As you Know I have been off line lately. I have been following up on some research that I have been doing and actually fired another letter to Dr. Rosenberg. It all has to do with Tregs (CD4+ CD25+ T-cells). They are Known for surpressing the immune response that we want. In Adoptive cell transfer done at the NCI, Rosenberg and colleagues do Lymphodepleting step before injecting the patient with (TILs) tumor-infiltrating lymphocytes. This is a systemic chemotherapy that transient elimination of host immune system includes:
suppressive cells
regulatory T (Treg) cells,
myeloid derived suppressor (MSC) cells,
Natural killer T cells (NKT) cells
cells competing for cytokines
transiently increased function of antigen presenting cells (APCs)
By doing this It gives the TILs a fighting chance of survival and activation. Il-2 is added for maintance and survival of the TILs.
So I came across a paper "CTLA-4 Blockade Confers Lymphocyte Resistance to Regulatory T-Cells in Advanced Melanoma: Surrogate Marker of Efficacy of Tremelimumab?"
Author by:
Cédric Ménard1,2, François Ghiringhelli1,4,5, Stephan Roux1,2, Nathalie Chaput1,2, Christine Mateus3, Ursula Grohmann6, Sophie Caillat-Zucman7, Laurence Zitvogel1,2 and Caroline Robert1,3
Authors' Affiliations: 1 Center of Clinical Investigations, CBT507, 2 Institut National de la Sante et de la Recherche Medicale U805, and 3 Department of Medicine, Dermatology Unit, Institut Gustave Roussy, Villejuif, France; 4 Department of Medicine, Centre Georges Francois Leclerc, 5 CRI Institut National de la Sante et de la Recherche Medicale 866, Faculté de Médecine, Dijon, France; 6 Department of Experimental Medicine, University of Perugia, Perugia, Italy; and 7 Institut National de la Sante et de la Recherche Medicale U561, Hôpital St. Vincent de Paul, Paris, France
Purpose: Anti–CTL antigen-4 (CTLA-4) monoclonal antibody (mAb) has led to encouraging antitumor activity associated with immune-related adverse events in patients with heavily pretreated melanoma. However, mechanisms of action and surrogate immunologic markers of efficacy have not been reported thus far.
Experimental Design: We monitored the immune responses of 10 melanoma patients included in a phase II clinical trial, which evaluated the efficacy of a second line of therapy of tremelimumab anti–CTLA-4 mAb in patients with metastatic melanoma. The frequency of blood leukocyte populations in association with T cell and regulatory T cell (Treg) functions were evaluated.
Results: Prior to therapy, patients with advanced melanoma presented with a severe CD4+ and CD8+ T cell lymphopenia associated with blunted T-cell proliferative capacities that could be assigned to Treg. Tremelimumab rapidly restored the effector and memory CD4+ and CD8+ T-cell pool and TCR-dependent T-cell proliferation that became entirely resistant to Treg-mediated suppression. Progression-free survival and overall survival was directly correlated with the acquisition of a biological response defined as the resistance of peripheral lymphocytes to Treg-inhibitory effects (obtained in 7 of 10 patients).
Conclusion: CTLA-4 blockade seems to be a valuable strategy to revive reactive memory T cells anergized in the context of stage IV melanoma, and our work suggests that memory T-cell resistance to Treg resulting from anti–CTLA-4 treatment might be a biological activity marker for tremelimumab in patients with melanoma.
I am the process of obtaining this Paper. I believe it holds another piece of the Melanoma puzzle.
Take Care
Jimmy B
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