Sunday, September 26, 2010

Eureka!!!The Right Immune Response..It is All in the Timing and IL-2 Concentration!!! Melanoma..Jim Breitfeller










So now we have the immune response in full progress. Are we creating the right response?

The difference between CD4+ T-cells and CD8+ T-cells revealed herein must be
interpreted in the context of its significance for the development of an effective
T cell immune response. Within T cell populations, CD4+ T-cells are the primary
source of IL-2 after antigen activation. Consequently, the finding that CD4+ T-cells
cell clonal expansion is only about 25% of the proliferative expansion achieved by
CD8+ T-cells indicates that IL-2 itself is the major parameter retarding clonal
expansion within the total cell population; especially because the rate of T-cell
proliferation is directly dependent on the amount of IL-2 available to the cells. et al Kendall A Smith

The ratio of CD4+ to CD8+ is about 2:1.
Thus, the immunologic relevance of the CD4+ T-cells IL-2 refractory state resides in
its potential as a feedback regulatory control retarding the extent and duration
of IL-2-dependent CD4+ T-cells and CD8+ T cell clonal expansion, ensuring that IL-2-
producing cells ultimately will become limiting.
This interpretation is entirely consistent with observations in lab experiments which indicate that IL-2 rapidly disappears from the culture medium of stimulated T cells.

So what happens if you have excess IL-2 in the Medium?
Studies show that a premature development of CD4+ T-cells IL-2-unresponsiveness arises and the CD4+ T-cells loose their functionality.
This means that premature excess of IL-2 can lead to unresponsiveness of the CD4+T-cells.

Thus, two mechanisms contribute to the depletion of IL-2 from the Medium of rapidly proliferating T cells:

1. The IL-2 internalization and degradation (the uptake) by responding cells
2. The end of CD4+ T-cells + (IL-2 producer) cell proliferative expansion


IL-2 concentration in the surrounding cell environment can regulate the expansion of the CD4+ T-cell population by effecting cell death.
As you keep the IL-2 concentration limiting, you can change the expansion profile if the CD4+T-cells. At low concentrations, the expansion distribution is sharpe and evenly distributive on the time axis. On the hand, at higher or excess concentrations, the distribution becomes skewed, with a longer life cycle.

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.
So by increasing the Treg population, you make it that much harder to break the immune tolerance to start an immune response.

So by limiting the excess IL-2 that is introduced into the host at the early expansion phase, you limit the expansion of the CD4+ T-cells. As the Tregs are a subset of the CD4+T-cells, you limit the expansion of the Tregs. By limiting the Tregs and CD4+ T-cells, you limit the CTLA-4 receptors. So blocking the B7 receptors with anti-CTLA-4 antibodies, and limiting the IL-2 in the matrix, you can shift the tolerance balance toward activation.


It is widely accepted that the CD4+ T-cells expand before the CD8+ T-cells.




Activation and Differentiation of (CTLs) Cytotoxic T Lymphocytes

Naïve CD8+ T-cells are referred to as CTL-precursors (CTL-Ps), which are incapable of performing any function other then recognizing the class I MHC-antigen complex on the Tumor cells through the (TCR) T Cell Receptor. For activation, the CTL-P needs at least three signals:

1. Antigen specific signal transmitted by the MHC I peptide/TCR complex for the recognition of the Antigen

2. The Costimulatory signals transmitted by the CD28 receptor and the B7 molecule of the Antigen Presenting Cells (APCs)

3. Cytokine induced signal, IL-2 interaction with the IL-2r (receptor) on the CTL-P leading to activation and differentiation of the CTL-P into effector CTL

The Cytokine IL-2 came from the TH1 cells which means the CTL-P is IL-2 limited and can only be activated by the secreted IL-2 if there is any to be had or by introducing IL-2 through IL-2 therapy. Now you know the reasoning behind using the IL-2 therapy as the second part of the combinatorial Therapy. If there is not enough IL-2 in the host environment, you will only get partial expansion of the CTLs. It may not be enough to eradicate large bulky tumors.

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. 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.

Research suggests that the primary mode of the destruction of the tumors by CTL is by initiating death through the Fas-FasL pathway. Studies have shown that CTLs store Cytotoxic proteins in the form of granules in their cytoplasm. These proteins belong to two categories:
1. Perforins: involved in pore formation
2. Granzymes: responsible for hydrolysis of the cellular products.

Granzymes breaks down the tumors cells just like your detergent enzymes in your laundry detergent.

Immediately following a CTL contact with the tumor cell, the Golgi sacks load with granules and granzymes which create pores to allow the granzymes to enter and destroy the tumors cells.


So what if there is not enough IL-2 produced to supply the overall expansion?

We know the Naïve CD8+ T-cells needs IL-2 for the activation and the differentiation into effector T-cell call Cytotoxic T Lymphocytes (CTLs). We also know IL-2 is needed to upregulate perforin and granzyme A, B and C genes which need to turn the effector cell into a cytotoxic killing machine.

Does the timing of the addition of IL-2 make a difference in the outcome of the immune response?

It surely does. There are a number of research papers that state if the IL-2 is added to early in the expansion phase, you produce non-responsive T-cells. As a matter of fact you could expand the subtype Tregs by a factor 5 under certain conditions. On the other hand, waiting until the expansion is at just passed peak or contracting generates the Cytotoxic T Lymphocytes (CTLs) that we as patients, have been waiting for. That is why Dr. Rosenberg uses IL-2 in his ACT Therapy. It is to generate and maintain the Cytotoxic T Lymphocytes.









Eureka!!!The Right Immune Response..It is All in the Timing and IL-2 Concentration!!! Tumor Shrinkage!!!!
Complete Response!!!!!!


“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

Disclaimer

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
(not a PASSIVE RECIPIENT)"

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.

Preview:

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..

https://app.box.com/shared/kjgr6dkztj

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.


http://www.melanomaresearchalliance.org/news/PSA/

Source Fastcures blog



Join the Relay for Life!!!

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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!!!

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Sincerely,

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

How Skin Cancer Develops by "About.com : 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)
PingpankJF@UPMC.edu


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.