Using Immunohistologic Characteristics of Tumor Infiltrating Immune Cells to the advantage of Melanoma Patients.Jim Breitfeller

In the research paper “Immunotype and Immunohistologic Characteristics of Tumor Infiltrating Immune Cells are Associated with Clinical Outcome in Metastatic Melanoma”1 et al Slingluff 2012, it breaks down the Immunohistologic Characteristics into three distinct immunotypes:

A) No infiltration of immune cells in the tumor’s microenvironment.
B) Infiltrating Immune cells only in close proximity to the tumor’s vascular system
C) Diffuse immune cell infiltrates throughout a metastatic tumor and its microenvironment.





Overall, the most predominant immune cells were T cells (53%), followed by the B cell lineage cells (33%), and then by macrophages (13%), with NK and mature dendritic cells only hardly present.

With the setting of the tumor’s microenvironment evaluated, we will focus the low survival immunotype A patients. How can we improve the overall survival and the immune response to Melanoma?

Here are just some of the therapies we have to date:

Dacarbazine (FDA approved)
High Dose Interluekin-2 (FDA approved)
Yervoy (Anti-CTLA-4) (FDA approved)
Zelboraf (Braf inhibitor) (FDA approved)

These therapies work well in a subset of melanoma patients but the overall survival rates are still quite low. We need to somehow combine these immunotherapies with a cancer vaccine to invoke an immune response with memories T-cells so we can eliminate any reoccurrence.
Oncologists have been working on this for decades.

I believe they may have discovered the right combination to just that. Dr. Kingston Mills and colleagues from the Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Immunotherapy with PI3K Inhibitor and Toll-Like Receptor
Agonist Induces IFN-g þIL-17þ Polyfunctional T Cells That
Mediate Rejection of Murine Tumors

Neil A. Marshall1, Karen C. Galvin1, Anna-Maria B. Corcoran1, Louis Boon3,
Rowan Higgs2, and Kingston H.G. Mills1,2

Authors' Affiliations: 1Immune Regulation Research Group, School of
Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity
College Dublin, Dublin, Ireland; 2Immunology Research Centre, Trinity
Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; and
3Bioceros, Utrecht, The Netherlands


Dr. Mills and colleagues discovered that if you combine a PI3k inhibitor with TRL agonists (TRL-9 and or 5) with DC vaccine/tumor antigen, you invoke a tremendous immune response along with memory cells.





This combination actually tilts the T-cell differentiation towards the Th1 phenotype that is needed to activate the CD8+ T-cells. I believe this is a major breakthrough toward curing/stabilizing the Melanoma Cancer.

The immune activation by CpG ODN +(PI3k inhibitor) initiates with specific binding to the TLR-9 receptor in B cells and plasmacytoid DCs. TLR-9 ligation in DCs results in secondary activation of lymphocytes, macrophage, monocyte, NK-cell, and T-cell populations through the elaboration of cytokines generating a Th1 cytokine milieu. This results in increased NK activity as well as improved antigen presentation and T cell help that can augment
humoral and cell-mediated immune responses. In addition, TLR ligation results in the production of IL-6 by DCs, which helps overcome the suppressive effect of CD4 CD25 Treg cells.

We must break the tolerance to generate immune responses against the tumor antigens.

This combination developes a population of polyfunctional T-cells that produce interferon-gamma and IL-17, both potent mediators of the immune response. Moreover, the combination has a lasting effect. This combination also produces the “Danger Signal” that is needed to recruit the immune cells to the tumor’s microenvironment.






A fledgling startup company (Trimod Therapeutics) holds the patent to this technology.

Dr. Jeremy Skillington
http://www.trimodtherapeutics.com/

As stated in my previous post, we need a cancer vaccine with Anti-CTLA-4 and IL-2 to produce a lasting immune response. I believe this company holds the future of immunotherapy cure/stabilization for Melanoma and maybe more cancers. Only time will tell with the right Clinical protcol in place. This is years away, but holds a temendous promise due to the science behind it. We need to expidite this rationale for the good of the Cancer patients.





“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