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Redirecting the Melanoma Tumor’s Microenvironment in Favor of the Activation of T-cells

Forums General Melanoma Community Redirecting the Melanoma Tumor’s Microenvironment in Favor of the Activation of T-cells

  • Post
    jim Breitfeller
    Participant

      Redirecting the Melanoma Tumor’s Microenvironment in Favor of the Activation of T-cells 

       

       

       

      Redirecting the Melanoma Tumor’s Microenvironment in Favor of the Activation of T-cells 

       

       

       

      Studies show that regulatory T (Treg) cells play a detrimental role in cancer immunotherapy because these cells accumulate in the tumor microenvironment and suppress immune responses. Moreover, Researchers recently showed the presence of tumor-specific CD4+, CD8+, and γδ Treg cells in several types of tumors, suggesting that they can induce antigen-specific, local immune tolerance at tumor sites. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MSC) could also play an important role in inhibiting immune responses and chronic inflammation, which has been linked to cancer development and progression. Both tumor-associated macrophages/DCs and MSCs promote tumor growth either by secreting immunosuppressive cytokines, including interleukin 10 (IL-10), transforming growth factor-β (TGF-β), and IL-1β, or by inducing Treg cell differentiation. More importantly, tumor cells have been shown to express inhibitory factors (IL-10, TGF-β, GAL-3, and IDO) to alter T-cell function. Immunosuppressive factors, such as FasL and TGF-β expressed by tumor cells, may directly inhibit tumor-reactive T-cell expansion or induce T-cell apoptosis. A recent studies suggest that tumor-associated galectin-1(Gal-1) and or Gal-3, a membes of the animal lectin family, contributes to tumor immune escapes by inhibiting the function of tumor-reactive T cells. Therefore, tumor cells constantly modulate T-cell responses by presenting tumor antigens and secreting immunoregulatory cytokines. Understanding the interplay between tumor cells and immune cells in the tumor microenvironment is essential for the development of effective cancer immunotherapy.

      Researchers tested whether Gal-3 could activate other tumor-reactive or antigen-experienced T cells. Five melanoma-reactive T-cell lines, one prostate cancer–derived T-cell line, and two breast cancer–derived T-cell lines were selected and cocultured with 293 cells expressing Gal-3 for 12 to 16 h. they found that Gal-3–expressing 293 cells activated all of these T-cell lines to secrete IFN-γ but failed to activate naive CD4+ and CD8+ T cells purified from peripheral blood mononuclear cells (PBMC) of healthy donors . Suggesting that naive T-cell activation requires a strong T-cell receptor (TCR)-mediated activation, whereas tumor-reactive T cells can be readily activated by Gal-3. They also evaluated the cytokine profiles of CT28 T cells on Gal-3 stimulation. Gal-3 induced a high level of IFN-γ, granulocyte macrophage colony-stimulating factor, and low to middle levels of IL-4, which is similar to cytokine production induced by anti-CD3 (OKT3) stimulation. This is an indication that the Gal-3 complexes with the TCR synapse causing impaired signaling. Gal-3 binds and activates tumor-reactive T cells through carbohydrate-specific interaction.

      Galectin-3 (GAL-3) localize mainly in Tumor cells, macrophages, epithelial cells,
      Fibroblasts , and activated T-cells. Although galectin-1 has been shown to induce T-cell apoptosis, galectin-3 has conversely been shown to prevent cell death induced by Fas ligation. Galectin-3 has been shown to rescue cells from apoptosis by protecting against alterations of the mitochondrial membrane and formation of reactive oxygen species. A growing body of evidence supports the involvement of galectin-3 in tumor growth and metastasis.

      Galectin-3 and IL-10 receptor needs to be inhibited to break the rest of the tolerance so the immunotherapy can have a greater effect with a better response rate.

      Radiation + Yervoy + Anti-PD-1 + Anti-IL-10 receptor + GAL-3 Inhibitor= Robust immune response

      “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,
      Jimmy B
       

       

       

       

    Viewing 2 reply threads
    • Replies
        boot2aboot
        Participant

          who is doing the primary research on this? Do we know how far along a Gal3 inhibitor is?  

          boots

            jim Breitfeller
            Participant

              Galectin Therapeutics

              http://www.galectintherapeutics.com/programs/pipeline.php 

              The drug GM-CT-01  is in a phase 1/2

              Tumor Vaccines

              We are initiating a clinical trial program to investigate our compounds for enhancing the immune system to kill cancer cells in conjunction with tumor vaccines. Galectin-3 is thought to play a key role in diminishing the ability of TIL to kill tumor cells and blocking the action of galectin-3 is believed to improve the efficacy of T lymphocytes in killing tumor cells, as demonstrated in preclinical studies.

               

              We recently initiated a Phase 1/2 clinical trial of GM-CT-01 in combination with a tumor vaccine in patients with advanced melanoma, a deadly skin cancer. The trial is being conducted at three centers in Belgium and one in Luxembourg. The operational conduct of the trial is under the control of the Cancer Centre at the Cliniques Universitaires Saint-Luc and the Ludwig Institute for Cancer Research. The study has been initiated and the operations for beginning to enroll patients are underway. Positive results from this study could indicate that inhibiting the "Galectin Effect" could be an enabling technology for therapy in other tumor types. 

              http://www.galectintherapeutics.com/programs/tumor-vaccines.php 

               

              Best regards,

               

              Jimmy B

               

               

              jim Breitfeller
              Participant

                Galectin Therapeutics

                http://www.galectintherapeutics.com/programs/pipeline.php 

                The drug GM-CT-01  is in a phase 1/2

                Tumor Vaccines

                We are initiating a clinical trial program to investigate our compounds for enhancing the immune system to kill cancer cells in conjunction with tumor vaccines. Galectin-3 is thought to play a key role in diminishing the ability of TIL to kill tumor cells and blocking the action of galectin-3 is believed to improve the efficacy of T lymphocytes in killing tumor cells, as demonstrated in preclinical studies.

                 

                We recently initiated a Phase 1/2 clinical trial of GM-CT-01 in combination with a tumor vaccine in patients with advanced melanoma, a deadly skin cancer. The trial is being conducted at three centers in Belgium and one in Luxembourg. The operational conduct of the trial is under the control of the Cancer Centre at the Cliniques Universitaires Saint-Luc and the Ludwig Institute for Cancer Research. The study has been initiated and the operations for beginning to enroll patients are underway. Positive results from this study could indicate that inhibiting the "Galectin Effect" could be an enabling technology for therapy in other tumor types. 

                http://www.galectintherapeutics.com/programs/tumor-vaccines.php 

                 

                Best regards,

                 

                Jimmy B

                 

                 

                jim Breitfeller
                Participant

                  Galectin Therapeutics

                  http://www.galectintherapeutics.com/programs/pipeline.php 

                  The drug GM-CT-01  is in a phase 1/2

                  Tumor Vaccines

                  We are initiating a clinical trial program to investigate our compounds for enhancing the immune system to kill cancer cells in conjunction with tumor vaccines. Galectin-3 is thought to play a key role in diminishing the ability of TIL to kill tumor cells and blocking the action of galectin-3 is believed to improve the efficacy of T lymphocytes in killing tumor cells, as demonstrated in preclinical studies.

                   

                  We recently initiated a Phase 1/2 clinical trial of GM-CT-01 in combination with a tumor vaccine in patients with advanced melanoma, a deadly skin cancer. The trial is being conducted at three centers in Belgium and one in Luxembourg. The operational conduct of the trial is under the control of the Cancer Centre at the Cliniques Universitaires Saint-Luc and the Ludwig Institute for Cancer Research. The study has been initiated and the operations for beginning to enroll patients are underway. Positive results from this study could indicate that inhibiting the "Galectin Effect" could be an enabling technology for therapy in other tumor types. 

                  http://www.galectintherapeutics.com/programs/tumor-vaccines.php 

                   

                  Best regards,

                   

                  Jimmy B

                   

                   

                boot2aboot
                Participant

                  who is doing the primary research on this? Do we know how far along a Gal3 inhibitor is?  

                  boots

                  boot2aboot
                  Participant

                    who is doing the primary research on this? Do we know how far along a Gal3 inhibitor is?  

                    boots

                Viewing 2 reply threads
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