The information on this site is not intended or implied to be a substitute for professional medical advice, diagnosis or treatment. Content within the patient forum is user-generated and has not been reviewed by medical professionals. Other sections of the Melanoma Research Foundation website include information that has been reviewed by medical professionals as appropriate. All medical decisions should be made in consultation with your doctor or other qualified medical professional.

Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors

Forums General Melanoma Community Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors

  • Post
    jim Breitfeller
    Participant

      Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: Clinical activity, safety, and a potential biomarker for response.
      Suzanne Topalian, MD Johns Hopkins University School of Medicine Baltimore, MD

       

      Video at The ASCO 2012 Meeting

      Anti-PD-1 (BMS-936558, MDX-1106) 

      Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: Clinical activity, safety, and a potential biomarker for response.
      Suzanne Topalian, MD Johns Hopkins University School of Medicine Baltimore, MD

       

      Video at The ASCO 2012 Meeting

      Anti-PD-1 (BMS-936558, MDX-1106) 

       I have been following this new treatment for a number of years and am trying to get my arms around the science. 

      When a T-cell is activated, the PD-1 , CTLA-4, ICOS, and others molecules are expressed and upregulated to the surface of the T-cell. Both PD-1 and CTLA-4 are checkpoint molecules that regulate the immune response. They are inhibitory to the point that they can shut down T-cell activation. ICOS on the other hand is a costimulatory molecule that is needed, along with IL-2 to keep the T-cell activated and help proliferate the T-cells.Elevated levels of ICOS mRNA can be detected already one hour after TCR engagement, followed by surface expression within 12 hours. Protein expression reaches a maximum after 48 hours and declines then slightly.

      It has been shown that ICOS is inducible within 48 hours of T-cell activation on both CD4+ and CD8+ cells; after; CD28 signaling; whereas cytotoxic T lymphocyte  antigen-4 (CTLA-4) ligation prevents its upregulation. 

      First, CTLA-4 engagement on resting T-cells was found to indirectly block ICOS costimulation by interferring with the signals needed to induce ICOS cell surface expression. Second, on preactivated cells that had high levels of ICOS expression, CTLA-4 ligation blocked the ICOS-mediated induction of IL-4, IL-10, and IL-13, suggesting an interference with downstream signaling pathways. The addition of IL-2 not only overcame both mechanisms, but also greatly augmented the level of cellular activation suggesting synergy between ICOS and IL-2 signalling.

      So after T-cell Activation, IFN gamma is secreted (30 minutes then IL-2 is secreted (45 minutes in) and so on 

       

      The surface expression of ICOS is within 12 hours of activation. Since CTLA-4 blocks ICOS costimulation, Yervoy (anti-CTLA-4) must be used to counter the surpressive signalling. PD-1 also upregulates to the surface in the early activation process. PD-1 is upregulated within 24h after T cell activation, PD1-Mediated Suppression of IL->2 Production Induces CD8+ T Cell …anergy was associated with a marked down regulation of IL-2.

      Blockade of PD-1 by monoclonal antibodies specific to its ligands (PD-L1 and PD-L2) results in significant enhancement of proliferation and cytokine (gamma interferon [IFN-gamma] and interleukin-2 [IL-2] secretion by tumor-specific CTLs. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Tregs.

      PD-1 blockade seem to augment the proliferation of the CD4+ helper cells.

      Now you know why just using Anti-PD1 and or Yervoy as a monotherapy will not have a large response rate. Combinational Therapy is a must if we are to see synergistic responses. IL-2 also plays a major roll in the immune response. IL-2 is added to help maintain fuctionality and survival of the Cytotoxic T Lymphocytes (CTLs) that is despartly needed to eradicate the Melanoma tumors. Our immune system can cure cancer.

       

      Jimmy B

       

      “It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

       ~Charles Darwin~

       

      Take Care

    Viewing 2 reply threads
    • Replies
        melissa ann
        Participant

          Hi JImmy, Thank you for posting this information.  My husband, Peck is in the pd1 1106 trial at Moffitt.  He just received his fourth infusion yesterday.  So, am I correct in saying that the summary of this info is to follow up the anti-PD1 infusions with IL2.    Does this mean after all infusions are finished or should IL2 be done on a regular schedule with the infusions?  Also, since this is a research study trial, would they be "allowed" to administer IL2 at any time to some one in the trial?  We appreciate all the info you share!  Thanks, Melissa

          melissa ann
          Participant

            Hi JImmy, Thank you for posting this information.  My husband, Peck is in the pd1 1106 trial at Moffitt.  He just received his fourth infusion yesterday.  So, am I correct in saying that the summary of this info is to follow up the anti-PD1 infusions with IL2.    Does this mean after all infusions are finished or should IL2 be done on a regular schedule with the infusions?  Also, since this is a research study trial, would they be "allowed" to administer IL2 at any time to some one in the trial?  We appreciate all the info you share!  Thanks, Melissa

            melissa ann
            Participant

              Hi JImmy, Thank you for posting this information.  My husband, Peck is in the pd1 1106 trial at Moffitt.  He just received his fourth infusion yesterday.  So, am I correct in saying that the summary of this info is to follow up the anti-PD1 infusions with IL2.    Does this mean after all infusions are finished or should IL2 be done on a regular schedule with the infusions?  Also, since this is a research study trial, would they be "allowed" to administer IL2 at any time to some one in the trial?  We appreciate all the info you share!  Thanks, Melissa

                LynnLuc
                Participant

                  Melissa, I am also in the trial at Moffitt…been doing it since fall of 2010. I also rec'd the peptide injections. I am stage 4 and NED for over 2 years. I have Dr Weber. I am thinking he is planning on doing a TIL trial of sorts using anti PD 1 trial( among other trials)…

                  LynnLuc
                  Participant

                    Melissa, I am also in the trial at Moffitt…been doing it since fall of 2010. I also rec'd the peptide injections. I am stage 4 and NED for over 2 years. I have Dr Weber. I am thinking he is planning on doing a TIL trial of sorts using anti PD 1 trial( among other trials)…

                    LynnLuc
                    Participant

                      Melissa, I am also in the trial at Moffitt…been doing it since fall of 2010. I also rec'd the peptide injections. I am stage 4 and NED for over 2 years. I have Dr Weber. I am thinking he is planning on doing a TIL trial of sorts using anti PD 1 trial( among other trials)…

                Viewing 2 reply threads
                • You must be logged in to reply to this topic.
                About the MRF Patient Forum

                The MRF Patient Forum is the oldest and largest online community of people affected by melanoma. It is designed to provide peer support and information to caregivers, patients, family and friends. There is no better place to discuss different parts of your journey with this cancer and find the friends and support resources to make that journey more bearable.

                The information on the forum is open and accessible to everyone. To add a new topic or to post a reply, you must be a registered user. Please note that you will be able to post both topics and replies anonymously even though you are logged in. All posts must abide by MRF posting policies.