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

Smart bombing Melanoma..Jim Breitfeller

Smart bombing Melanoma

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

“Most tumors arise from a single normal cell through a sequential evolutionary process of mutation and selection. Tumors are initiated by escaping non-immune surveillance, which includes defective DNA repair, gene alternation, resistance to apoptosis and loss of intercellular contact inhibition. Tumor cells harbor mutations in a number of critical genes that provide selective advantages at various stages during the evolution of the tumor. The tumor cells that circumvent the tumor suppressor mechanisms of the non-immune surveillance process are edited by the immune system, resulting in the selection of a resistant tumor variant. The selection of the tumor cell is further shaped by its interactions with cells and other factors in its microenvironment. Tumor evolution is thought to adhere to Darwinian principles by escaping both non-immune (intrinsic) and immune (extrinsic) responses against self-altered tumor cells. At end-stage, tumors have escaped both non-immune and immune surveillance with increased threshold of apoptosis. Combination therapy has been proposed, by exploring the non-immune and immune suppressive nature of the tumor, and has been found to have a therapeutic efficiency on tumor regression as compared with monotherapies. The combination of immunotherapy and other different modalities, especially vaccines, with conventional anticancer therapies with optimized dosage and scheduling can offer synergistic antitumor effects.”

Source: http://www.cellbiolint.org

Chemotherapy

The combination of chemotherapy and immunotherapy is synergized as chemoimmunotherapy; chemotherapy can kill or slow the growth of cancer cells and immunotherapy stimulates or restores the ability of the immune system to fight against cancer (Emens and Jaffee, 2005; Gulley et al., 2007). Apoptotic death, particularly massive apoptosis by chemotherapy, can be a priming event for antitumor immunity, allowing the tumors to act as its own vaccine by releasing a large amount of tumor antigen. This priming event sets the stage and the direction of the immune response. With the right tumor antigen, the activated T-cells (CTL’s) Cytotoxic T Lymphocytes can zero in on their target, the tumor cell. Smart bombing Melanoma!!!!!



Source: http://thefutureofthings.com/articles/1012/smart-bombing-cancer.html


Source: NCI



“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

Letter to Dr. Steven Rosenberg at the National Cancer Institute from Jim Breitfeller

Dr.Rosenberg, Friday, January 09, 2009

We’ve been communicating off and on since 2006 through your research staff on my Melanoma situation. I want to personally thank you and you staff for all the knowledge that you have generated over years and have shared with me and others. I been trying to follow your research through abstracts and online papers. Thank you for publishing your results. They are a Godsend to the patients and researchers alike.

Now, Let me get back to my situation. I am under the care of your friend and colleague, Dr, John Kirkwood. As you might know , I did a combo regiment but not like the

Tumor Regression and Autoimmunity in Patients Treated With
Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and
Interleukin 2: A Phase I/II Study

See, I only did one course of CTLA-4 and then I jumped to high dose interlukin-2 for three courses but on the forth course, I has a mild heart attack and the stopped the treatment.

On September 6th, I had another CT scan and MRI for the next trial which was Anti-CTLA-4. On September 13 I had my first infusion. On October 8, 2006 My wife noticed two new growths on my back. It was confirmed on October 11th it was new tumors.
Dr. John Kirkwood has decided that IL-2 Interleukin 2 would be next course of action. I have completed another round of tests (CT scan, Pulmonary Function, and a Nuclear Stress Test). The CT scans shows 40+ nodules in my lungs ranging from 15mm to less than 5mm.
I am slated to be High dosage IL-2 on November 1st 2006.

I am presently washed out an IL-2 clinical trial that started in November 1, 2006. On the fourth cycle I had a heart attack and the doctors determined to abort the IL-2 on February 2, 2007. On August 23 2007 there was no change to the tumors in my back or lungs but also no growth. In October 24 2007 I got the word that the tumors and the lung nodules were shrinking. In April 14, 2008, the 40 + nodules in my lungs decrease to 2. In July 2008, the nodules in my lungs were undetectable and the ones on my back were all but one gone. Presently, CT and MRI

In November 2008 show no signs cancerous activity.

I am stabilized for the time being.

The Melanoma type that I have is nodular. Dr. Kirkwood has taken one of the tumors and stored it cryogenically.

Now here comes the thousand dollar question.

With your expert knowledge, would molecular profiling or mapping of the tumor aid in your research? If so, Please contact me and/or Dr. Kirkwood.

See, as a researcher myself for Eastman Kodak Research Labs in the field of “Surface Science” I believe there is some value in what made my tumor tic. Since we know that the CTLA-4 -IL-2 worked for me, it may be specific to Nodular Melanoma. And if that is the case, when people get diagnosed, they may a have one line of defense lined up. So please, let me know what you think.

Thank for you time and again, thank you for all the great research you are doing on the behalf of the Melanoma Patient. We surely appreciate it.

Sincerely,


James M.Breitfeller

Just lining up My Ducks!!!!!!!!!!!!!!

am Contacting Dr. Steven A.Rosenberg at the National Cancer Institute in Bethesda, Maryland.
He is the lead the researcher on the Gene Therapy Trials.Log onto the CBS website for the story!!!!!!http://www.cbsnews.com/stories/2006/08/31/health/main1955526.shtml
The research team recently applied to the Food and Drug Administration (FDA) to try the new cells in about 100 patients. The FDA is expected to respond to the request by mid-September.
Dr. Rosenberg, I just got the news of your Gene Therapy Experiments. The initial results look somewhat promising. I applauded you and your team for making great strides in the cure for melanoma cancer.I am a cancer patient (48 yrs. old) under the care of Dr. John Kirkwood at the Hillman Cancer Center at the University of Pittsburgh. I have gone through a wide incision, lymph nodes removal, Interferon therapy, and Dicarbazine therapy without success. I am presently on track to start a clinical trial with CTLA-4 monoclonal antibodies September 13, 2006. I have some tumors on my right side of my back and some in each lobe of my lungs. I would like to be considered for your next round of Gene Therapy in the coming months if I have no response to the CTLA-4 treatment. Please let me know if you would need a copy of my medical records to date.Thanks again for the great work you are doing and I hope to hear from you in the near future.

Best Regards,

Jim Breitfeller

Scientists alter blood cells in attempt to treat melanoma Gene therapy stops cancer in 2 dying men

Scientists alter blood cells in attempt to treat melanomaGene therapy stops cancer in 2 dying men

BY LAURAN NEERGAARD, Associated Press
8/31/2006

WASHINGTON - Mark Origer entered the last-ditch experiment hoping to beat back his melanoma for a few months, long enough to walk his daughter down the aisle. He got far luckier: Almost two years later, his body shows no signs of the invasive cancer that starts on the skin.Government scientists rescued Origer and one other man with advanced melanoma by genetically altering their own white blood cells to turn them into tumor fighters.The treatment didn't help 15 other melanoma victims. So scientists are trying to strengthen it to work better.Still, the National Cancer Institute called its experiment, revealed Thursday, the first real success in the long quest for gene therapy for cancer - because it fought the disease's worst stage, when it had spread through the body, not just single tumors.And it did so in a way far different from today's standard options - by harnessing patients' immune systems to continually search out and kill tumors."It's not like chemotherapy or radiation, where as soon as you're done, you're done," said Dr. Steven Rosenberg, the NCI surgery chief who led the research reported Thursday by the journal Science. "We're giving living cells, which continue to grow and function in the body."Doctors can't predict how the therapy's first two successful patients will fare long-term. Melanoma, which kills almost 8,000 Americans annually, is notorious for returning years after patients think they've subdued it."I'm cured for now," Origer, 53, of Watertown, Wis., puts it gratefully.He recalls his doctors' wide grins when, just a month after his December 2004 treatment, his tumors started to shrink. By his daughter's wedding last fall, just one small cancerous spot remained, on his liver. Surgeons later cut it out. A checkup from NCI doctors this week confirmed that Origer is still cancer-free."I know how fortunate I am to have gone through this and responded to this. Not everybody's that lucky," he said.Cancer specialists praised the work, but warned that years of additional research are needed."Clearly this is a first step," cautioned Dr. Len Lichtenfeld of the American Cancer Society. "We have to be very cautious about not raising hopes too much."But he added: "It is exciting. It certainly is a proof of concept that this approach will work."More importantly, the gene therapy can be customized to create cells that should attack more common cancers, said Dr. Patrick Hwu, melanoma chairman at the M.D. Anderson Cancer Center of the University of Texas, who once worked with the NCI team.In a few months, the NCI team hopes to begin studying the approach in small numbers of patients with advanced breast, colon and other cancers.White blood cells called T-lymphocytes hunt down germs and other foreign tissue.But cancerous cells look a lot like healthy cells, making it hard for those T-cells to spot a problem.By 2002, Rosenberg had made a breakthrough. He found small numbers of cancer-fighting T-cells inside some patients with advanced melanoma. He literally pulled those cells out of their blood and grew billions more of them in laboratory dishes, enough to have a chance at overwhelming a tumor when they're pumped back into patients. About half significantly improve after this cell-transfer therapy.But few melanoma patients make enough cancer-fighting T-cells naturally to be spotted in their bloodstream, and T-cells that attack other cancers are virtually impossible to find. So Rosenberg and colleagues set out to create those tumor fighters from scratch.The scientists took normal lymphocytes - ones that don't recognize cancer - out of patients with advanced melanoma who had exhausted their treatment options. They infected those cells with a virus carrying genes that create T-cell receptors, essentially homing devices for, in this case, melanoma. (Different genes create receptors for other cancers.)"We can take a normal cell from you or me or any patient and ... convert that cell into a cell that recognizes the cancer," Rosenberg explained.Here's the key: When scientists infused the newly armed cells into 17 patients, only Origer and his fellow survivor maintained super-high levels for more than a year, and only their tumors gradually faded. In most of the other patients, only low levels of the tumor-fighting cells persisted for a few months.No patients suffered serious side effects, although they required a few weeks of chemotherapy to suppress their natural immune system and make room for the extra T-cells.Why did those cells flourish in only two people?"That's the critical question," said M.D. Anderson's Hwu.Picking the right lymphocyte to alter genetically isn't easy - there are many different kinds - or perhaps more precise T-cell receptors were needed for the cells to take root better and do the job, he suggested."These are all solvable issues," Hwu stressed, calling the study "one of the first documented, effective cases of cancer gene therapy working."

This might end up as one of my options down the road.