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Halozyme Therapeutics, Inc. Message Board

fezziwig2008 32 posts  |  Last Activity: Feb 5, 2016 12:33 PM Member since: May 2, 2010
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  • fezziwig2008 fezziwig2008 Nov 27, 2015 12:34 AM Flag

    The 1st patient was dosed Nov 5th- of 81 total in a 2 yr study from which I expect a case report or two to emerge much like the recent CLLS and BLUE case reports- I believe the Peg-Pem Combination is synergistic in a way not seen before. This will finaly spur one of the CAR-T herd to partner HALO as well- anti IL-10 properties of PegpH20 are just as helpful for High HA solid tumor CAR-T.

  • Morningstar
    News: BusinessWire
    Tara Immuno-Oncology Acquires Exclusive City of Hope Licenses to Develop Clinical Stage p53MVA Oncology Vaccine and Salmonella-Based Therapy shIDO-ST

    11/03/15 08:00 AM EST
    Tara Immuno-Oncology Acquires Exclusive City of Hope Licenses to Develop Clinical Stage p53MVA Oncology Vaccine and Salmonella-Based Therapy shIDO-ST

    shIDO-ST targets the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO) and in combination with an enzyme, PEGPH20, successfully combats pancreatic tumors.

    Tara Immuno-Oncology LLC (Tara I-O, Private, with offices in NY and CA) announced today the acquisition of licenses from City of Hope for the development of p53MVA (modified vaccinia ankara) and a Salmonella-based therapy targeting Indoleamine 2,3-Dioxygenase (shIDO-ST), both for multiple oncology indications. Both technologies originate from the pioneering work of Don J. Diamond, Ph.D., chair of the Department of Experimental Therapeutics at City of Hope, an independent biomedical research institution and cancer treatment center. Tara I-O will pay City of Hope upfront and milestone payments in excess of $10 million, in addition to commercial royalties for the exclusive licenses.

    (Like T cells Neutrophils carry CD44 so This is a Preview of what PegpH20 will do for CAR-T and TCR- High Hyaluronan Tumor Penetration)

  • fezziwig2008 fezziwig2008 Nov 25, 2015 12:32 AM Flag

    Hyaluronan carried by tumor-derived microvesicles induces IL-10 production in classical (CD14++CD16−) monocytes via PI3K/Akt/mTOR-dependent signalling pathway

    Abstract
    Tumor-derived microvesicles (TMV) can mimic effects of tumor cells leading to an increased anti-inflammatory cytokine production, such as interleukin 10 (IL-10), by tumor-infiltrating monocytes and macrophages. Yet, the mechanism of IL-10 induction by TMV in monocytes remains unclear.

    The co-incubation of TMV derived from the human pancreas carcinoma cell line (HPC-4) with human monocytes resulted in a nearly 30-fold increase in IL-10 protein production. This effect operates at the level of transcription since monocytes transduced with an adenovirus containing IL-10-promoter luciferase reporter gene showed a 5-fold induction of luciferase activity after treatment with TMV. Since tumor cells can express hyaluronan (HA), which participates in tumor invasion and metastases, we have tested its effect on IL-10 expression. We showed that HA at the concentration of 100 μg/ml induces IL-10 protein expression and the IL-10 promoter activation in monocytes. Moreover, hyaluronidase treatment of TMV reduced IL-10 protein production by **50% and promoter activity by 40%. Inhibitors of the PI3K/Akt/mTOR pathway reduced both, TMV-induced IL-10 promoter activity and protein production, and the same was observed in monocytes when stimulated by HPC-4 cells or HA. Inhibition of PI3K activity down-regulated phosphorylation of the Akt and (to a lesser extent) mTOR proteins in monocytes following TMV or HA stimulation. When comparing monocyte subsets, TMV induced IL-10 protein and mRNA synthesis only in classical CD14++CD16− but not in CD16-positive monocytes. Our data show that TMV induce IL-10 synthesis in human classical monocytes via HA, which, in turn, activates the PI3K/Akt/mTOR pathway.

  • fezziwig2008 fezziwig2008 Nov 24, 2015 11:40 PM Flag

    "approval" here means the granting of an IDE- Investigational Device Exemption.

  • fezziwig2008 fezziwig2008 Nov 22, 2015 9:07 PM Flag

    Only Peer Reviewed and Company sources now- Read and Learn about IL-10 and PD-1:

    Cancer Res. 2015 Apr 15;75(8):1635-44. doi: 10.1158/0008-5472.CAN-14-3016. Epub 2015 Feb 26.
    IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells.
    Sun Z1, Fourcade J1, Pagliano O1, Chauvin JM1, Sander C1, Kirkwood JM1, Zarour HM2.
    Author information
    Abstract
    Immune checkpoint inhibitors show great promise as therapy for advanced melanoma, heightening the need to determine the most effective use of these agents. Here, we report that programmed death-1(high) (PD-1(high)) tumor antigen (TA)-specific CD8(+) T cells present at periphery and at tumor sites in patients with advanced melanoma upregulate IL10 receptor (IL10R) expression. Multiple subsets of peripheral blood mononucleocytes from melanoma patients produce IL10, which acts directly on IL10R(+) TA-specific CD8(+) T cells to limit their proliferation and survival. PD-1 blockade augments expression of IL10R by TA-specific CD8(+) T cells, thereby increasing their sensitivity to the immunosuppressive effects of endogenous IL10. Conversely, IL10 blockade strengthened the effects of PD-1 blockade in expanding TA-specific CD8(+) T cells and reinforcing their function. Collectively, our findings offer a rationale to block both IL10 and PD-1 to strengthen the counteraction of T-cell immunosuppression and to enhance the activity of TA-specific CD8(+) T cell in advanced melanoma patients.

    Should be a Great PegpH20-Keytruda trial.

  • fezziwig2008 fezziwig2008 Nov 22, 2015 2:54 PM Flag

    You're just lazy- no getting around it- I was told of and shared info about 1 death- you multiplied by 2- the information was obviously wrong. I have posted the direct messages I received from a formerly reliable source on Twitter. Don't ask honest questions any longer- I shall resume ignoring them and you - but look for Mabthera SC for CLL soon. Think of me when someone reads you the Roche release.

  • fezziwig2008 fezziwig2008 Nov 22, 2015 12:55 PM Flag

    Because Roche is Pushing Gazvya for CML BUT- As you Missed- has applied to EMA for the CLL Indication for MAbTheraSC- Expected shortly- as was illustrated at 2 previous Roche quarterly meetings- See Roche Group Development Pipeline- Slide 54 in Roche Half Year Report- under Registration. SNT951 is Right- you really should do some research before dumping on the board.

  • fezziwig2008 fezziwig2008 Nov 22, 2015 1:43 AM Flag

    Thanks- I've been spending some time developing what I believe will be a major story for HALO- Anti-IL-10 may one day sound like anti PD-1 to immunoOncology investors- recent papers suggest just how dependent cytokine IL-10 is on High Molecular Weight Hyaluronan. That makes pegpH20 an IL-10 blocker. Since IL-10 is an antiTumor surpressor, like PD-1, PegpH20 helps anti PD-1's, like Keytruda and Opdivo fight cancer. This synergy is Not priced in or yet realized. I can't wait for the PegpH20- Keytruda interim data report.

  • Also - "Roche has not definitively said whether they plan to launch Herceptin SC in the U.S., however, we believe it is likely"- CITI Report 11/18/15

  • "Hyaluronan-Binding T Regulatory Cells in Peripheral Blood of Breast Cancer Patients"
    Journal of Clinical & Cellular Immunology

    Jan 22, 2015

    "CD44 interactions with HA may be integrally related to Treg functions-promotes persistent expression of FoxP3, increased production of IL-10 and expression of membrane TGF-β, which are necessary for immunoregulatory activity. These effects on Tregs are shown to depend upon interaction with a high molecular weight form of HA."

    SO, High Molecular Weight HA- the kind PegpH20 breaks down into proinflammatory anti Cancer LMW HA- promotes IL-10 which suppresses anti Cancer effort- like PD-1, PD-L1 - PegpH20 is a IL-10 blocker:

    "IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells."

    Cancer Research - April 15, 2015

    "IL10 blockade strengthened the effects of PD-1 blockade in expanding TA-specific CD8(+) T cells and reinforcing their function. Collectively, our findings offer a rationale to block both IL10 and PD-1 to strengthen the counteraction of T-cell immunosuppression and to enhance the activity of TA-specific CD8(+) T cell in advanced melanoma patients."

    PegpH20 and Keytruda will do just that - $ to be made.

  • Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors.
    Manuel ER1, Chen J2, D'Apuzzo M3, Lampa MG2, Kaltcheva TI2, Thompson CB4, Ludwig T5, Chung V6, Diamond DJ1.

    Bacterial-based therapies are emerging as effective cancer treatments and hold promise for refractory neoplasms, such as pancreatic ductal adenocarcinoma (PDAC), which has not shown significant improvement in therapy for more than 25 years. Using a novel combination of shIDO-ST, a Salmonella-based therapy targeting the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO), with an enzyme, PEGPH20, which depletes extracellular matrix hyaluronan, we observed extended survival with frequent total regression of autochthonous and orthotopic PDAC tumors. This observation was associated with migration and accumulation of activated polymorphonuclear neutrophils (PMN) from spleens into tumors, which was not seen using a scrambled control (shScr-ST). Purified splenic PMNs from PEGPH20/shIDO-ST-treated mice exhibited significant IDO knockdown and were able to kill tumor targets ex vivo through mechanisms involving FasL and serine proteases. In addition, CD8(+) T cells were observed to contribute to late control of pancreatic tumors. Collectively, our data demonstrate that entry of shIDO-ST and PMNs into otherwise impermeable desmoplastic tumors is facilitated by PEGPH20-mediated HA removal, further highlighting an important component of effective treatment for PDAC. Cancer Immunol Res; 3(9); 1096-107. ©2015 AACR.
    ©2015 American Association for Cancer Research.

  • fezziwig2008 by fezziwig2008 Nov 11, 2015 12:15 AM Flag

    PegpH20 Phase 2 will end recruitment in 2015 and will report 2H 2016- Probably @ESMO

    PegpH20 202 has open data being kept under wraps (see ESMO15) but encouraging

    The Keytruda -PegpH20 initiation and Primal Docetaxel-PegpH20 Expansion- Why does

    A company with Limited Funds Begin/Expand 2 Trials based on Open Data?

    Because the Data is Encouraging.

    Docetaxel is Already the 2nd Line Chemotherapy of Choice in NSCLC.

    Keytruda is Already approved for NSCLC (10/2/15).

    So the addition of PegpH20 removes a major barrier to the further success of these two agents.

    Addition of Enoxaparin to PegpH20 has removed the threat of added thromboemboli (1mg/kg/d)

    There is a High Probability of success from these combinations in high Hyaluronan cancer- given the 9.2 month leading PFS in PDA already reported. It is also possible that 2016 will see a Cellectis type report in PDA, NSCLC, or Gastric Cancer emerging from one of these 3 trials- most likely with Keytruda.

    So, the outspending of R&D in relation to Royalties presents an excellent buying opportunity.

HALO
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