Friday, April 10, 2009

Controlling Cancer by anti-CTLA-4 blockage Melanoma ..Jim Breitfeller

Controlling cancer by blocking exhaustion?

By iayork

"The other day I talked about about resurrecting the antiviral response in HIV patients. 1 Antiviral T cells in HIV (and other chronic immune responses) become exhausted: After long exposure to antigen, the cytotoxic T lymphocytes (CTL) become dysfunctional, incapable of mounting a potent response to the virus. This exhausted state is correlated with a number of surface flags, especially the molecules PD-1 and CTLA-4. These aren’t merely flags, but rather they actually transmit the signal to become exhausted. So it turns out that blocking PD-1 reversed the exhaustion, restored CTL to their youthful vigor, and allowed them to effectively suppress the virus replication. All the monkeys treated with PD-1 blockade survived, whereas most of those left untreated died within a few months.

As I say, exhaustion isn’t unique to HIV. Probably any chronic exposure to antigen tends to cause T cell inhibition. There’s molecular logic behind this; if you’ve been fighting an infection for many months, you’re probably not winning, and your immune response is probably doing as much damage as the infection would. Or — even worse — you’re not fighting an infection at all, you’re attacking yourself (because of course you can’t eliminate your own antigens). So maybe it’s time to back off a few notches on the attack and try to reach an accommodation with the antigen.

There are a number of cases — probably many cases — where this seems to work well. Rodents that are chronically infected with hantaviruses turn on a regulatory T cell (TReg) type response, shutting own the attack on the virus and letting them become persistent infections. This comes with some cost, but not too much; probably the infected rodents do much better by letting the virus persist, than if they kept trying to fight the infection.

TRegs in skin

There’s another condition when T cells chronically attempt to attack foreign antigen, frequently fail to eliminate it, and become inhibited. This is, of course, cancer. The nature of the CTL inhibition may not be exactly the same as in HIV infections and other CTL exhaustion scenarios, but it’s pretty clear that in general, CTL are not very effective against tumors. After all, most tumors don’t spontaneously regress after a few weeks.

This is probably because when CTL are effective against tumors, that tumor never becomes detectable. In other words, we are only aware of those cancer where CTL are ineffective. (See here (part I) and here (part II) for more detail.) What often happens with tumors, that may be less of an issue with virus infections, is that TRegs become activated and move into the tumor; TRegs shut down aggressive immune responses. As a result, even if you infuse the patient with active anti-tumor cells, or vaccinate and activate the anti-tumor response that way, the anti-tumor response is often quickly shut down by the TRegs and the response never really goes very far.

So can the ineffective T cell response in tumors be reversed, as was done with the ineffective T cell response in SIV? It certainly can — but, as with most anti-tumor immune therapies, it doesn’t work all the time.

With tumors, unlike virus-associated exhaustion, the CTL dysfunction seems to be often associated with the CTLA-4 cell marker. As with PD-1, CTLA-4 isn’t just a marker, it transmits signals into the T cell and actively drives the cells into an inhibited state. (CTLA-4 is probably part of the TReg arsenal, though not the whole of it.) So blocking CTLA-4 in tumor patients has been of intense interest for quite a long time — I think Jim Allison first tried it well over a decade ago2. In general the results have been encouraging, but unspectacular. (It seems that immune treatment of cancer is always encouraging but unspectacular. The problem has been to get consistent effectiveness, rather than occasional amazing cures.)

Melanoma blood vessel

This isn’t a safe and innocuous treatment. CTLA-4 is part of the normal immune regulation machinery, and given that, it’s not surprising that CTLA-4 blockade often leads to autoimmunity. In fact, it seems that the more effective the anti-tumor effect is, the more likely the patient is to develop autoimmunity - sometimes quite severe. Compare this to the PD-1 blockade in monkeys, where there wasn’t much autoimmunity, if any. (Incidentally, before the PD-1 blockade that seemed to work, CTLA-4 blockade has been tried in SIV-infected monkeys. It didn’t seem to do much.)

A recent paper3 has connected CTLA-4 blockade to the emerging theme of polyfunctionality. As I’ve noted before, it’s become clear over the past couple of years that not all CTL are equal. In HIV infection, polyfunctional CTL — CTL that are capable of producing a wide range of effects, rather than just one or two — are often linked to suppression of the virus. In melanoma patients treated with CTLA-4 blockade, not only were more T cells specific for melanoma antigens present, but those CTL were more likely to be polyfunctional — thus more likely to be effective at destroying the tumor — and those patients were much more likely to have regression of their tumors than in people without CTLA-4 blockade.

So the concept that TRegs — or some other inhibitory effect associated with CTLA-4 — suppress anti-tumor immune responses is likely to be correct, and it seems that at least in some cases it’s possible to override that inhibition and drive T cells to once again attack the tumor effectively. When that happens, cancer can be cured. It’s just a question of being able to do this on a consistent basis. Unfortunately, that’s still the hard part."

Controlling cancer by blocking exhaustion?

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.