Jim Breitfeller, a patient/survivor/researcher of Matastatic Melanoma has so far beaten the odds of survival. After years of researching his own treatment, he has scientifically figured out why his treatment has worked. Jim explains it like this:
“You need the tumor specific antigens, (The Keys), you need the (Spark Plug) Anti-CTLA-4 and you need the (Gas) IL-2. Without these three key components your car won’t run.”
CTLA4 Role in Immune Function
Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA4) is a protein involved in T-cell expansion or replication and activation in response to an immune event. Following T-cell stimulation, T-cell proliferation is up-regulated. Following successful response, CLTA4 is also up-regulated, which then sends an inhibitory signal to down-regulate or decrease T-cell proliferation and IL-2 production. This is one of the brakes associated with immune system so it won’t go into overdrive and create a possible autoimmune event.
In the presence of the tumor’s microenvironment, the CTLA4 molecule is upregulated on the T-Cells with the help of TGF-beta, a suppressive Cytokine secreted by the tumor cells. TGF-beta requires CTLA-4 early after T-Cell Activation to Induce FoxP3 and generates adaptive CD4+CD25+ Regulatory Cells. et al Song Guo Zheng and colleagues.
If you add the combination of IL-2 and TGF- beta at the beginning of the treatment, it induces naive or total CD4+CD25– cells to develop strong suppressive effects both in vitro and in vivo according to Horwitz et al 2001. The T-Cell differentiation is pushed towards developing Treg suppressive immune cells.
Anti-CTLA4 monoclonal antibodies block the ability of CTLA4 molecule to down-regulate T cell proliferation. The theory behind this therapy is that by decreasing the inhibitory signal, there will be a subsequent increase in the number of activated T-cells available, to improve the ability of the T-cells to recognize melanoma cells as non-self.
Tregs show remarkably suppressive activities on different components of the immune system, including T lymphocytes and dendritic cells, suggesting they act both at the initiation phase (DC) and at the effector phase (activated T cells) of the immune response. Interestingly, temporal depletion of Treg has been shown to enhance anti-tumor immune responses and in case of prolonged absence of Treg even autoimmunity.
The green boxes show possible Therapeutic Intervention,
By blocking the CTLA-4 receptor, you keep the T-cell activated, you push the T-cell differentiation towards the TH17 cells and you now have that the Third signal, (The inflammatory signal) that is needed to induce an Immune response. et al Ribas
By adding the HD IL-2 after the expansion of the T-cells, IL-2 therapy was highly beneficial during the death phase, resulting in increased proliferation and survival of tumor-specific T cells. IL-2 treatment also increased proliferation of resting memory T cells. et al Wherry
CTLA-4 blockade in cancer immunotherapy.
Dendritic cells can sample tumor antigens and present them to T cells. (A) Although activation of dendritic cells may result in upregulation of B7.1/B7.2, the potentially responsive T cells expressing reactive TCR may be inhibited from effector function by inhibitory signaling via CTLA-4 and PD-1.
Blockade of CTLA-4 signaling may allow unopposed CD28 costimulation, resulting in recruitment of these T cells as antitumor effectors, either directly or as helpers of CD8-mediated T cells responses. Activated cytotoxic T cells can then affect antitumor responses. CTLA-4 expressing regulatory T cell populations may still be locally active in suppressing antitumor responses. Their activity could also be directly downregulated by CTLA-4 blockade, although the relative importance of CTLA-4 expression to their function remains controversial.
Recent research by Probst et al reveal that resting dendritic cells induce peripheral CD8+ T-cell tolerance through the PD-1 and the CTLA-4 molecule/surface receptor. Blocking the costimulatory molecule CTLA-4 resulted in breaking the tolerance.
When you put the Melanoma Puzzle together, this is what you get,
A well Orchestrated Event, your immune system in action.
The Perfect Storm, the Orchestration of an Immune Response Unrehearsed
• Early after the CD4+ T-cells are activated, the CTLA-4 receptors are upregulated according to the research.
• TGF- beta requires CTLA-4 upregulation early after T Cell Activation to Induce FoxP3 and generate adaptive CD4+CD25+ Regulatory Cells. Song Guo Zheng et al and colleagues.
• By blocking the CTLA-4 receptor, you keep the T-cell activated, you push the T-cell differentiation towards the TH17 cells and you now have that the Third signal, (The inflammatory signal) that is needed to induce an Immune response. Ribas et al
• If you add the combination of IL-2 and TGF- beta at the beginning of the treatment,it induces naive or total CD4+CD25– cells to develop strong suppressive effects both in vitro and in vivo according to Horwitz et al in 2001.
• By adding the The HD IL-2 after the expansion of the T-cells, IL-2 therapy was highly beneficial during the death phase, resulting in increased proliferation and survival of tumor-specific T cells. IL-2 treatment also increased proliferation of resting memory T cells. Wherry et al
Here are some other papers I have written that puts the Melanoma Therapy into perspective.
Melanoma and the Magic Bullet [Monoclonal Antibodies]
The Making of an Immune Response by Combinatorial Therapy using Anti-CTLA-4 Blockade and Interluekin-2
Déjà vu Blame it on the tregs]
The Missing Link in T-cell Activation
Take Care,
Jimmy B
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