Thursday, July 30, 2009

The Devil is in the Details.. All in the Timing and concentration of the Interluekin-2..Melanoma ..Jim Breitfeller

The Devil is in the Details.. All in the Timing and concentration of the Interluekin-2

This short paper is dedicated to all the Melanoma Patients that didnot get a complete response with IL-2 Therapy.

“Administration of (IL-2) Interluekin-2 during the initial phase of the response, clonal expansion and development of the effector function had no effect on the number of (CTL) Cytotoxic T Lymphocytes generated or control of tumor growth. In contrast, a short two day times course of low dose IL-2 at the peak of clonal expansion or at later times resulted in prolonged and expanded responses by the OT-1 CTL, with concomitant decrease in tumor load (Shrinkage) and extension of Survival.”1

An antigen (Ag) recognition event is not predetermined. T-cells that are stimulated by self Ag generally fails to proliferate effectively and undergo induced Apoptosis (programmed cell death) or develop clonal anergy (lack of energy leading to inactivity).

T-cells that are activated with non-self Antigen (Tumor specific antigen) undergo robust clonal expansion that leads to a large generation of effector T-cells, clearance of the foreign antigen-tumors, as well as development of memory cells.

A new cell growth model: IL-2 T-cell system has been postulated by K A Smith and colleagues. In their model, they show that three factors are critical for T-cell cycle progression.

1. Interleukin-2 concentration
2. Interleukin-2 receptor density on the T-cells
3. The duration of the interleukin-2 receptor interaction

Since we only have somewhat of control over Interleukin-2 concentration, the rest of the paper will focus on IL-2 concentration.

By limiting the exogenous IL-2 at the initial response phase, the T-cells in particular, the CD4 + and the CD8 + T-cells have to compete for the IL-2 that is secreted from the cells after activation. It is generally accepted that the T-cells must secrete IL-2 to aid in the expansion and survival of the T-cells. With this clonal expansion of the CD4 + T-cells also generates more subsets including the T-Regulatory foxp3 (CD4+ CD25+ FoxP3).
Tregs cells are notorious for suppressing an immune response. The Tregs cells make up
only 2-5 percent of the overall population of the CD4 + T-cells.

It has been shown that a 4-6 hour window of time was enough time to program the CD4 + T-cells to proliferate even after the separation of the antigen bearing presentation cell (APC). This activation time reflects the time needed to up-regulate the high affinity IL-2 receptor and secrete IL-2, thus facilitation of the IL-2 dependent expanding CD4 + T-cells.

It has been indicated Mueller et al that sustained (TCR) T-cell receptor and CD28 signaling is necessary to maintain an optimal rate of cell division in the presents of IL-2.
Once the antigen is cleared (used up) the CD4 + T-cells stop proliferating. So if you don’t have enough tumor specific antigens that are shed from the tumor, the expansion halts.
In a paper entitled “IL-2 Regulates Expansion of the CD4 + T-cell population by affecting Cell death, Ganusov and colleagues reported that the Il-2 has the most profound effect on the death rate of dividing CD4 + T-cells, specifically that the death rate increases with division number. Division number is the number of times the cells divide.

At the lowest IL-2 concentration, the CD4 + T-cells have the highest death rate over the divisions. They reported at the first cell division they encountered 20% of the cells dying. At the sixth division, the death rate increased to 90 %.


With the T-cells competing for IL-2, the consumption of the Interluekin-2 by the dividing CD4 + T-cells may cause the overall concentration in ones body to decrease causing a premature death to the T-cells. Without CD4 + helper cells, the CD8 + T-cells won’t get cross primed and activated. These CD4+ cells, called helper T cells, bind to antigen presented by B cells. The result is the development of clones of plasma cells secreting antibodies against the antigenic material.

As you can see it is a delicate balancing act. It is like the three bears, you need it just right. To little IL-2 will induce cell death and to much can cause a change in the feedback response loop causing the Tregs to undergo robust clonal expansion shutting down any chance of an immune response.

By increasing IL-2 concentration at the maximum propagation of the CD8+ T-cells, you actually extend the survival and the effector function of the CD8+ T-cells to mature into
Cytoxic T. Lymphocytes (CTLs).

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 devil is in the details!!!
Interluekin-2 concentration and timing of the addition of the exogenous IL-2 has a critical role to play in The Orchestration of an Inmmune Response.

Lastly, I am going to leave you with my graphical representation of my therapy that has save my life. Study it. I willing to bet that this graph is medical history in the making base on the science research that I did.



1. Opposing Effects of IL-2 in Tumor Immunotherapy: Promoting CD8 T Cell Growth and Inducing Apoptosis1
Protul Shrikant2 and Matthew F. Mescher3
Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455 The Journal of Immunology, 2002, 169: 1753-1759.

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.