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Celldex Therapeutics, Inc. Message Board

  • long_vrts2 long_vrts2 Nov 14, 2013 1:00 AM Flag

    Report: breakthrough in Alzheimer's disease cause and immune impairment (CDX-1127 to the rescue?)

    This study was published recently on the possible immune cause of Alzheimer's disease (AD). I provide the abstract in the next mssg but I wanted to first point out the important aspects of this report, especially as it relates to CDX-1127:

    Background:

    1. Immunological impairment has been implicated as a part of the pathogenesis in Alzheimer's disease (AD) previously.
    2. Cytomegalovirus (CMV) has been suggested as a contributing factor for. the impaired immune responsiveness.

    In this report:

    1. They compared blood samples from 50 AD pts vs 50 controls.

    2. Pts with AD had a 3.5-fold decrease in CMV-specific CD8 T-cells compared to controls. Otherwise the CD8 T-cell populations were similar in terms of differentiation AD vs controls.

    3. The results indicate that although AD and non-AD pts mount comparable immune responses, for some reason the CMV specific immune response is impaired in AD pts.

    The CDX-1127 angle:

    1. CDX-1127 has been show to stimulate, in combination with an antigen, Ag-specific CD8 T-cells. From the most recent 1127 publication:
    "Administration of 1F5 (CDX-1127) to hCD27-Tg mice enhanced Ag-specific CD8(+) T cell responses to protein vaccination comparably to an agonist anti-mCD27 mAb."

    2. The application for CDX-1127 would be to treat pts with CMV deficient immune response with 1127- in combination with a CMV antigen- with the goal of increasing CMV specific CD8 T-cells. If impaired CMV immune response is the cause of AD- or a major contributor- then activating the immune system with CDX-1127 to provide a robust, long-lasting response would have clinically beneficial effects in AD pts.

    AD studies take a long time to complete, especially compared to end-stage cancers like melanoma and renal cell carcinoma where CDX-1127 is currently being tested. So CLDX will continue to focus on cancer- however, it underscores the tremendous potential of a safe, effective immune activator like CDX-1127 in a variety of indications.

    Sentiment: Strong Buy

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    • I always thought that Celldex would have a go at Alzheimer's through a route similar to CDX-1135 (Dense deposit disease).
      However, the activation of the virus specific response might be a path to recovery from Alzheimer's. The preclinical tests with AD mice would not be that difficult nor take that long either. I did not catch if there evidence that the missing CMV specific response is a cause and not a result of AD?

      Sentiment: Strong Buy

    • I doubt Celldex will go after Alzheimers on their own in the near term. However, it's good to think about what the possibilities could be with CDX-1127. I'm sure they'll be doing some brainstorming as to what can be done with CDX-1127 then take a look at the finances to see where the best chances of approval and ROI is. I expect some joint studies with other companies using CDX1127 in combination with their therapies. We won't hear more until next year.

    • LV
      Did you notice royalties paid to cldx regarding HIV vaccine.

      Sentiment: Strong Buy

    • LongV- Do you think the potential for CDX-1127 warrants clinical study in multiple combination treatments and indications at once or is there one combination and indication in particular that you could think Celldex will pursue quickly to expedite the development process and get to approval fastest? Thanks in advance.

      Sentiment: Strong Buy

    • LV attached is rec update on CMV program in HCT at VICL!
      [TransVax is the first CMV vaccine to reach the phase III stage.]
      Thoughts please?

      Fraz

      Astellas Pharma Inc. ( ALPMY ) and its partner Vical Inc. ( VICL ) recently commenced a multinational phase III registration study of TransVax to control cytomegalovirus (CMV) in hematopoietic cell transplant (HCT) recipients.

      [TransVax is the first CMV vaccine to reach the phase III stage.]

      The randomized (1: 1 ), double-blind, placebo-controlled study will be performed in CMV seropositive patients undergoing HCT procedures. This study is divided into two parts -- the first part will enroll around 100 patients with the primary endpoint being overall survival, and the second part will enroll roughly 400 patients with the primary endpoint either survival or a composite endpoint including survival and some other variables.

      Vical has a licensing agreement with Astellas for the development and commercialization of TransVax. Vical received a $25 million upfront payment from Astellas in 2011 and a $10 million milestone payment in 2012.

      Vical and Astellas intend to commence a phase II study of TransVax in solid organ transplant (SOT) recipients in the latter half of 2013.

      TransVax has orphan drug designation in the US and Europe for HCT and SOT patients.

      We note that Roche 's ( RHHBY ) Valcyte is approved for the prevention of CMV disease in patients who have undergone a heart, kidney, or kidney-pancreas transplant.

      Another candidate that is currently being studied for the treatment of CMV infections in transplant recipients is maribavir, which is in two phase II studies. The studies are being conducted in Europe and the US.

      Sentiment: Strong Buy

    • LV good pick up and we discussed CMV infection long ago as you will remember in the Rindo early trials/ Duke Experience!

      The PEP-3-KLH (CDX-110) vaccine in glioblastoma multiforme patients

      Amy B. Heimberger, MD and John H Sampson, MD, PhD

      GBMs, but not the normal surrounding brain, express highly immunogenic Cytomegalovirus (CMV) antigens [140-143] which can be used as tumor-associated targets. The cellular arm of the immune system surveys and eradicates virally-infected cells, even within the “immune privileged” CNS, through the induction of well-characterized cytolytic mechanisms [144-147]. Thus, CMV-directed immunotherapy may effectively elicit the selective killing of CMV-infected tumor cells in patients with GBM

      That being said CMV infection is a very bad apple in many Immune Modulating Scenarios. Ive held onto my VICL for just this reason after the debacle on Alovectin in Melanoma. Do you follow VICL at all and are you aware of their CMV vaccine program? Pretty far along and looks quite viable to me.Thoughts please?

      Fraz

    • "AD studies take a long time"...but why not use the same principle as with advanced cancers? To take the most sick patience with AD and to see if any improvement happens in lets say 6m? Or at least to run some animal models (if possible?). From s/p point of view - just a hint that such studies conducted will bring us at least +10...

      • 1 Reply to kot882001
      • kot,

        The treatment objectives are different: in AD the goal is to save as many brain cells as possible, so intervention should happen fairly early in disease and then it needs to be monitored over several years. In cancer pts, the goal is to kill as many tumor cells as possible (while trying to minimze harm to healthy cells), and can be done in end-stage disease: CDX-1127 produced a complete response in the Stage IV Hodgkins lymphoma pt. mentioned in the release.

        I heard from a colleague that the Swedish team that did the AD study may be interested in testing CDX-1127 in impaired immunity AD. I'll keep the MB posted as I get more concrete info.

        Sentiment: Strong Buy

    • Thanks Long for this great find.

      Sentiment: Strong Buy

    • 2013 Oct 14;8(10):e77921. doi: 10.1371/journal.pone.0077921.
      Decreased proportion of cytomegalovirus specific CD8 T-cells but no signs of general immunosenescence in Alzheimer's disease.
      Westman G, Lidehall AK, Magnusson P, Ingelsson M, Kilander L, Lannfelt L, Korsgren O, Eriksson BM.
      Source

      Department of Medical Sciences, Uppsala University, Uppsala, Sweden ; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
      Abstract

      Cytomegalovirus (CMV) has been suggested as a contributing force behind the impaired immune responsiveness in the elderly, with decreased numbers of naïve T-cells and an increased proportion of effector T-cells. Immunological impairment is also implicated as a part of the pathogenesis in Alzheimer's disease (AD). The aim of this study was to investigate whether AD patients present with a different CMV-specific CD8 immune profile compared to non-demented controls. Blood samples from 50 AD patients and 50 age-matched controls were analysed for HLA-type, CMV serostatus and systemic inflammatory biomarkers. Using multi-colour flow cytometry, lymphocytes from peripheral blood mononuclear cells were analysed for CMV-specific CD8 immunity with MHC-I tetramers A01, A02, A24, B07, B08 and B35 and further classified using CD27, CD28, CD45RA and CCR7 antibodies. Among CMV seropositive subjects, patients with AD had significantly lower proportions of CMV-specific CD8 T-cells compared to controls, 1.16 % vs. 4.13 % (p=0.0057). Regardless of dementia status, CMV seropositive subjects presented with a lower proportion of naïve CD8 cells and a higher proportion of effector CD8 cells compared to seronegative subjects. Interestingly, patients with AD showed a decreased proportion of CMV-specific CD8 cells but no difference in general CD8 differentiation.

      Sentiment: Strong Buy

 
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