Peptide Vaccine Significantly Improves Response in Metastatic Melanoma, but also Rasies questions.Melanoma..Jim Breitfeller

Peptide Vaccine Significantly Improves Response in Metastatic Melanoma, but also Rasies questions.

The current study raises several questions, Dr. Ribas said, including the following:
Question- How does high-dose IL-2 induce tumor regression? "With over 20 years of study, we still don't have an answer."

Answer_I have a theory: The NaiveCD4 + the helper T cell, when activated, the Helper T –cell secretes mostly IL-2 which promotes growth and proliferation, and activation of T-cells, helper T cells and Natural Killer Cells. Once the helper cells mulitply, they start secreting other cytokines base on their costimulatory signals., concentration of antigen, and exposure to their microenviroment. This attracts more immune cells and the assault on the foreign invader begins. The HD IL-2 helps activates the CD4-T cell.Cell to to cell comunication.

At the Lymp Node drainage area, the lymphocytes (CD4+ and CD8+) with their T-cell receptors (TCRs) are able to scan the Dendtric cells (DC’s) for antigen-MHC molecules. (ag-MHC) major histocompatability complex (class I or II). Based on the two signal model, a second signal from CD28 molecule is needed to activate the T-cells (T-lymphocytes). If communcation breaksdown, and the TCR signal only happens, it can lead to tolerance by means of fuctional paralysis of the (APCs) Antigen presenting cells (Anergy) or by the induction of clonal deletion (apoptosis).

Anergic cells can act as regulatory T cells by competing at the sites of antigen presentation and adsorbing out stimulatory cytokines such as IL-2. This can halt the activation of the T- lymphocytes and no immune response is initiated. But after activation of the CD4+ T cells and growth of the T- cells, they cross-prime the CD8+ T cells and in the presence of HD IL-2 mature into (CTL) Cytotoxic T lymphocytes. Cross-priming is another name for cross-presentation. The role of the CD8+ T cells is to monitor all the cells of the body, ready to destroy any that express foreign antigen fragments in their class I molecules.

CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. When the CTL binds to its target, the contents of the granules are discharged. A dozen or more perforin molecules insert themselves into the plasma membrane of target cells forming a pore that enables granzymes to enter the cell. Granzymes are serine proteases. The serine proteases are a family of enzymes that cut certain bonds in other proteins. It is similar to what is in your laundry detergent. They are known as detergent enzymes. They break the bond between the dirt and the fabric. By breaking up these proteins, they start destroying the intracellular workings of the tumor cells.

Question- How do gp100 peptides improve outcomes of high-dose IL-2?


Answer-My guess, They attach to the Antigenic protein and form some sort of a complex and when the complex is processed by the Antigen Presenting Cell you now have more antigenic fragments then you would other wise, which means activating more T-cells improving the microenvironment.






The answers are base on my research and intuition.



Take Care,

Jimmy B