Monday, March 12, 2012

Is this the smoking gun to Melanoma and the reoccurrence the plasticity of the Macrophages?..Jim Breitfeller

Is this the smoking gun to Melanoma and the reoccurrence the plasticity of the Macrophages? The (TAM) Tumor Associated Macrophage or more precisely M2-Like Phenotype.
In my search for answers, I have been focusing in on how the tumor escapes detection by the immune system. We need to know what is going on in vivo during the different stages of melanoma.

The tumor mass is undoubtedly a multifaceted show, where different cell types, including neoplastic cells, fibroblasts, endothelial, and immune-competent cells, interact with one another continuously. Macrophages represent up to 50% of the tumor mass, and they certainly operate as fundamental actors. Macrophages constitute an extremely heterogeneous population; they originate from blood monocytes, which differentiate into distinct macrophage types, schematically identified as M1 (or classically activated) and M2 (or alternatively activated).

It is now generally accepted that TAMs have an M2 phenotype and show mostly pro-tumoral functions, promoting tumor cell survival, proliferation, and dissemination. High levels of TAM are often, although not always, correlated with a bad prognosis, and recent studies have also highlighted a link between their abundance and the process of metastasis.

In a recent 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.

Immunohistologic Characteristics of Tumor Infiltrating Immune Cells

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? We need to push the differentiation of the macrophages towards the M1 phenotype.

Macrophages are important tumor-infiltrating cells and play pivotal roles in tumor growth and metastasis. Macrophages participate in immune responses to tumors in a polarized manner: classic M1 macrophages produce interleukin (IL) 12 to promote tumoricidal responses, whereas M2 macrophages and M2-Like produce IL10 and help tumor progression. The mechanisms governing macrophage polarization are unclear but in 1990 it was discovered treatment of M2 macrophages with GM-CSF or IFN-gamma led to production of M1 phenotypic markers upon LPS stimulation. It also has been seen that if you block the IL-10 receptor with an antibody along with LPS (TLR4 agonist) stimulation or CpG (TLR9 agonist) stimulation you shift the Macrophage plasticity towards the M1 phenotype.

So what causes the high Macrophage (M2) to migrate towards the Tumor and its microenvironment? Does the tumor somehow recruit these (TAMs) Tumor Associated Macrophages? What are the characteristics of the M2 phenotype?

Hallmarks of M2 macrophages are IL-10high IL-12low IL-1rahigh IL-1 decoyRhigh production, CCL17 and CCL22 secretion, high expression of mannose, scavenger and galactose-type receptors, poor antigen-presenting capability and wound-healing promotion.

CCL17 and CCL22 chemokines within tumor microenvironment are related to infiltration of regulatory T cells in Macrophage 2 in melanoma. Early Detection of Tumor Cells by Innate Immune Cells leads to Treg Recruitment through CCL22 Production by Tumor Cells and Tumor Assocated Marophages (TAMs). It has been suggested that at early times during tumorigenesis, the detection of tumor cells by innate effectors (monocytes and NK cells) imposes a selection for CCL22 secretion that recruits Treg to evade this early antitumor immune response. The activated T-cells upregulate the CTLA-4 and PD-1. PD-1 ligation induces IL-10 production by monocytes, which together with PD-1 inhibits CD4+ T cell responses/activation. This is way for the immune system to use a checkpoint so that immune response does not lead to an autoimmune response. These receptors keeps the immune system in check.

Now in another paper I found this:

If you look at the above micrographs, you will see that the two patients that had relapsed (10710 and 10737) had IL-1b and IL-6 and TNF alpha missing. The macrophages were not activated!!!! The "Danger Signal" known as inflammation was missing! The non-responders most likely had their macrophages polarized to a M2-like phenotype by the Tregs and or IL-10.

So if the Macrophages are M2-like in the Tumor’s microenviroment, then if we control the Tregs, the upregulation of the of CTLA-4, PD-1 on the T-cells including the Tregs, and control the IL-10 production through anti-IL-10 antibody on the macrophages, we can shift the M2-like Macrophages into the M1 thus producing IL-12 shifting the differentiation of the Niave CD4+ T-cell the TH1 phenotype to activate the T-cells.

This all can be done with Yervor, Anti-PD-1 and Anti-IL-10 receptor antibody. You can get the tomor to shed antigentic protein by either whole radiation, Chemotherapy (TMZ- + Patrin-2) or Heat Shock.

CpG oligonucleotides induced NF-_B activation through the triggering of TLR9 signaling in TAM (Fig. 2), and the co-use of an IL-10 receptor Ab reduced IL-10 signaling in TAM, thereby reducing their M2 polarization.

Plasticity of Macrophage Function during Tumor Progression: Regulation by Distinct Molecular Mechanisms

HMGB1 from the dying tumors (irradiation, Chemotherapy, Heat Shock) will act as the Danger signal and bind to the TLR4 and activating the Macrophage (M1) and secrete IL-12 which acts upon the naïve CD4 T helper cells to differentiate to the Th1 phenotype.

petoh et al. has revealed an interesting role of TLR signalling in cancer therapy. They studied the immune-stimulatory properties of dying tumour cells after chemotherapy or radiation therapy. Using TLR4 and MyD88-deficient DCs, they show that TLR4 signaling is required for crosspresentation of antigens from apoptotic tumour cells on MHC class I to generate antitumour cytotoxic T cell (CTL) responses. Apetoh et al.also identified a “danger signal” from dying tumour cells, the nuclear protein highmobility group box 1 protein (HMGB1, see Figure) that triggers this protective immune response through activation of TLR4. According to their work, the interaction of high mobility group box 1 protein (HMGB1) released from dying tumour cells with Toll-like receptor 4 (TLR4) on dendritic cells is required for the crosspresentation of tumour antigens and the promotion of tumour specific cytotoxic T-cell responses.

So to sum it up, If you take Yervoy + Anti-PD1 + Anti-IL-10 along with radiation/Chemo could we get the right T-cell activation and Immune Response?

My guess you will activate the TLR4 pathway and induce the RIGHT IMMUNE RESPONSE.

So can we Get the Oncologists on board to propose and setup a clinical trial?
Time will only tell.
Remember the this blog. It will lead to a CURE!!!

“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


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Greetings to One and All

This Blog is dedicated My Brother Kenny B. who passed away in the late 1970's with Cancer before the Internet.

It was he, who showed me How to live and give back. He was wise beyond his years.

Kenny B

Jimmy and Dee

Carepage: Jimmybreitfeller
Jimmy Breitfeller

My Profile as of 2009

My photo
Last July (2005)I was riding my bicycle to work at the Eastman Kodak Research Labs about 3 miles from home. I was wearing a knapsack to carry my things to and from the labs. I started noticing an ache on my back. So I decide to go to the dermatologist. To make the long story short, it was cancer. I knew from my research that I would be needing adjuvant therapy. So I started communicating with Sloan Kettering, University of Pittsburgh Cancer Center, and a couple of others including the Wilmot Cancer Center at Strong. I realized that by telling my story, I might help someone else out there in a similar situation. So to all who are linked by diagnosis or by relation to someone with melanoma, I wish you well. Stay positive, read as much as you can (information helps to eliminate the fear associated with the unknown), and live for today, as no one can predict what tomorrow may bring. Jimmy B. posted 12/15/08


The information contained within this Blog is not meant to replace the examination or advice of your Oncologist or Medical Team. The educational material that is covered here or Linked to, does not cover every detail of each disorder discussed.

Only your physician/Oncologist can make medical decisions and treatment plans that are appropriate for you. But, An Educated Consumer is a Smart consumer.

As Dr. Casey Culberson Said:

"The BEST melanoma patient is an ACTIVE PARTICIPANT in his or her treatment

Melanoma and the “Magic Bullet” (Monoclonal Antibodies)

Just to let you know I posted the first draft of the Melanoma and the “Magic Bullet” (Monoclonal Antibodies). on Melanoma Missionary In the Shared File Section. you can download it for 19.95 (Only kidding) it is Free for the taking.

It is 33 pages long and may help you in your quest for the Yellow Brick Broad. Just to let you know it is only the first draft. Revisions are sure to come. I wanted to get it to the people that need it the most, the Melanoma Patients.


So, where does Interluekin-2 (IL-2) come into play? According to Byung-Scok et al and recent reports, IL-2 is not needed for developmental CD4+ CD25+ Treg cells in the thymus but does play an important role in the maintenance and function in the peripheral.18 Peripheral is defines as secondary system outside the bone marrow and thymus. It entails the site of antigen, immune system interaction. IL-2 is required for the peripheral generation of Tregs based Abbas’s and colleagues research.19

IL-2 prevents the spontaneous apoptosis of the CD4+ CD25+ Treg cells. It has been reported that patients with multiple advance-stage tumors have elevated levels of Tregs within the tumor microenviroment.20 Interluekin-2 is the survival factor for CD4+ CD25+ Treg cells.21 If the addition of IL-2 is on or before the maximum propagation of the CD4+ T cells, the Tregs population can increase 5-fold in a 96 hour period based on certain growth mediums.

By controlling the addition of the endogenous IL-2, one has a knob to turn and can lead to the control of the expansion of the Tregs. When you combined this control with the anti-CTLA-4 blockage, you can shift the balance of the immune response.

Now here is the catch. The maintenance and function of the CD8+ T-cells require CD4+ cells which secrete IL-2. So we don’t want to deplete the CD4+ cells, we want to control the expansion of the Tregs which are a subset of the CD4+ cells. It has been postulated by some researchers that the Anti-CTLA-4 blockage also suppresses the Treg function in a different mechanism. By using IL-2 as the rate limiting factor, we can suppress the CD4+ CD25+ Treg cell expansion by controlling the concentration and timing of the Inerluekin-2 at the tumor microenvironment.

The Interluekin-2 plays another role in this Melanoma Maze. In a study by Janas et al, Il-2 increases the expressions of the perforin and granzyme A, B and C genes in the CD8+ T-cells. This increase expression causes the CD8+ T-cells to mature into Cytoxic T Lymphocytes (CTLs). The exogenous IL-2 is required for the granzyme proteins. As stated previously, CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. 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. Once in the tumor cell, these enzymes are able to breakup (lyse) the cell and destroy it. This is the beginning of the end for the cancer cells. The tumors begin to shrink and the rest is history,

On the other hand, prolong therapy with Il-2 can result in causing apoptotic death of the tumor- specific CD8+ T-cells.23

Clearly in a clinical setting, timing, dose, and exposure to these drugs play a major roll in the immunotherapy, and can have dramatic effects on the outcome.

All it takes is that one magic bullet to start the immune reaction..

Melanoma And The Magic Bullet (Monoclonal Antibodies)

Public Service Announcement

A call for Melanoma Patients by Dr. Steven A Rosenberg

"We continue to see a high rate of clinical responses in our cell transfer immunotherapy treatments for patients with metastatic melanoma", Dr. Rosenberg said.

"We are actively seeking patients for these trials and any note of that on a patient-directed web site would be appreciated."

If you would like to apply for his trials, here is the website and information.

Dr. Rosenberg's information

Dr. Rosenberg's Clinical Trials

For the Warriors

The Melanoma Research Alliance has partnered with Bruce Springsteen, the E Street Band, and the Federici family to alleviate suffering and death from melanoma. Please view Bruce Springsteen’s public service announcement inspired by Danny Federici. Danny was the E Street Band’s organist and keyboard player. He died on April 17, 2008 at Memorial Sloan-Kettering Cancer Center in New York City after a three year battle with melanoma.

Source Fastcures blog

Join the Relay for Life!!!


Dear Family and Friends,

I’ve decided to take a stand and fight back against cancer by participating in the American Cancer Society Relay For Life® event right here in my community! Please support me in this important cause by making a secure, tax-deductible donation online using the link below.

To donate on line now, click here to visit my personal page.
Jimmy B AKA Melanoma_Missionary

Relay For Life® is a life-changing event that brings together more than 3.5 million people worldwide to:

CELEBRATE the lives of those who have battled cancer. The strength of survivors inspires others to continue to fight.

REMEMBER loved ones lost to the disease. At Relay, people who have walked alongside people battling cancer can grieve and find healing.

FIGHT BACK. We Relay because we have been touched by cancer and desperately want to put an end to the disease.

Whatever you can give will help - it all adds up! I greatly appreciate your support and will keep you posted on my progress.

Keep the Fire Burning!!!



Jimmy Breitfeller
Turn off Music before you "Click to Play"
Signs of Melanoma Carcinoma Skin Cancer

How Skin Cancer Develops by " : Dermatology"

Call for Patients with Unresectable Liver Metastases Due to Melanoma

Delcath Systems Granted Orphan-Drug Designations for Cutaneous and Ocular Melanoma

Delcath is actively enrolling patients in a Phase III clinical trial testing its proprietary drug delivery system, known as Percutaneous Hepatic Perfusion (“PHP”), with melphalan for the treatment of ocular and cutaneous melanoma metastatic to the liver.

This NCI-led trial is enrolling patients at leading cancer centers throughout the United States. Commenting on these orphan-drug designations, Richard L. Taney, President and CEO of Delcath, stated, “These favorable designations are important steps in our efforts to secure Delcath’s commercial position upon conclusion of our pivotal Phase III trial for metastatic melanoma. We remain steadfast in our commitment to become the leader in the regional treatment of liver cancers and we continue to enroll patients in this study, and advance our technology and the promise that it offers to patients with these deadly forms of melanoma and other cancers of the liver, all with limited treatment options.”

Orphan drug designation, when granted by the FDA’s Office of Orphan Products Development, allows for up to seven years of market exclusivity upon FDA approval, as well as clinical study incentives, study design assistance, waivers of certain FDA user fees, and potential tax credits.

Current Trial Centers

Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using
Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies

James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology
Suite 406, UPMC Cancer Pavillion
5150 Centre Avenue
Pittsburgh, PA 15232
412-692-2852 (Office)
412-692-2520 (Fax)

Blog Archive

Call For Melanoma Patients!!!!

Call For Melanoma Patients!!!!

Dr. Rosenberg Has a New Clinical Trial.

Our latest treatment has a 72% objective response rate with 36% complete responses.

We are currently recruiting patients for our latest trial.

Is there some way to post this “Call for Patients” on the web site?

Steve Rosenberg

Dr. Rosenberg's Clinical Trials

(For a copy of the research paper.. see My Shared files)

The news headlines shown above for Melanoma / Skin Cancer are provided courtesy of Medical News Today.