation for this (other than Alpha Seeking). The author has no business relationship with any of the companies whose items 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.
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