Inducing a Immune Response.. Melanoma ..Jim Breitfller

The best way to fight cancer (Melanoma) in my opinion is to have your own immune system do the work. First one must activate the T-cells.
Activation of T cells requires both engagement of the (TCR) T Cell Receptor with a cognate peptide–MHC complex and an additional costimulatory signal. The antigen must be in the right configuration and be specific to the cancer. The antigen becomes part of the MHC complex. The T cell receptor is restricted to recognizing antigenic peptides only when bound to appropriate molecules of the major histocompatibility complex (MHC), also known in humans as Human leukocyte antigen (HLA).
Secondly one must have a co-simulative signal.

The best known co-stimulatory ligands (proteins) are members of the B7-family, B7-1 (CD80) or B7-2 (CD86), that are expressed on professional antigen-presenting cells (APCs) such as dendritic cells (DCs); these act through their receptor CD28 on T cells CTLA-4 (CD152) is a second receptor for CD80 and CD86, which is not expressed on most resting T cells but is induced upon T-cell activation. The interaction of CD80/CD86 with CTLA-4 has higher affinity than that with CD28, and down-regulates T-cell activation . Thus, CTLA-4 effectively competes with CD28 for CD80/ CD86 at later stages of the immune response to suppress the activation and bring about activation-induced nonresponsiveness (AINR) and/or activation-induced cell death (AICD). Down-regulation of T-cell function by CTLA-4 engagement appears to play a key role in development of T-cell tolerance or anergy towards self- or tumor antigens while antigenic stimulation in the absence of co-stimulatory signals is also tolerogenic.

So by introducing anti-CTLA-4, one can block the down-regulation of the T-cell and keep it activated for a longer period of time. By anti-CTLA-4 blockage, one can suppress the Treg and change the balance of the immune system to respond to the APC. Here is a list of Costimulatory receptors on T –Cells:

• CTLA-4
• PD-1
• 4-1BB
• HVEM
• CD 30
• OX40
• CD28
• CD27

By Treg depletion, you can also break the balance of anergy. Dr. Rosenberg uses Treg depletion prior to Adoptive Cell Transfer therapy.

Bottom line is you need to invoke this type activation to orchestrate an immune response.

Take care

Jimmy B