Poised for progress..Melanoma ..Jim Breitfeller

Poised for progress
By Bill Schaller

Dana-Farber Cancer Institute

Friday, September 17, 2010

A new focus on the immune system’s ability to both unleash and restrain its attack on disease has led scientists at Harvard-affiliated Dana-Farber Cancer Institute to identify cells in mice that prevent the immune system from attacking the animals’ own cells, protecting them from autoimmune diseases such as multiple sclerosis, Type 1 diabetes, and lupus.

The discovery, recently reported by the journal Nature, may give scientists an effective way of operating the immune system’s internal “control panel,” leading to improved therapies for a variety of diseases — from vaccines that prompt the immune system to stage a sustained assault on cancers, to treatments that derail the biological onslaught associated with autoimmune diseases. The fact that human immune system cells share key features with those in mice makes the prospect of such advances quite realistic, the study authors say.

“The traditional view of the immune system is of specialized groups of cells poised to attack foreign pathogens [disease-causing agents],” said senior author Harvey Cantor, the Baruj Benacerraf Professor of Pathology at Harvard Medical School and chair of the Department of Cancer Immunology and AIDS at Dana-Farber. “While that model is generally correct, we’ve come to appreciate that the immune system, like other complex biological information systems, includes a counterbalance mechanism — a set of cells programmed to suppress the immune response. Such cells are essential to preventing excessive reactions to pathogens and misguided attacks on the body’s own cells.”

The search for cells involved in quieting the immune response has previously focused on immune system cells known as CD4+ T cells, some of which have been shown to prevent abnormal inflammation in response to disease or infection. In the new study, lead author Hye-Jung Kim and her colleagues found that CD8+ T cells (known as killer T cells because of their ability to kill diseased cells) also include a subset that helps dampen the immune response. Instead of reducing inflammation like their CD4 cousins, the CD8+ T regulatory (CD8+Treg) cells ensure that the immune system doesn’t produce antibodies that attack normal cells.

The Dana-Farber team discovered how CD8+ Treg cells accomplish this feat. They mingle with cells known as follicular T-helper cells, which are intermediaries that prompt the immune system’s B cells to make disease-fighting antibodies. The meeting with CD8+ Treg cells essentially shuts off the follicular T-helper cells, preventing them from interacting with B cells. No interaction means no production of antibodies, which means no assault on an animal’s normal, healthy cells.

The critical point of contact between CD8+ Treg cells and follicular T-helper cells is a protein on the helper cells called Qa-1. When Kim and her colleagues bred a strain of mouse with abnormal Qa-1, the animals developed a form of lupus. The reason: the CD8+ Treg cells couldn’t latch onto the defective protein, leaving the follicular cells free to order the B cells to produce antibodies, some of which targeted the animals’ own tissue.

The significance of this work is that CD8+ Treg cells represent a new lever for raising or lowering the strength of the immune response. This class of cells, it turns out, depends for its survival on a cytokine (a regulatory compound) called interleukin 15. Increase the supply of CD8+ Treg cells and the immune response is suppressed — a potentially powerful way of dealing with autoimmune diseases. Decrease the amount of such cells and the immune response can be invigorated and extended — a useful complement to vaccines that unleash the immune system on cancer.

“Experience has shown that vaccines that simply activate or expand the number of T and B cells are not likely to result in a prolonged, robust anti-tumor response,” Cantor explains. “The balancing mechanism within the immune system means that when more disease-fighting cells are generated, there’s a countervailing increase in the number of immune-suppressing cells that are generated. The key is to break that loop. This work brings that goal closer.”

Source:http://news.harvard.edu/gazette/story/2010/09/poised-for-progress/

A Phase I Study of Intravenous Recombinant Human IL-15 in Adults With Refractory Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer
It is recruiting.

A Phase I Study of Intravenous Recombinant Human IL-15 in Adults With Refractory Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer

Maybe a combination of Anti-CTLA-4 blockage + IL-15 may be another protocol that will erradicate the Melanoma Tumor



“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

ew Method Takes Aim at Aggressive Cancer Cells..Melanoma ..Jim Breitfeller

Released: Mon 10-Aug-2009, 11:00 ET

Newswise — A multi-institutional team of Boston-area researchers has discovered a chemical that works in mice to kill the rare but aggressive cells within breast cancers that have the ability to seed new tumors.

These cells, known as cancer stem cells, are thought to enable cancers to spread — and to reemerge after seemingly successful treatment. Although further work is needed to determine whether this specific chemical holds therapeutic promise for humans, the study shows that it is possible to find chemicals that selectively kill cancer stem cells. The scientists’ findings appear in the August 13 advance online issue of Cell.

“Evidence is accumulating rapidly that cancer stem cells are responsible for the aggressive powers of many tumors,” says Robert Weinberg, a Member of Whitehead Institute for Biomedical Research and one of the authors of the study. “The ability to generate such cells in the laboratory, together with the powerful techniques available at the Broad Institute, made it possible to identify this chemical. There surely will be dozens of others with similar properties found over the next several years.”

“Many therapies kill the bulk of a tumor only to see it regrow,” says Eric Lander, Director of the Broad Institute of MIT and Harvard, and an author of the Cell paper. “This raises the prospect of new kinds of anti-cancer therapies.”

An emerging idea in cancer biology is that tumors (breast, prostate, colon, lung, etc.) harbor a group of cells with the unique ability to regenerate cancers. In addition to promoting tumor growth, these so-called cancer stem cells are largely resistant to current cancer therapies. If it were possible to identify chemicals that selectively kill cancer stem cells, such chemicals might become critical candidates for future drug development.

However, researchers have struggled to study cancer stem cells directly in the laboratory. The cells’ relative scarcity compared to other tumor cells, combined with a tendency to lose their stem cell-like properties when grown outside of the body, have severely limited the amount of material available for analysis.

To overcome these hurdles, Broad and Whitehead Institute researchers drew upon recent findings from Weinberg and his colleagues that suggested a way to generate in the laboratory large numbers of cancer cells with stem cell-like qualities. The technique works by coaxing adult cells to undergo a critical change (known as an “epithelial-to-mesenchymal transition”) that alters their shape and motility. At the same time, the cells also adopt similar properties as stem cells.

“A critical aspect of our work was to generate relatively homogenous and stable populations of cancer stem-like cells that could then be used for screening,” says Tamer Onder, a former graduate student in Weinberg’s lab and co-first author of the study. (Onder is now a postdoctoral research fellow at Children’s Hospital in Boston.) “We were able to achieve this by inducing the cancer cells into an epithelial-to-mesenchymal transition using novel reagents that we had developed in the lab.”

With an ample number of stem cells in hand, the Broad-Whitehead team undertook a large-scale analysis of thousands of chemical compounds, applying automated methods to search for ones with activity against breast cancer stem cells. From a pool of more than 30 promising candidates, the researchers identified a compound with surprising potency.

The compound, called salinomycin, kills not only laboratory-created cancer stem cells, but also naturally occurring ones. Compared to a common chemotherapeutic drug prescribed for breast cancer (known as paclitaxel), salinomycin reduced the number of cancer stem cells by more than 100-fold. It also diminished breast tumor growth in mice.

To further dissect the function of salinomycin, the researchers also examined its genetic effects. Previous studies of tumors from breast cancer patients have revealed groups of genes that are highly active in cancer stem cells. Many of these same genes are linked with particularly aggressive tumors and poor patient prognoses. The researchers’ studies show that salinomycin (but not paclitaxel) treatment can decrease the activity of these genes, revealing a possible molecular basis for the chemical’s biological effects.

“Our work reveals the biological effects of targeting cancer stem cells,” says co-first author Piyush Gupta, a researcher at the Broad Institute. “Moreover, it suggests a general approach to finding novel anti-cancer therapies that can be applied to any solid tumor maintained by cancer stem cells.”

Although the new findings signal a noteworthy scientific milestone, it is still too early to know whether cancer patients will reap benefits from it. Additional research is needed to determine exactly how salinomycin works to kill cancer stem cells and if it can wield the same tumor-reducing power in humans as it does in mice. These types of analyses generally take several years to complete.

But even with such tempered enthusiasm, there is also cause for optimism. In the current study, just 16,000 chemical compounds were tested, of which a small subset showed toxicity against cancer stem cells. Therefore, deeper investigations of these compounds as well additional tests of broader collections of chemicals may yield other potential additions to the anti-cancer arsenal.

Paper cited:
Gupta et al. “Identification of selective inhibitors of cancer stem cells by high-throughput screening.” Cell, published online August 13, 2009

A complete list of the study’s authors and their affiliations:

Piyush B. Gupta,1,3,7,* Tamer T. Onder,1,2,7 Guozhi Jiang,1,3 Kai Tao,4 Charlotte Kuperwasser,4 Robert A. Weinberg,1,2,6,8,* and Eric S. Lander 1,2,3,5,8,*

1Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

2Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA

3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA

4Department of Anatomy and Cell Biology, Tufts University School of Medicine and Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA

5Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA

6MIT Ludwig Center for Molecular Oncology, Cambridge, MA 02139

7These authors contributed equally to this work

8These authors contributed equally to this work

*Corresponding authors

About the Whitehead Institute for Biomedical Research
Whitehead Institute for Biomedical Research is a nonprofit, independent research and educational institution. Wholly independent in its governance, finances and research programs, Whitehead shares a close affiliation with Massachusetts Institute of Technology through its faculty, who hold joint MIT appointments. For additional information about Whitehead Institute, please visit www.whitehead.mit.edu.

About the Broad Institute of MIT and Harvard
The Eli and Edythe L. Broad Institute of MIT and Harvard was founded in 2003 to empower this generation of creative scientists to transform medicine with new genome-based knowledge. The Broad Institute seeks to define all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.

Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to www.broad.mit.edu

Information hot off the press


Take Care,

Jimmy B

Cutting Edge Technology “Infection-mimicking materials to program dendritic cells in situ”Melanoma .. Jim Breitfeller

Cutting Edge Technology “Infection-mimicking materials to program dendritic cells in situ”

Thanks to Donald Bohlken for bring this to my attention.

“I thought you might be interested in that attached article from the January 25, 2009 issue of the journal "Nature Materials" concerning a Harvard study of a new vaccine methodology which resulted in a 90% survival of mice infected with a melanoma strain which would normally kill them in 25 days. The article speaks of this result as a "cure".

The article synopsis notes: "Cancer vaccines typically depend on cumbersome and expensive manipulation of cells in the laboratory, and subsequent cell transplantation leads to poor lymph-node homing and limited efficacy. We propose that materials mimicking key aspects of bacterial infection may instead be used to directly control immune-cell trafficking and activation in the body. It is demonstrated that polymers can be designed to first release a cytokine to recruit and house host dendritic cells, and subsequently present cancer antigens and danger signals to activate the resident dendritic cells and markedly enhance their homing to lymph nodes. Specific and protective anti-tumour immunity was generated with these materials, as 90% survival was achieved in animals that otherwise die from cancer within 25 days. These materials show promise as cancer vaccines, and more broadly suggest that polymers may be designed to program and control the trafficking of a variety of cell types in the body."
This is Nano and Transdermal Technology at its best.

Implants Mimic Infection To Rally Immune System Against TumorsMain Category:

Melanoma / Skin CancerAlso Included In: Immune System / Vaccines; Medical Devices / Diagnostics; Biology / Biochemistry

Article Date: 25 Jan 2009 - 0:00 PST

“Bioengineers at Harvard University have shown that small plastic disks impregnated with tumor-specific antigens and implanted under the skin can reprogram the mammalian immune system to attack tumors.

The research -- which ridded 90 percent of mice of an aggressive form of melanoma that would usually kill the rodents within 25 days -- represents the most effective demonstration to date of a cancer vaccine.

Harvard's David J. Mooney and colleagues describe the research in the current issue of the journal Nature Materials.

"Our immune systems work by recognizing and attacking foreign invaders, allowing most cancer cells -- which originate inside the body -- to escape detection," says Mooney, Gordon McKay Professor of Bioengineering in Harvard's School of Engineering and Applied Sciences. "This technique, which redirects the immune system from inside the body, appears to be easier and more effective than other approaches to cancer vaccination."

Most previous work on cancer vaccines has focused on removing immune cells from the body and reprogramming them to attack malignant tissues. The altered cells are then reinjected back into the body. While Mooney says ample theoretical work suggests this approach should work, in experiments more than 90 percent of the reinjected cells have died before having any effect.
The implants developed by Mooney and colleagues are slender disks measuring 8.5 millimeters across. Made of an FDA-approved biodegradable polymer, they can be inserted subcutaneously, much like the implantable contraceptives that can be placed in a woman's arm.
The disks are 90 percent air, making them highly permeable to immune cells. They release cytokines, powerful attractants of immune-system messengers called dendritic cells.
These cells enter an implant's pores, where they are exposed to antigens specific to the type of tumor being targeted. The dendritic cells then report to nearby lymph nodes, where they activate the immune system's T cells to hunt down and kill tumor cells throughout the body.”

Source: Http://www.medicalnewstoday.com/articles/136473.php

Implants Mimic Infection To Rally Immune System Against Tumors



Donald Bohlken actually contacted one of the collaborators, Dr. Glenn Dranoff of the Dana Farber Cancer Institute and Harvard Medical School. He indicated: "We are initiating efforts to bring this to clinical testing, but it will take some time to adapt the procedures to patients. A one year time frame is a reasonable guess."

If this crosses over from the mouse model to the human model, we may have a winner on our hands. A 90 % response and if they are complete responses, this technology would surpass any therapy out there to date. The main take away is that they are prompting our immune system to recognize the tumors by activation of the T-cell. Rosenberg and Hwu and other colleagues are doing just that with (ACT) Adoptive Cell Transfer. Kirkwood, Camacho, Webber, Hodi, Maker, O’Day and Wolchok did that with anti-CTLA-4 blockage.

I can see the Light at the end of the tunnel!!!!!!!!!!!!!!!!!!!!!!!!!!!

Thank you Don for advocating for us and your Brother Ron who is a fighting Warrior of Melanoma.

I will post the research paper on Melanoma Missionary for everybody.

Jimmy B

EDITORIAL CTLA-4 Blockade: Unveiling Immune Regulation Melanoma ..Jim Breitfeller

Originally published as JCO Early Release 10.1200/JCO.2005.09.923 on December 21 2004

CTLA-4 Blockade: Unveiling Immune Regulation

Glenn Dranoff

Department of Medical Oncology, Dana-Farber Cancer Institute; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA

To maintain tissue homeostasis under the duress of infection or injury, the immune system is endowed with a diverse repertoire of soluble and cellular effectors. The innate response, composed of granulocytes, macrophages, dendritic cells, natural killer cells, and complement, is rapidly triggered into action, detecting tissue disturbance through a set of germline-encoded pattern recognition receptors. The adaptive reaction, consisting of antibody-producing B cells and T lymphocytes, is slower to develop, but manifests exquisite specificity and memory. These attributes reflect the requirement for expansion of rare clones harboring somatically rearranged immunoglobulin molecules or T-cell receptors specific for foreign proteins or processed peptides presented by major histocompatibility complex (MHC) molecules. These innate and adaptive responses are carefully orchestrated through soluble and membrane-bound regulators, resulting in the deployment of the most suitable effectors for containing the disorder, while minimizing tissue damage.

Cancer cells similarly provoke immune recognition. In one pathway, innate effectors detect tumor cells directly.1 Natural killer cells and phagocytes express NKG2D molecules that function as receptors for stress-related genes such as MICA and MICB, which are induced as a consequence of cellular transformation. Natural killer cells further scan for the loss of MHC class I molecules on the surface of tumor cells. Dendritic cells use a variety of scavenger receptors to result in the phagocytosis of dying tumor cells.

The adaptive response exploits an indirect pathway, termed cross-priming, to recognize cancer cells.2 In this mechanism, dendritic cells capture tumor cell debris, migrate to regional lymph nodes, and stimulate CD4+ and CD8+ T cells with tumor specificity. Primed T cells thereby acquire the capacity to detect tumor cells directly in a MHC-restricted fashion. CD4+ T cells also contribute to B-cell antibody production.

Antitumor innate and adaptive responses are frequently detected in cancer-bearing hosts, but their biologic importance remains incompletely understood. In some cases, endogenous reactions may function to attenuate disease progression. In multiple cancer types, clinicopathologic studies of early-stage lesions demonstrate that dense intratumoral lymphocyte infiltrates are strongly correlated with reduced frequencies of metastasis and improved patient survival.3 Moreover, in advanced ovarian carcinoma, lymphocyte infiltrates also predict for complete responses and prolonged survival following cytotoxic therapy.4 Consistent with this protective role, several strains of immune-deficient mice display enhanced susceptibility to spontaneous and carcinogen-induced tumors.5 Nonetheless, other compelling data indicate that tumor cells sometimes exploit host responses to promote disease progression.6 Unresolved inflammation may facilitate tumor development by modulating tumor cell growth, apoptosis, invasion, and metastasis. Together, these divergent outcomes underscore a dual role for immunity in carcinogenesis.7

Source:http://jco.ascopubs.org/cgi/content/full/23/4/662
CTLA-4 Blockade: Unveiling Immune Regulation




Take care

Jimmy B

Oncogene Inhibits Tumor Suppressor To Promote Cancer: Study Links B-RAF And LKB1..Melanoma .. Jim Breitfeller

Oncogene Inhibits Tumor Suppressor To Promote Cancer: Study Links B-RAF And LKB1

Scientists have uncovered an interesting connection between two important protein kinase signaling pathways that are associated with cancer. The research, published by Cell Press in the January 30th issue of the journal Molecular Cell, may direct new therapeutic strategies for multiple types of cancer.


The protein kinase LKB1 is a known tumor suppressor and the LKB1-AMPK signaling pathway couples energy metabolism with cell growth, proliferation and survival. “Mutations in LKB1 are not frequent in human cancers and it is not clear how tumor cells suppress the signaling pathway to gain growth advantage under conditions of energy stress (common in cancer cells),” explains senior study author Dr. Lewis C. Cantley from Beth Israel Deaconess Medical Center and Harvard Medical School.

Dr. Cantley and colleagues, including Dr. Bin Zheng, designed a study to investigate the molecular mechanisms associated with suppression of the LKB1-AMPK pathway in tumor cells. The researchers used malignant melanoma cells that often have a mutation called “V600E” in the RAF protein B-RAF. The RAF-MEK-ERK pathway is well established as a key regulator of cell growth, proliferation, differentiation and survival.

Mutations in the RAF kinase B-RAF have been found in many types of human cancer but, while oncogenic B-RAF V600E has been linked with tumor induction, growth, maintenance and progression, the specific molecular mechanisms have not been identified. Dr. Cantley’s group found that melanoma cells with the B-RAF V600E mutation had impaired AMPK activation and that inhibition of B-RAF signaling activated AMPK.

The researchers went on to show that LKB1 was phosphorylated by two kinases that are downstream of B-RAF, ERK and Rsk. The phosphorylation of LKB1 interfered with the ability of LKB1 to bind and activate AMPK. Importantly, expression of mutant LKB1 that could not be phosphorylated resulted in activation of AMPK and an inhibition of melanoma cell proliferation.

“Taken together, our results provide a molecular linkage between the LKLB1-AMPK and the RAF-MEK-ERK pathways and suggest that suppression of LKB1 function by B-RAF V600E plays an important role in B-RAF V600E-driven tumorigenesis,” says Dr. Zheng. “It’s conceivable that tumor cells must turn off the LKB1-AMPK signaling pathway to gain a growth advantage under conditions of energy stress.”

Given that B-RAF mutation and loss of LKB1 are associated with multiple types of cancer, the work is likely to have a significant clinical impact. “Further understanding of how the intriguing molecular linkage between LKB1-AMPK and RAF-MEK-ERK functions in tumorigenesis could potentially provide great therapeutic opportunities for cancer treatment,” offers Dr. Cantley.

The researchers include Bin Zheng, Harvard Medical School, Boston, MA; Joseph H. Jeong, Dana-Farber Cancer Institute, Boston, MA; John M. Asara, Harvard Medical School, Boston, MA; Yuan-Ying Yuan, Harvard Medical School, Boston, MA; Scott R. Granter, Brigham and Women’s Hospital, Boston, MA; Lynda Chin, Dana-Farber Cancer Institute; and Lewis C. Cantley, Harvard Medical School, Boston, MA.

Source: Cathleen Genova
Cell Press

Jimmy B