Friday, February 4, 2011

Immunotherapeutic Barriers at the Level of the Tumor Microenvironment..Melanoma .Jim Breitfeller

Last year I Blogged about the Missing Link in T-cell activation with a vaccine. We were missing the Proflammatory Cytokines that produce the "Danger Signal" to the Immune system. Well Dr. Gajewski has come out and has backed up my theory.

Along with that, there are Two companies that are persuing this theory with Cytokine Therapy.

Thomas F. Gajewski, MD, PhD (University of Chicago) presented on the key role that the tumor microenvironment plays in determining the outcome of a tumor immune response. He noted the complexity of the tumor with respect to its structural and cellular composition and that the functional phenotypes of these cells may or may not permit an effective anti-tumor response at either the priming or effector phase. Characteristics of the tumor microenvironment may dominate during the effector phase of an anti-tumor T cell response, limiting the efficacy of current immunotherapies by inhibiting T cell trafficking into the tumor, eliciting immune suppressive mechanisms within the tumor, altering tumor cell biology and susceptibility to immune-mediated killing, or modifying the tumor stroma (i.e., vasculature, fibrosis). These features can be interrogated through pre-treatment gene expression profiling of the tumor site in individual patients; such an analysis may identify a predictive biomarker profile associated with clinical response. This strategy may also help identify biologic barriers that need to be overcome to optimize therapeutic efficacy of vaccines and other cancer immunotherapies. Mouse models have helped to define the hallmarks of an anti-tumor response, taking into account the effector phase within the tumor microenvironment. Based on these models, a DC subset (CD8α+) appears necessary for priming of host CD8+ T cells through cross-presentation of antigen within the draining lymph node. Antigen specific naïve CD8+ T cells that recognize the antigen within the lymph node and receive appropriate co-stimulatory and proliferative signals acquire their effector phenotype. In order to assert immune control over the tumor, these effector CD8+ T cells must enter the bloodstream, and via chemokine signals, traffic to the tumor site; once there, these T cells must overcome immune regulatory/suppressive mechanisms. In a small study of an IL-12-based melanoma vaccine, Dr. Gajewski and colleagues correlated pre-treatment biopsy gene expression to outcomes and noted that in responding patients, tumors expressed chemokines (e.g., CXCL9 which binds CXCR3 on activated CD8+ T cells), which in some instances were able to recruit T cells into the tumor site. A broader transcript analysis of banked melanoma tissue demonstrated a subset of tumors with T cell markers co-associated with a panel of chemokines. Among responders in the vaccine trial, there was a pattern of expression of T cell- recruiting chemokines, T cell markers, innate immune genes, and type I IFN—all of which indicate productive inflammation. These results were supported by other cancer vaccine studies that demonstrated a strong correlation between survival and the expression of T cell markers and chemokines within the tumors. The results from these gene expression studies may be useful in identifying biomarkers that could provide valuable information for selecting patients most likely to respond to immunotherapies. Additionally, these studies point toward specific strategies for overcoming immunologic barriers to immunotherapy at the level of the tumor microenvironment. Thus, based on gene expression profiling, tumors can be categorized as T cell poor tumors, which lack chemokines for recruitment and have few indicators of inflammation, and T cell rich tumors, which express T cell recruiting chemokines, contain CD8+ T cells in the tumor microenvironment, and have a broad inflammatory signature. A strong presence of T cells within the tumor is predictive of clinical benefit from vaccines.

These observations prompt several important questions:

1) What dictates recruitment of activated CD8+ T cells into the tumor?
2) Why are tumors with CD8+ T cells not spontaneously rejected?
3) What are the innate immune mechanisms that promote spontaneous T cell priming in a subset of patients?
4) What oncogenic pathways in tumor cells drive these two distinct phenotypes?

Studies of CD8+ T cell recruitment to the tumor site point to a panel of chemokines, all of which may be produced by the melanoma tumor cells themselves. These studies suggest potential strategies to promote effector T cell migration to the tumor site that may include: direct introduction of chemokines; direct induction of chemokine production from stromal cells; eliciting local inflammation that generates chemokines (e.g., via type I IFNs, TLR agonists and possibly radiation); and altering signaling pathways in melanoma cells to enable chemokines expression by the tumor cells. Studies that have been designed to evaluate why melanomas that attract CD8+ T cells are not spontaneously rejected have pointed to several mechanisms that may exert negative regulation of T cells within the tumor microenvironment, including T cell inhibition via IDO and PD-L1, extrinsic suppression via CD4+CD25+FoxP3+ Tregs, and T cell anergy due to deficiency of B7 costimulation in the tumor microenvironment. Dr. Gajewski presented data that indicate that the immune inhibitory mechanisms present in the melanoma tumor microenvironment are driven by the CD8+ T cells, not the tumor. For example, IFNγ is the major mediator for IDO and PD-L1; and CCL22 production by CD8+ T cells is the major mediator for Tregs. Thus, blockade of these mechanisms may represent attractive strategies to restore anti-tumor T cell function and promote tumor rejection in patients.
To address questions underlying the mechanisms that promote spontaneous T cell priming in a subset of melanoma patients, Dr. Gajewski and colleagues used gene array data to identify markers of innate immunity that correlated with T cell infiltration. Melanoma metastases that contained T cell transcripts also contained transcripts known to be induced by type I IFNs. A knock-out mouse model demonstrated the necessity of the type I IFN axis for effective priming of a spontaneous T cell response and tumor rejection. Additional studies in knock-out mice have demonstrated that the CD8α+ DC subset is responsible for this spontaneous T cell priming. In an effective anti-tumor response sensing of the tumor by a separate DC subset drives type I IFN production, which is required for CD8α+ DC cross-priming of T cells. This suggests additional pathways that could be altered to promote spontaneous priming and an effective tumor response (e.g., provision of exogenous IFNβ). In summary, there is heterogeneity in patient outcomes to cancer immunotherapies (e.g., melanoma vaccines). One component of that heterogeneity is derived from differences at the level of the tumor microenvironment. Key factors in the melanoma microenvironment include
chemokine-mediated recruitment of effector CD8+ T cells, local immune suppressive mechanisms, and type I IFNs/innate immunity. Understanding these aspects should improve patient selection for treatment with immunotherapies (predictive biomarker), as well as aid the development of new interventions to modify the microenvironment to better support T cell-mediated rejection of tumors.


Induction of an immune response by antigen vaccination. Active immunization occurs following administration of tumor antigens, which are processed by antigen-presenting cells resulting in activation of immune effector cells such as T lymphocytes and B lymphocytes. Effector cells fight the tumor through several different effector pathways such as antibodies, cytokines or direct cellular interaction (Fas/Fas ligand, perforin/granzymes). Ideally this results in immunologic memory with long-lasting immunity against the tumor. Stimulation of the innate immune system is also known to have an important role in the evolution of an adaptive immune response (e.g. a rapid burst of inflammatory cytokines leads to activation of DC and macrophages). However, tumor-specific T cells also secrete chemokines (e.g. RANTES, MIP-1) that attract cells of the innate immune system to the tumor site. This mechanism may further contribute to the tumoricidal activitiy exhibited during T cell-mediated tumor regression. (TCR: T cell receptor, MHC: major histocompatibility complex, DC: dendritic cell, PMN: polymorphonuclear neutrophil, NK: natural killer cell, NKT: NK T cell, RANTES: regulated upon activation, normal T cell expressed, and secreted, (MIP-1): macrophage inflammatory protein 1)

Two companies that are pursuing Cytokine Therapies with a product of “Natural Mixtures of Cytokines.” They may provide the missing signal needed to raise the red flag, “The Danger Signal”

Multikine is in the Phase 3 and IRX-2 is in the Phase 1 clinical trial Phase
IRX Therapeutics seems to have the most appropriate mixture. Cel-SCI is missing the chemoattractants and proinflammatory cytokines.

If you combine the Cytokine therapy with anti-CTLA-4 blockage, will you get a synergistic immune 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


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.