Pearls of Wisdom: Melanoma ..Jim Breitfeller

Pearls of Wisdom: Melanoma
Reviewed by Douglas Johnson, MD and Jeffrey Sosman, MD

This entry was posted on Tuesday, January 8, 2013 at 6:33 pm Management of Advanced Disease


Metastatic melanoma historically has had a very poor prognosis with a median survival of 6-9 months. However, recent advances in molecularly targeted therapy as well as immune based therapies have provided several effective treatment options for oncologists and their patients. In 2012 there are several important issues to consider in the management of patients with newly diagnosed advanced melanoma.


Advanced Stage III/Stage IV resectable disease

• In patients with advanced stage III disease or oligometastatic disease, consultation with an experienced surgical oncologist is warranted, as patients can experience long term survival with an aggressive surgical approach. Despite the advances in systemic therapy, surgical resection is still our preferred option in most of these clinical situations. One series of 64 patients showed a >30% four year survival in patients who had completely resected metastatic disease.1

•Another option we have offered is a short course of systemic therapy for 6-12 months prior to surgery with the intent to improve the chance that rapid recurrence of disease does not occur and to define the tumor’s responsiveness to the treatment.
•Patients should be considered for clinical trials in the adjuvant setting. Studies are ongoing to assess whether ipilimumab or vemurafenib is effective in preventing recurrences in high risk patients. For stage IV (M1) disease after complete surgical treatment there is no standard of care adjuvant treatment.


•Interferon, the current standard of care for fully resected stage IIb-III disease, is also an option in the adjuvant setting.
Molecular Testing

•All patients with metastatic disease should undergo testing for BRAF V600 mutations given the availability of targeted therapy for this mutation. This should include testing for the alternate V600 mutations that make up about 20% of BRAF mutations at this codon and appear sensitive to the BRAF inhibitors such as vemurafenib and dabrafenib.2 Patients with advanced local or regional disease can also be considered for testing since there are a number of clinical trials either recently or soon to be activated with BRAF inhibitor based therapy in BRAF V600 mutated melanoma at stage IIC-IIIC. Additionally, results will be available on progression so that therapy can be rapidly initiated if needed.
•Evaluation of several KIT mutations should also be considered in at least specific clinically defined subsets of patients. Though KIT mutations are present in only ~2% of all melanomas, acral (feet and hands) and mucosal melanomas harbor KIT mutations in 15-20% of cases. KIT mutations are sensitive to imatinib in about 25% of the cases based on limited numbers of patients.3
•NRAS mutations are also present in 15-20% of patients and though no targeted therapies are yet established as standard for this subset, there are a number of studies underway specifically targeting this mutation. Furthermore, the NRAS mutation may confer a poor prognosis to the melanoma.4


Standard therapies for metastatic disease

Vemurafenib
Vemurafenib is a BRAF inhibitor approved for patients with metastatic melanoma with BRAF V600 mutations (40-50%). In phase III trial data, objective tumor shrinkage was seen in well over 50% of patients, and clinical benefit seen in nearly all patients during the initial few weeks of administration. Median progression-free survival was 6.9 months (compared to 1.6 months with dacarbazine).5 Some important points regarding vemurafenib therapy:
•Responses are often rapid and dramatic. If patients with mutated BRAF V600 melanoma are highly symptomatic, vemurafenib would be our first line therapy in nearly all such patients.
•Patients will inevitably progress or relapse, often within the first year. Strategies to prevent or delay resistance are being pursued. In fact, recently the addition of a MEK inhibitor, trametinib, demonstrated an ability to improve the frequency of objective responses and the duration of progression-free survival in those melanoma patients receiving dabrafenib (BRAF inhibitor).
•Vemurafenib has clinical activity in patients with brain metastases in small series. Prospective phase II trials are pending completion. Trials with dabrafenib have also demonstrated frequent clinical benefits in such patients.6
•Secondary squamous cell carcinomas are common in BRAF inhibitor trials (10-25%).7 Suspicious lesions should be biopsied. Additionally, secondary melanomas and CMML have been reported in the presence of vemurafenib; almost certainly the drug has played a role to accelerate the appearance and growth of these tumors.
Ipilimumab (Yervoy)


Ipilimumab is an antibody to CTLA-4 and functions as an immune checkpoint inhibitor. This “removes the brakes” on the immune system which decreases immune tolerance to the tumor but may also cause autoimmune toxicities. In phase III trials, overall survival was increased compared to a vaccine in previously treated patients (10 mos vs. 6.4 mos), and in combination with dacarbazine compared with dacarbazine alone in the first line setting (11.2 vs. 9.1 months).8,9 Some important points to consider:
•Tumor burden on exam or on imaging may transiently worsen even in patients destined to respond. We do not repeat imaging until after 12 weeks of therapy unless the patient develops concerning new or progressive symptoms.
•Since even responding patients may have tumor growth or slow shrinkage, we are hesitant to use this therapy in highly symptomatic patients, especially if there are reasonable alternatives.
•Autoimmune side effects may be severe. Colitis, hepatitis, dermatitis, neuropathy, and endocrinopathies are the most common toxicities.
•Patients should be monitored closely for colitis. Concerning symptoms (diarrhea, melena/hematochezia, abdominal pain) require rapid evaluation. Though Imodium is appropriate for mild diarrhea (grade I), grade II toxicities or worse require prompt initiation of steroids. Colonoscopy should be performed to confirm the diagnosis in patients with severe colitis. Bowel perforation and death have been reported in extreme cases almost always when initial therapy is delayed.
•Headaches, with or without vision changes and fatigue may represent hypophysitis. Evaluation of TSH, cortisol, and testosterone, and brain MRI can aid in this diagnosis.
•We monitor TSH, cortisol, and liver enzymes at every visit.

•Other rare immune mediated side effects such as Guillan Barre syndrome, myasthenia gravis, sarcoidosis, and hemophilia have also been described.
Interleukin-2 (IL-2)


IL-2 has been used for many years in treating metastatic melanoma. It is associated with 6% durable remission rate (cures) and 15-20% overall response rate.10 Its use is limited to centers familiar with the associated severe side effects. Some points to consider when treating or referring patients:


•Therapy is limited to healthy patients usually under 70 years of age with adequate cardiac, pulmonary, renal, hepatic, and hematopoietic organ function and well controlled brain metastases. Nearly all patients experience treatment associated hypotension, multi-organ dysfunction, and vascular leak syndrome

•Though newer agents exist, IL-2 has the most long term data showing durable remissions in the minority of patients. We still consider this therapy in interested, eligible patients.
•Advantages of using IL-2 compared to ipilimumab include longer duration of use and more rapid assessments of benefit (8 weeks vs. 12+ weeks). Advantages to ipilimumab include outpatient use, generally less severe side effects, and possibly higher rates of durable remissions.



Cytotoxic chemotherapy

•Dacarbazine, temazolamide, and carboplatin/paclitaxel occasionally benefit patients with metastatic disease.
•No consistent survival benefit has been demonstrated with cytotoxic chemotherapy. Response rates are typically in the 5-10% range.
•We use chemotherapy only in patients who are not eligible for other therapies.
Which therapy should be chosen as first line therapy in patients with BRAF V600E/K mutations?
•This decision should be individualized. No head to head comparisons have been done with immunotherapy in the form of ipilimumab or interleukin-2 therapy. BRAF inhibitors are associated with high response rates but inevitable progression, while immune therapies have low objective response rates but durable remissions in a minority of patients.

•In patients with rapidly progressive or highly symptomatic disease, we typically use vemurafenib. In patients with asymptomatic disease, we favor immune based therapies for interested patients. An intergroup randomized cross over trial will address this issue, where half the patients start with vemurafenib and the other half on ipilimumab.



Promising Therapies


Therapy for metastatic melanoma is rapidly evolving. Many clinical trials are ongoing, and patients should be encouraged to participate in clinical trials for first line therapy or at progression if treated with standard therapy options. Some therapies that are likely to be approved are listed below.
•BRAF/MEK inhibitor combination therapies: Dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) have both shown benefit individually over dacarbazine in phase III trials in patients with BRAF mutant metastatic melanoma. However, interest lies especially in combination therapy to delay resistance and disease progression. In a randomized phase II trial, combination therapy was associated with an improved objective response rate (54% vs 76%) and progression free survival compared to dabrafenib alone (9.4mo vs. 5.8mo).11 Additionally, the incidence of squamous cell carcinomas was dramatically decreased with combination therapy. Trials are ongoing comparing this combination with vemurafenib in untreated patients with BRAF mutations. An additional trial is evaluating vemurafenib in combination with GDC-0973, a MEK inhibitor.



•Anti-PD-1 therapy:

Several newer checkpoint inhibitors block the interaction between PD-1 (expressed on T-cells) and PD-L1 (expressed on tumor) which activates the immune system, hopefully in a tumor specific manner. A phase I trial with nivolumab (anti-PD1 BMS) data shows a 31% response rate with fewer autoimmune side effects than ipilimumab.12 Pneumonitis was described in several patients. Trials are ongoing in patients who have progressed on ipilimumab. Early reports of another anti-PD1, MK-3475 also show a remarkable response rate in patients either following Ipilimumab or de novo in the 40-50% response range.

•Anti-PD-1 + Yervoy therapy:

By using both Checkpoint inhibitors, you and block two pathways that the melanoma can't use for immunosuppression. This allows the activated T-cells to go unchecked and keeps the immune response switch on. This clinical trial is ongoing at Sloan Kettering, and Yale. Rumor has it that they are seeing high response rates.



References

1.

Sosman JA, Moon J, Tuthill RJ, et al. A phase 2 trial of complete resection for stage IV melanoma: Results of Southwest Oncology Group Clinical Trial S9430. Cancer 2011.
2.

Lovly CM, Dahlman KB, Fohn LE, et al. Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PloS one 2012;7:e35309.
3.

Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA : the journal of the American Medical Association 2011;305:2327-34.
4.

Devitt B, Liu W, Salemi R, et al. Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment cell & melanoma research 2011;24:666-72.


5.

Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. The New England journal of medicine 2011;364:2507-16.     “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

Promising New Approach To Treating Cancer Means Hope For Many, But Remember This Is Just The Start Of The Journey..Melanoma ..Jim Breitfeller

Promising New Approach To Treating Cancer Means Hope For Many, But Remember This Is Just The Start Of The Journey

http://www.cancer.org/AboutUs/DrLensBlog/post/2012/06/02/Promising-New-Approach-To-Treating-Cancer-Means-Hope-For-Many-But-Remember-This-Is-Just-The-Start-Of-The-Journey.aspx






A while back , in 2011 I wrote about combinatorial therapy as the way to form a curative therapy for melanoma.See blog entry "“Schedule and Dose for Combination Therapy,”




It is now just starting to gain acceptance in the oncology world ASCO 2012. You need to block multiple pathways to shutdown the tumor's ability to side-step the immune system.If you search on my blog using the search field, you will be able to follow the science.

“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
 

Complexities of cancer elude magic bullet..Melanoma ..Jim Breitfeller

Complexities of cancer elude magic bullet


"True change will entail extending survival not by months, but by years, moving ever closer to the five-year cancer-free mark that is considered a cure. Unfortunately, this remains an elusive goal for many types of cancer due to the near inevitability of recurrence.
The reasons for this are many and controversial, but few dispute that the problem lies in the complexity of cancer, the growth and metastasis of which involve multiple processes, pathways and cell types. Because most drugs target only one of the many factors that give rise to cancer, it is not surprising that the disease so commonly displays an aptitude for evading them.
Given cancer's complexity, most agree that the long-coveted cure will be found not in a magic bullet, but in a combination of bullets aimed simultaneously at several specific targets. Here, immune-based drugs present a number of distinct advantages: their favorable safety profile is conducive to combination therapy, and a number of different immunotherapy candidates have shown promising activity against well-established tumor targets.
However, because the U.S. Food and Drug Administration requires each of these experimental treatments to be tested individually, it is far from clear that any of these products alone could pass the demanding test of significantly improving overall survival - even if there is good reason to believe that they could provide significant benefit together. " ~Swiss Trader~

We need the FDA to consider Combinatorial Therapy as a new Product/Process that is capable to win this war on Cancer.
I have lived it first hand, and have benefited from this form of therapy. It was no fluke that I was able to jump-start my immune system. With the help of my Oncologist we were able to string the right clinical trials together to produce the right immune response. Some day we will all look back to this day and say to ourselves, why did no one take notice.
The CURE is right under our noses. Think outside the box!

Best regards,

Jimmy B

“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
 

Macrophage Activation… The Missing Link to Activation an immune response to Melanoma..Jim Breitfeller

"The development of Th1 cells producing high levels of IFN-gamma could not be induced with dendritic cells alone but required the addition of appropriately activated macrophages." Et al A. O'Gara March 23, 1993 "Dendritic cells and macrophages are required for Th1 development of CD4+ T cells from αβ TCR transgenic mice: IL-12 substitution f.or macrophages to stimulate IFN-γ production is IFN-γ-dependent"
Local IL-12 therapy stimulates Th cells to secrete Th1 cytokines. Exogenous IL-12 application creates an environment rich in IL-12 around the cancer site. In such a local environment, newly activated Th cells, responding to the presence of cancer, exit the blood and are influenced to become Th1 cells and secrete more Th1 cytokines and activate macrophages and NK cells. Activated macrophages will produce more IL-12 and via positive feedback, cell-mediated immunity can be promoted to battle the cancer thereby leading to the prevention of reoccurrence. As you can see, the activated macrophage secretes IL-12, IL-1a, IL-1b, and IL-6 along with a Chemoattractant, IP-10. Without macrophage activation, the immune response does not take place and the patient will relapse.(see graphic below)

With IL-1b and IL-6 missing, the T-Regulatory Cells (Tregs) rule the Tumor's Microenviroment. IL-6 controls Th17 immunity by inhibiting the conversion of naive CD4+ T cells into Foxp3+ regulatory T cells. IL-1β–Mediated Signals Preferentially Drive Conversion of Regulatory T Cells but Not Conventional T Cells into IL-17–Producing Cells (Danger Signal).So if the IL-1b signaling is missing,conversion of the Tregs never take place along with no Danger Signals.

Dr. Steven Rosenberg is using engineered T-cells that secrete IL-12 to stimulate Th cells to secrete Th1 cytokines. This sets in motion the positive feed back loop needed to initiate an immune response. His therapy is show great promise. “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

“I have your results”..Melanoma..Jim Breitfeller

Tuesday, Jan 31, 2012 3:00 PM 17:47:41 EST

“I have your results”

Mary Elizabeth Williams is a staff writer for Salon

Three months into a draining clinical trial, the doctor called with news. Was it working -- or not?
I had just settled into a chair for my regular Tuesday night cancer support group when I got the call. An unfamiliar number. A split second of wondering whether or not to answer. And then my doctor, calling from his own phone to say, “I have your results.”

People with metastatic, Stage 4 melanoma rarely get happy endings. They usually just get endings. The odds of surviving five years once the cancer has spread into your lungs and bloodstream are generally ballparked at around 10 percent. So when I entered a Phase I immunotherapy clinical trial in October, I knew the whole enterprise had the pungent aroma of Last Ditch. My doctors said brightly that my relative youth and good health made me “an ideal candidate.” They said that the drug combination I’d be on – the newly approved Ipilimumab and the experimental, sexily named MDX-1106 – were highly “promising.” Because it was a trial, Bristol-Myers Squibb would essentially foot the bill. They had also just told me that the malignant cancer I had surgery for in 2010 had broken off; there was now a tumor in my lung and another one under the flesh of my back. In the stark absence of other options, I signed a 27-page consent form alerting me to potential side effects from diarrhea to hepatitis and even death. And with that, I started on a protocol that I hoped wouldn’t kill me before the cancer did.
Every three weeks, I spend a day on the fourth floor at Memorial Sloan-Kettering, hooked up to an IV as strange new drugs drip into my system. Every week, I am monitored and quizzed and examined and have truly ludicrous amounts of blood drawn. The external effects of the regimen presented themselves early on – crushing exhaustion, an itchy rash, dizzy spells – but I would have to wait three months, until January, to learn whether the drug combo was doing any real work on my cancer. The fact that the lump on my back subsided after the very first treatment was encouraging enough to get my doctor enthusing, but having been declared “cancer free” once before, I knew to temper optimism with caution. Especially because these are uncharted waters.

Immunotherapy, my doctor says, is like religion. “For years,” he tells me, “we just had to go on faith.” It differs radically from chemo in that it coaxes your body’s own defenses to attack disease – and then, astonishingly, to continue defending the body after treatment has ended. It’s still considered a new frontier in cancer care, and at first glance, it’s easy to see why. Its main forerunner is Interleukin-2, an immune-system treatment for patients with metastatic cancer that is infrequently used and only sporadically effective. And one of the immunotherapy drugs I’m on, Ipilimumab, won FDA approval last year with a mere 30 percent success rate.
Yet the way we treat – and try to head off – cancer is changing radically. Look no further than the rise of the vaccine Gardasil. Since its approval in 2006, it has been routinely given to girls to help ward off HPV, which can cause cervical cancer. And just last week, the Roswell Park Cancer Institute in Buffalo launched a Phase 1 clinical trial for a vaccine researchers say “harnesses the power of the body’s immune system to kill cancer cells.” Imagine a world in which preventing and treating cancer didn’t automatically mean harsh protocols like chemo, radiation or interferon. Imagine something that might someday be as simple as getting a shot. It’s coming. Because as my clinical trial nurse puts it, “It’s the immune system, stupid.”
That dramatic day, however, is still a long way off. In the meantime, if the other 10 people doing this trial at MSKCC are anything like me, they’ve been dealing with scarred veins, side effects and nagging uncertainty. Science may be moving at a breathtaking clip, but when you’ve got a cancer that often kills within a year, it simply may not be moving quickly enough for all of us.
That’s why when my doctor said he had my results, I wasn’t sure I wanted to know. I had been at MSKCC just that morning, guzzling sickly sweet, room-temperature liquid and holding my breath inside the CT scan machine. After three months of infusions, I’d now know whether that spot in my lung was growing or shrinking, whether my cancer was accelerating or diminishing. That night, as I stood in the hall outside my support group, I held my breath again. And then my doctor told me, “I have good news.”

“The tumor in your lungs is gone,” he continued, “and the one on your back has receded completely.” I don’t know a lot of fancy medical jargon, but I do know that “good news,” “gone” and “receded completely” are, for a person with distant metastases, downright extraordinary.
Two days later, I was back at Sloan-Kettering, awaiting my next infusion. “I know you can’t reveal much,” I’d asked, “but can you say anything about how the other people in the trial are doing?” I may be thriving, but if it turned out other patients were dropping like flies, I’d hold off on popping a bottle of Dom.
“We had two other patients who had scans this week,” the doctor said. “Both of their tumors have shrunk significantly. But you’re at 100 percent, so that makes you our valedictorian.” And while it’s nice to be valedictorian, what it really means to a team of researchers — and Bristol-Myers Squibb — is that I am solid results.
This isn’t a happy ending. People with Stage 4 cancer don’t really get those. This isn’t even an ending. I’m still only halfway through a trial that is kicking my ass. After I complete it in March, I will be on maintenance treatment every three months for the next two years. I will have skin checks and MRIs and scans for the rest of my life. I live with the reality that melanoma, as I have already learned firsthand, makes more comebacks than Cher. And nobody really knows for sure what the long-term effects of my treatment are, because nobody’s ever done this particular course before. I’m hoping they include super strength and sexual charisma, but liver damage seems likelier.

Yet right now, I have hope that the middle-aged woman in Treatment Suite 26, the one whose elderly father sits by her side as they watch “Dr. Phil” together, is getting better. That the tall, 20-something guy in the Superman T-shirt, a genial fellow who tells me the cancer has already come back twice before, is too. And it’s a humbling and fantastic thing to consider that, someday, because of what the sick and the healers are doing on the fourth floor, you might get to survive, too.

When I went in for my last treatment, my doctor asked if I wanted to see my scans. You bet I did. He sidled over to a monitor in the corner of the exam room and brought up an image dated Oct. 6, 2011. “This is your lung,” he said. “See that there? That blob? That’s the tumor.” Then he brought up another image right next to it. “This is you now.” It looked just the other one, but with one significant difference. No blob. He did the same for the picture of my back. “Here’s the cancer,” he said. There was a green arrow pointing to it, a flag that some technician added three months ago, a little signpost of malignancy. “And this,” he said, double-clicking on a different picture, “is you now. Nothing.” Nothing has never looked so beautiful.

“Wow,” I replied. “That’s amazing.”
“Yeah, it is,” he said, beaming. “It’s more fun when it works.” I looked at the monitor and smiled too. Within those weird, abstract images I could see so much, so clearly. I could see sunsets and birthday parties; I could see snowmen and sand castles. And I thought, yup, it’s the best fun ever. It’s even better than a happy ending. It’s a future.

Immunotherapy + Cancer Vaccines will be the future.

In my next post I will show you how we can beat cancer (Melanoma) with combinational therapy. This is so new that your Oncologists don't even know about. It is the culmination of the last 5 years of my my search for a cure.




“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

Cancer immunotherapy comes of Age,,Melanoma..Jim Breitfeller

Author:Ira Mellman1, George Coukos2 & Glenn Dranoff3

Nature:4 8 0 | NATURE | VOL 480 | 22/29 DECEMBER 2011

"Activating the immune system for therapeutic benefit in cancer has long been a goal in immunology and oncology. After decades of disappointment, the tide has finally changed due to the success of recent proof-of concept clinical trials. Most notable has been the ability of the anti-CTLA4 antibody, ipilimumab, to achieve a significant increase in survival for patients with metastatic melanoma, for which conventional therapies have failed. In the context of advances in the understanding of how tolerance, immunity and immunosuppression regulate antitumour immune responses together with the advent of targeted therapies, these successes suggest durable and long-lasting response in cancer patients."

We as patients of the Clinical trials are right in the middle of this awakening!!!!

Here is the article:

Cancer immunotherapy comes of age



“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

The Anti-PD-1 Therapy Race for Approval by the FDA is On..Melanoma ..Jim Breitfeller

When it rains, it pours!!!! Melanoma patients over the last twenty years have not seen any progress in the fight to cure Melanoma. That has all changed in 2011 when the FDA approved Yervoy (Ipi..Ipilimumab), an anti-CTLA-4 monoclonal antibody and Zelboraf (vemurafenib). Well, this all going to change Melanoma from a cancer to a chronic disease that may be stabilized or even cured. The new Kid on the block( PD-1) is another Surface molecule that is unregulated when the T-cells are activated. This molecule is time dependent , which means that over time it migrates to the surface. Base on the research today, PD-1 molecule causes global inhibition to activated T-cells and down regulates the IL-2 expression by the PI3K/Akt pathway. It also inhibits the ICOS molecule that is an important co-stimulator for the T-cells.




So with stakes high to be the first to market, Bristol Myer Squibb, a little known company, Amplimmune, co-sponsored by GlaxoSmithKline and Curetech, a subsidiary of Teva Pharma of Israel are in the race of their lives. Winner takes all. And to throw Icing on the cake, the blockage of both inhibitors (PD-1 and CTLA-4) have shown remarkable ability to eradicate Melanoma tumors in mice.



Bristol Myer Squibb seems to be leading this race with a clinical trials recruiting at Sloan Kettering in New York and Yale in Connecticut.

The study is “Dose-escalation Study of Combination BMS-936558 (MDX-1106) and Ipilimumab in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma”
Trial: NCT01024231

So with this in mind, if was seeking to try a clinical trial at this time, I would seek out the combination first, then PD-1 and if all else fails, Anti-CTLA-4 therapy followed by IL-2.

I see a Stabilization/Cure on the horizon for this disease and others based on these immunotherapies.



“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

Why Is Interleukin-2 so important for mounting an immune response?.Melanoma..Jim Breitfeller

The T-cell-specific cell-surface receptors CD28, CTLA-4, ICOS and PD-1 are important regulators of the immune system. CD28 potently enhances those T-cell functions that are essential for an effective antigen-specific immune response, and the homologous CTLA-4 counterbalances the CD28-mediated signals and thus prevents an otherwise fatal overstimulation of the lymphoid system. PD-1 engagement can prevent ICOS but not CD28 costimulation. The inability of ICOS costimulation to override PD-1 inhibition is directly related to the low IL-2 levels it induces upon its engagement. ICOS Costimulation requires IL-2 and can be prevented by CTLA-4, PD-1 engagement. With the CD3/CD28 blocked downstream at the P13K and the Akt pathways, the T-cell is activated but the proliferation and survival of T-cells/immune response is terminated.



A picture is worth a thousand words.






Based on the above model, Downstream of the CD3/CD28 signaling the co-inhibitors down modulate the P13/Akt signaling. Signaling via CD28 is required for optimum IL-2 production, cell cycle progression, and survival. CD28 is constitutively expressed on naive CD4+ T cells is slightly upregulated after T cell activation.







The CTLA-4 and the PD-1 expression increase over time in Melanoma patients. This is why it is so very hard to eradicate Melanoma in the late stage IV.


To counteract the inhibition, one can use Antibodies to block the suppressive signaling coming from the CTLA-4 and PD-1. This is where Yervoy (Anti-CTLA-4) and Anti-PD-1 come into play. So if you can do a therapy with a systematic approach, you may be able to beat Melanoma.
It is now known, that IL-2 can down regulate PD-1 receptor so you might not need to do Anti-PD-1 therapy. Or you might do anti-PD-1 instead of IL-2 therapy to cut down the harsh effects of the IL-2 therapy. It is now known that the T-cell activation/immune response needs IL-2 to produce a robust 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

How does Ipilimumab (Yervoy) work? Melanoma..Jim Breitfeller

Ipilimumab is anti-CTLA-4 monoclonal antibody.

Ipilimumab C6742H9972N1732O2004S40
immunoglobul has a calculated molecular formula of C6472H9972N1732O2004S40 and a molecular weight of 145.4 kDa.in G1, anti-(human CTLA-4 (antigen)) (human gamma1-chain), disulfide with human kappa-chain, dimer [CAS] immunoglobulin G1, anti-(human CTLA-4 (antigen)) (human g1-chain), disulfide with human k-chain, dimer [CAS]

Half Life = 15 days

Tremelimumab (from Pfizer) is an IgG2
Tremelimumab is a fully human cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) IgG2 monoclonal antibody, presumably manufactured using transformed mammalian cells. Tremelimumab is a dimer (composed of two chains) linked by a disulfide/sulfhydryl bond. Tremelimumab has a calculated molecular formula of C6500H9974N1726O2026S52 and a molecular weight of ~150 kDa

Half life= 21 days




In T-cell activation, the receptor, CTLA-4 is upregulated on about day 3.

The CTLA-4 complex can suppress the immune response.

CTLA-4 that interferes with Dendritic cell (DC) costimulation via reduced CD80/CD86, (B7-1-2) expression and CD25 (IL-2 receptor) to allow for Treg survival, activation, and effective competition for limited IL-2 during infection.

Ipilimumab (Yervoy) works by blocking the CTLA-4/ B7-1/2 complex, which allows the costimulation of the CD28// B7-1/2 complex to take place. This takes the brakes off the immune response allow the response to go unchecked.

Another thing Yervoy does is that it decreases the signaling of STAT5 with increasing concentrations. That is why the best overall concentration is 10mg/Kg.

Phosphorylation of STAT5 decreased significantly with increasing concentrations of tremelimumab/Ipilimumab in monocytes from five healthy donors and from three patients with melanoma. Overall, these data demonstrate that monocytes express mostly intracellular CTLA4 and that CTLA4 is biologically active in this cell subset since exposure to tremelimumab/ipilimumab induces changes in intracellular signaling molecules.
By decreasing the signaling of STAT5 during Cell differentiation, TH17 and TH1 cells are mostly produced.






“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

Melanoma International Foundation Exposed!!!! Melanoma ..Jim Breitfeller

In the last couple of days I have been comunicating with a caregiver on the subject of Help! Interleukin-2 or Yervoy?? (lauram)Posted: 1:38:56 pm on 7/15/2011

As I went into my posts I linked some papers that I wrote on the subject matter. It was based on years of research and I thought it had some added value to the subject.
Posted:

"Based on my interpretation of the science, I would do Ipilimumab (Yervoy) first. Make sure you have your ALC (Absolute Lymphocyte count) tested before the trial. If it doubles by week 7, you are most likeely a responder. If not, do the HD-IL-2 regime. Here is a paper that may help you understand the science behind the treatment."




Well, I was in great disbelief that Catherine Poole, the President and Founder of the Melanoma International Foundation had deleted my link and said

Re: Help! Interleukin-2 or Yervoy?? (Catherine Poole)
Posted: 12:24:21 pm on 7/16/2011 Modified: 12:27:43 pm on 7/16/2011


"Jimmy,

I don't think this is based on "the science" but more your opinion on the science. It just hasn't been proved in enough of the population to warrant the recommendation. We must be careful in these assumptions we make. So please do not suggest that here to patients without ample evidence in large segment of the population. We had to edit out your link since it appeared to be a virus within it."


I contunued to post links to clinical data that backed up the science.

Re: Help! Interleukin-2 or Yervoy?? (jimmy_b)
Posted: 8:57:41 pm on 7/16/2011 Modified: Never


Catherine, if you read my intial post: I said"



Based on the science, I would do Ipilimumab (Yervoy) first. Make sure you have your ALC (Absolute Lymphocyte count) tested before the trial. If it doubles by week 7, you are most likeely a responder. If not, do the HD-IL-2 regime. Here is a paper that may help you understand the science behind the treatment."



I am saying the what you are. Do Yervoy first. If you fail, then try HD IL-2. A response from IL-2 can be durable and long lasting (Over 10 Years in some cases)


Patient information:Melanoma treatment; advanced or metastatic melanoma




Author Jeffrey A Sosman, MD



http://www.uptodate.com/contents/patient-information-melanoma-treatment-advanced-or-metastatic-melanoma


MELANOMA TREATMENT

Treatment of metastatic melanoma focuses on:


Shrinking or getting rid of metastases

Preventing the disease from spreading

Keeping you comfortable



In most cases, it is not possible to completely eliminate or cure the cancer. Depending upon where and how big the metastases are, treatment may involve drug treatments, surgery, or radiation therapy.



Drug treatments — There are three main categories of drug treatments:

Immunotherapy – drugs that work with your immune system to stop or slow the growth of cancer cells

Chemotherapy – drugs that stop or slow the growth of cancer cells by interfering with their ability to divide or reproduce themselves

Molecularly targeted therapy- drugs that act to inhibit specific pathways or molecules important to the cancer cells



These drug treatments may be given alone or in combination. Most of these treatments must be given into a vein (intravenously) or injected under the skin, although a few can be given in pill form. Each medication is given over a period of time, sometimes up to several months, depending upon how you respond.



Immunotherapy — Because immunotherapy works differently than chemotherapy, it has different side effects.



Interleukin-2 (IL-2) — IL-2 is a form of immunotherapy that has been found to help some people with metastatic melanoma when given in high doses. In some people treated with high dose IL-2, the benefit can be long-lasting [1-3].



However, high dose IL-2 can cause serious and toxic side effects and it is generally reserved for people who are otherwise healthy (with good heart and lung function).



IL-2 is usually given into a vein three times per day for five days twice per month. Treatment is usually completed while you are in the hospital.


Potential side effects of IL-2 — Potential side effects of high dose IL-2 include low blood pressure, irregular heart rhythms, accumulation of fluid in the lungs, fever, and rarely death.


Ipilimumab — Ipilimumab is a drug that stimulates the body’s immune system to react against the melanoma. This is given once every three weeks for a total of four doses. Treatment with ipilimumab may decrease the extent of your melanoma and help you live longer. But ipilimumab can also cause the body to develop an immune reaction against its own tissues. This can result in a wide range of side effects that may be severe or life threatening. The most important of these include colitis (causing diarrhea, bleeding, or more serious complications), hepatitis, rash or inflammation of the skin, and inflammation of endocrine organs (pituitary, thyroid, or adrenal). If this occurs, you might have to stop the ipilimumab and receive additional treatment for the complications.



If you take this drug, it is important to tell your doctor about any side effects you experience, even mild ones. This will help avoid the more serious complications.



MELANOMA SURVIVAL



Significant progress has been made in the treatment of metastatic melanoma over the past decade. Two drugs that stimulate the immune system, high dose interleukin-2 (IL-2) and ipilimumab, are more effective for controlling metastatic melanoma and allowing some people to live longer. However, both of these forms of immunotherapy can be associated with severe side effects.



In deciding what treatment is right for you, you and your family must consider the risks and benefits of each option according to your values and preferences."



warm regards

Jimmy B
Melanoma Missionary





Advances in Immunotherapy for the Treatment of Metastatic Melanoma


For your Information:

http://www.asco.org/ascov2/Home/Education%20&%20Training/Educational%20Book/PDF%20Files/2011/zds00111000363.PDF



"THE FIRST randomized clinical trial demonstrating an effect on patient survival for the treatment of metastatic melanoma has been recently reported using the immune-stimulating antibody ipilimumab.


This is an important advance in this disease as well as a proof of concept of the ability of immunotherapy to affect the natural course of advanced melanoma. However, the objective tumor response rates are low with CTLA4-blocking antibodies. Response rates up to 50% to 70% have been achieved with an optimized combination of ex vivo, clonally expanded, tumor-infiltrating lymphocytes (TILs) administered after lymphodepleting chemotherapy and followed by high-dose IL-2 administration."

"This provides further evidence of the potential of immunotherapy for the treatment of melanoma."

Dr. Antonio Ribas 2011


My Therory, is that instead of clonally expanding the (TILs) tumor-infiltrating lymphocytes ex vivo, and not depleting the Tregs, WE are doing it all in vivo (Inside the Body). The reason we skip the Lymphodepleting is that the CD4-T-cell in need to secrete just the right amount of IL-2 to activate the and prime the CD-8 T-cells. The High dose IL-2 is there to muture the CD8- T-cells into Cytotoxic T lymphocytes (CTLs).

I know there are skeptics out there, but we need to read the research papers that are cutting edge to make any progress. Why is Dr. Steven Rosenberg using IL-2 in his ACT therapy?

You need to think outside the box and not reject things that you don't understand.
best regards

Again Catherine poole responded:

Again, Jimmy, we don't believe the science until it is proven in many individuals. Hundreds of patients should show these results before it is proven fact and enough to base an opinion about. Rosenberg has been using IL2 for 20 years or more, it is his drug of choice. Why? I'm not certain, but I've not been impressed by the results of research at NCI in melanoma. So I imagine there is funding from the industry for this particular drug to be used. And they need funding desperately for melanoma at NCI, it is not a priority. I would just suggest that our recommendations be based on large studies here and so far Yervoy has more promise than IL2 and is far less debilitating..

Catherine M. Poole, President/Founder

Melanoma International Foundation


Again I responded with :

Re: Help! Interleukin-2 or Yervoy?? (jimmy_b)
Posted: 9:58:59 pm on 7/16/2011 Modified: Never


Ipilimumab in Combination with IL-2

Author: Jeffrey Weber, M.D., Ph.D., H. Lee Moffitt Cancer Center



July of 2008



Thirty-six patients with stage IV metastatic melanoma were treated with ipilimumab at doses in the range of 0.1–3mg/kg every 3 weeks combined with IL-2 at 720,000 IU/kg every 8 hours to a maximum of 15 doses [20]. There was an ORR of 22%, with three patients having a CR and five patients having a PR. Five of the responses occurred among the 24 patients treated with ipilimumab at 3 mg/kg, and one each occurred in those treated with 0.3, 1, and 2 mg/kg. Six of the eight responders had ongoing responses at follow-up of 11–19 months. The 22% ORR reflects an additive rather than a synergistic effect for these two agents, although durable responses were demonstrated.



Based on the initial experience with ipilimumab in combination with chemotherapy or IL-2, additive effects have been seen, as opposed to synergy. However, the results from these trials suggest that combination therapy with ipilimumab may play an important role in the treatment of metastatic melanoma; larger trials are required, including an ongoing phase III trial of ipilimumab plus dacarbazine compared with dacarbazine alone in frontline therapy, before further conclusions can be drawn.

http://theoncologist.alphamedpress.org/content/13/suppl_4/16.full

Jimmy B
Melanoma Missionary


Re: Help! Interleukin-2 or Yervoy?? (jimmy_b)
Posted: 10:35:56 pm on 7/16/2011

Cytotoxic T lymphocyte-associated antigen 4 blockade with ipilimumab: Long-term follow-up of 179 patients with metastatic melanoma 2010 ASCO Annual Meeting



Abstract No:8544

Citation:
J Clin Oncol 28:15s, 2010 (suppl; abstr 8544)


Author(s):


P. A. Prieto, J. C. Yang, R. M. Sherry, M. S. Hughes, U. S. Kammula, D. E. White, C. L. Levy, S. A. Rosenberg, G. Q. Phan; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; National Cancer Institute, National Institutes of Health, Bethesda, MD; National Cancer Institute, Bethesda, MD; Surgery Branch, National Cancer Institute, Bethesda, MD



Abstract:


Background: We have previously shown objective clinical responses in patients with metastatic melanoma treated with CTLA-4 blockade using ipilimumab. We have treated 179 patients in 3 separate clinical trials and now have long-term follow-up to evaluate the durability and unique features of this immunotherapy. Methods: A total of 179 patients with metastatic melanoma were treated in 3 trials: In Protocol 1, 56 patients received ipilimumab with gp100 peptide vaccines. In Protocol 2, 36 patients received ipilimumab with high-dose interleukin-2 (IL-2). In Protocol 3, 87 patients received intra-patient dose escalation of ipilimumab and were randomized to receive gp100 peptides. We have updated and analyzed the follow-up and survival data for these trials. Results: With median follow-up for Protocol 1, 2, and 3 being 80, 71, and 60 months, median survival was 15, 16, and 13 months, respectively. Objective tumor regression was 12% for Protocol 1, 25% for Protocol 2, and 21% for Protocol 3. Patients in Protocol 2 had a 17% complete response rate (6 patients: 77+, 74+, 72+, 71+, 71+, and 69+ months), as compared to 7% in Protocol 1 (4 patients: 82+, 81+, 79+, and 66+ months) and 8% in Protocol 3 (5 patients: 64+, 63+, 62+, 60+, and 55+ months); all complete responses are ongoing. Many patients who eventually became complete responders had continual tumor shrinkage after stopping therapy. Conclusions: CTLA-4 blockade with ipilimumab can achieve durable objective tumor regression in patients with metastatic melanoma. The combination of ipilimumab and IL-2 appears to have an increased complete response rate, although this needs to be tested in a prospective randomized trial. This report represents the largest single-institution experience with the longest follow-up for this agent; our results support its role as a viable treatment option for patients with metastatic melanoma.



Catherine My Theory does have Merit. It is the Science backup with some clinical Data.



Lets Think OUTSIDE THE BOX!!!!



best regards

Jimmy B
Melanoma Missionary


Re: Help! Interleukin-2 or Yervoy?? (Catherine Poole)
Posted: 7:10:37 am on 7/17/2011 Modified: 7:15:36 am on 7/17/2011


This just isn't the place for you to post all of this. Just give the citations. As I mentioned in the other response to your post, you are not a peer reviewed credentialled medical researcher. We always think outside the box here but we also keep in mind the validity of research and whether large numbers of people benefitted. We also talk in terms that people can understand easily. You are a missionary by your self description, bent on a mission and we are navigators exploring all options.


Catherine M. Poole, President/Founder



Melanoma International Foundation


The MIF Website and Forums are designed for educational purposes only and are not engaged in rendering medical advice or professional services. The information provided through this Website should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you have or suspect you may have a health problem, you should consult your health care provider.



Re: Help! Interleukin-2 or Yervoy?? (Catherine Poole)
Posted: 7:12:02 am on 7/17/2011 Modified: Never


This just isn't the place for you to post all of this. Just give the citations. As I mentioned in the other response to your post, you are not a peer reviewed medical researcher.



Catherine M. Poole, President/Founder



Melanoma International Foundation



The MIF Website and Forums are designed for educational purposes only and are not engaged in rendering medical advice or professional services. The information provided through this Website should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you have or suspect you may have a health problem, you should consult your health care provider.



Re: Help! Interleukin-2 or Yervoy?? (jimmy_b)
Posted: 8:21:51 am on 7/17/2011 Modified: Never


Catherine, What credentials do you have may I ask. How many patents do you have. I rest my case.



You are blinded by your own lack of understanding.





Jimmy B




Re: Help! Interleukin-2 or Yervoy?? (Catherine Poole)
Posted: 7:10:37 am on 7/17/2011 Modified: 10:53:34 am on 7/17/2011


This just isn't the place for you to post all of this and we don't like our forum to have the negativity that you exhibit. Just give the citations as you are taking space away from others. As I mentioned in the other response to your post, you are not a peer reviewed credentialed medical researcher. I have never claimed to be either. I rely on the opinion of medical experts who are credentialed and peer reviewed in their work in melanoma research from the outstanding cancer centers who specialize in melanoma. We always think outside the box here but we also keep in mind the validity of research and whether large numbers of people benefitted. I know you are promoting what worked for you and then backing it with research you have found that could be interpreted in a different light. We also talk in terms that people can understand easily. You are a missionary by your self description, bent on specific therapy mission and we are navigators exploring all options. You have your own website for that purpose and we'd appreciate you keeping your lengthy opinions there.


Catherine M. Poole, President/Founder



Melanoma International Foundation




This forum is moderated by specialists in melanoma, primarily by volunteer dermatologists and oncologists on a weekly basis. In addition, Catherine Poole, President and Founder of the Melanoma International Foundation, a melanoma survivor, and patient navigator for 20 years and co-author with DuPont Guerry, MD a melanoma expert, of Melanoma, Prevention, Detection and Treatment, (Yale University Press: 2005) monitors this site many times daily. Information on


Re: Help! Interleukin-2 or Yervoy?? (jimmy_b)Posted: 11:33:12 am on 7/17/2011
Laura,



Re: Help! Interleukin-2 or Yervoy?? (jimmy_b)
Posted: 11:33:12 am on 7/17/2011 Modified: Never


Laura,

Thanks, as you can see, Catherine Poole is pushing her own agenda and has delete my entries.



What happen to the Freedom of Speech act?



This forum is NOT moderated by specialists in melanoma, primarily by volunteer dermatologists and oncologists on a weekly basis. This is very Sad.


Jimmy B
Melanoma Missionary

If you go to Melanoma International Foundation for advice, You may not be getting the whole picture.

I was not pushing my theory, I was giving my opinion. As for Catherine M. Poole,
who is sending out The Negativity.

"We don't like our forum to have the negativity that you exhibit."
~Catherine M. Poole_

You be the judge


I don't delete links and entries or comments on my web blog. Everyone is entitled to their opinoin.


“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

After Activation With Yervoy, IL-2 Produced by Activated CD4+ T Cells Helps CD8+ T-Cell Activation.Melanoma..Jim Breitfeller

YERVOY™ (Ipilimumab) Approved For The Treatment Of Previously-Treated Advanced Melanoma In The EU
Posted 6 minutes ago
Article Date: 14 Jul 2011 - 4:00 PDT

Bristol-Myers Squibb today announced that the European Commission has approved YERVOY™ (ipilimumab) for the treatment of adult patients with previously-treated advanced melanoma.


After Activation With Yervoy, IL-2 Produced by Activated CD4+ T Cells Helps CD8+ T-Cell Activation.

IL-2 Is Critical to CD8+ T Cell Activation at Early Time Points during Priming.




The Action of IL-2 on CD8+ T Cells Is through IL-2 Receptor
IL-2 signals to naïve CD8+ T cells through IL2 Receptor

It is hypothesized that IL-2 may help CD8+ T cell activation through enhancing the signal that drives proliferation.


IL-2 Signaling during Priming Helps CD8+ T Cells Acquiring Effector Functions,


Generation of Potent CD8+ T Cell Anti-Tumor Effector Function Depends upon IL-2 Help.


IL-2 signal at priming drove better anti-tumor CTL function in vivo.

This is why Combinatorial Therapy is a Must to CURE Melanoma

Yervoy (Ipilimumab) + IL-2 = Melanoma CURE!!!!

You must get the tumors's microenviroment in the right configuration for it to work.





“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

ASCO Review with Dr. John Kirkwood on Melanoma Therapies..jim Breitfeller

The full Audio of the Dr. Kirkwood interview at ASCO 2011


Please if you get a chance, listen to the full interview of Dr. John Kirkwood on the lastest therapies for Melanoma. It might help save your life or loveone's life.

Get a cup of coffee and a pad and pencil.

Enjoy




“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

Yervoy.. The Magic Bullet!!..Melanoma..Jim Breitfeller

Hi everyone

I´ve been reading posts at this Bulletin Board for almost a year now. Some posts I have read with tears in my eyes, and some with joy. Here is our story (short version):

I am the husband to a 39 year old woman from Denmark in Europe.

In 2003 she had a mole removed from her thigh (Stage II). It contained melanoma-cells.

In 2007 melanoma had spread to a lymph-node in her groin (Stage III). Surgery was needed.

In 2008 melanoma relapsed in another lymph-node, surgery again.

In 2009 melanoma hit us hard (Stage IV). It had spread to her lungs, one met in each lung. The size of the mets was 25 mm and 16 mm respectively. Surgery was fortunately possible.

In October 2010 melanoma went back. This time there was multiples mets in each lung. About 5-6 mets in each lung. The biggest was 19 mm. It was unsurgeable, which was very hard to cope with.

In November she began Interferon/Interleukin-2 treatment. It was tough beyond imagination. She had all the known sideeffects, and she was so bad during hospitalization. The midway PET/CT scans in January revealed that she was a responder! Scans showed that all the mets had become inactive or necrotic. Some mets had even shrunk a little bit. We were delighted, and she continued with the third and fourth series of Interferon/IL-2.

February 15 we got the results of the next scan. We were optimistic because the midway scans was indeed promising. We were shocked when told that the melanoma had began to grow again. There was 2 active mets now. One big met, about 32 mm in diameter, in her right lung lightened up. In addiction there was a lot of fluid in the right lung membrane, and it probably contained melanoma-cells. All other mets was still inactive, except one, and our doctor feared that it would be only a matter of time, before the other mets would begin to grow again. We were devastated.

Our doctor suggested Ipilimumab, and my wife started March 11, on the same day Japan was shaken by the huge earthquake. I watched it on TV while she was receiving the first dose of ipilimumab (3 mg/kg dose). I remember wishing that the drug was the earthquake of our lives…

My wife have always been a positive and happy human being, no matter what challenges life would bring, she still truly believe that she could defeat this Melanoma Devil. She began consulting a Chinese doctor and received acupuncture twice a week. Beside this she trained 4-5 times a week, fitness and running. In these situations we talked about preparing your body to fight the cancer, with a "little" help from our friend, ipilimumab…

She received 4 doses every third week and got a CT scan in June.

Three days ago on June 21 we arrived to the hospital to talk with our doctor about the results of the CT scan. The time from the scans being done and to get the results is awful with a lot of anxiety, you guys all know… The scan showed that the 32 mm met in the right lung was completely GONE!!!!! The fluid was gone too, and the x-ray showed a nice healthy looking right lung. We were stunned. I hugged my wife with a lot of tears in my eyes. Our doctor was very delighted too. Ipilimumab had worked much better than expected. We had hoped for stabilization, maybe shrinkage, if we were lucky. But this???? Unbelievable. Some other small mets was still there but hasn´t grown in size in half a year, and our doctor said it very well could be necrotic tissue.

This is where we stand now. We´re thrilled and delighted and so so happy. We have now dared to plan for more than a month :-)

So this story is to all you Warriors out there, keep on fighting with believe and trust in your hearts. The path is very tough but the battle can be won, sooner or later. We´ll keep fighting this Devil.



Kind regards

willtolive

========================================================================


Did High Dose Interferon Alpha set the stage for the perfect Orchestration of an Immune Response?

As I continue my search for the Holy Grail, I need to keep grounding myself to what really took place in the Melanoma treatment. I can not keep wondering if Interferon therapy had played a part in our successful treatment.

Both Vicky and I did some IFN therapy first.



Vicky’s Treatment timeline:

1) Diagnosis 5/10/06
2) Excision and sentinel node biopsy 5/16/06. SN positive, MM 3.3 mm, amelanotic, ulcerated (I did just read that the ulcerated variant does seem to do well with high-dose interferon in terms of prolonging survival)
3) Elective radical lymph node dissection, right groin, 5/30/06 2 more positive lymph nodes
4) High-dose iv interferon all of July 2006, followed by subcutaneous interferon MWF for 2 months.
5) Enroll in anti-CTLA-4 study as adjuvant therapy for stage 3 MM with Dr. Jeffrey Weber at USC. First dose of intravenous infusion of anti-CTLA-4, dose of 10 mg/kg early Nov 2006, second dose was Jan. 9, 2007.
6) Chest CT, routine, for the study, was positive for bilateral pulmonary nodules on 1/18/07
7) Lung biopsy positive for MM on 2/03/07
8) First course of high-dose IL-2 was March 2007
9) 60% reduction in tumor burden on April 23 CT scans
10) Second course of IL-2 in June 2007 ( I believe I got 14 of 14 doses during the 3rd cycle or week 1 of the second course.
11) Complete response seen on CT 8/01/07
12) Took an elective 5th cycle of IL-2 in early September of 2007- got quite sick and stopped. I think I got around 9 doses that last time.


Did High Dose Interferon Alpha set the stage for the perfect Orchestration of an 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

2011 ASCO Annual Meeting Highlights on Melanoma and Neuroblastoma, with Lynn Schuchter, MD ..jim breitfeller

2011 ASCO Annual Meeting Highlights on Melanoma and Neuroblastoma, with Lynn Schuchter, MD
June 5, 2011

2011 ASCO Annual Meeting Highlights on Melanoma and Neuroblastoma, with Lynn Schuchter, MD



“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

Ipilimumab and Beyond: New Therapies Imminent in Melanoma..Jim Breitfeller

Ipilimumab and Beyond: New Therapies Imminent in Melanoma
By: SUSAN LONDON, Internal Medicine News Digital Network


05/11/11
LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life. But historically, it has not been a major focus in oncology, in part because of its propensity to metastasize early and the very limited treatment options when it does.

This is changing – and not just because of the landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients, Dr. Steven O’Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference


Ipilimumab targets the immune system so that it can contain the cancer, rather than targeting the tumor to eradicate the disease, explains Dr. Steven O'Day.


Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O’Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

The rest can be viewed at Internal Medicine News


Remember:Ipilimumab and Beyond!!!!

You heard it first back in 2006 right here. It may not be a cure, but it is a durable response that can last for YEARS!!!

With combinatorial therapy, the response rate will improve greatly.



“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

Ipilimumab is Working,, Melanoma..Jim Breitfeller

T-cell Activation!!!!!! Ipilimumab (Yervoy) is working!!!





“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

F.D.A. Approves Drug to Treat Melanoma..Jim Breitfeller

The FDA just announced that they have approved Yervoy "ipi" for unresectable and metastatic melanoma. This is the first time a drug has been approved for melanoma in 13 years, so great news!

Here's the announcement:

FDA NEWS RELEASE

For Immediate Release: March 25, 2011

Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov

Consumer Inquiries: 888-INFO-FDA

FDA approves new treatment for a type of late-stage skin cancer

Melanoma patients lived longer with treatment

The U.S. Food and Drug Administration today approved Yervoy (ipilimumab) to treat patients with late-stage (metastatic) melanoma, the most dangerous type of skin cancer.

Melanoma is the leading cause of death from skin disease. An estimated 68,130 new cases of melanoma were diagnosed in the United States during 2010 and about 8,700 people died from the disease, according to the National Cancer Institute.

"Late-stage melanoma is devastating, with very few treatment options for patients, none of which previously prolonged a patient's life," said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research. "Yervoy is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment."

Yervoy is a monoclonal antibody that blocks a molecule known as cytotoxic T-lymphocyte antigen or CTLA-4. CTLA-4 may play a role in slowing down or turning off the body's immune system, affecting its ability to fight off cancerous cells. Yervoy may work by allowing the body's immune system to recognize, target, and attack cells in melanoma tumors. The drug is administered intravenously.

Yervoy's safety and effectiveness were established in a single international study of 676 patients with melanoma. All patients in the study had stopped responding to other FDA-approved or commonly used treatments for melanoma. In addition, participants had disease that had spread or that could not be surgically removed.

The study was designed to measure overall survival, the length of time from when this treatment started until a patient's death. The randomly assigned patients received Yervoy plus an experimental tumor vaccine called gp100, Yervoy alone, or the vaccine alone.

Those who received the combination of Yervoy plus the vaccine or Yervoy alone lived an average of about 10 months, while those who received only the experimental vaccine lived an average of 6.5 months.

Common side effects that can result from autoimmune reactions associated with Yervoy use include fatigue, diarrhea, skin rash, endocrine deficiencies (gland or hormone), and inflammation of the intestines (colitis). Severe to fatal autoimmune reactions were seen in 12.9 percent of patients treated with Yervoy.When severe side effects occurred, Yervoy was stopped and corticosteroid treatment was started. Not all patients responded to this treatment. Patients who did respond in some cases did not see any improvement for several weeks.

Due to the unusual and severe side effects associated with Yervoy, the therapy is being approved with a Risk Evaluation and Mitigation Strategy to inform health care professionals about these serious risks. A medication guide will also be provided to patients to inform them about the therapy's potential side effects.

Yervoy is marketed by New York City-based Bristol-Myers Squibb.

For more information:

FDA: Office of Oncology Drug Products

http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm091745.htm

FDA: Approved Risk Evaluation and Mitigation Strategies (REMS)

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm

FDA: Approved Drugs: Questions and Answers

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm054420.htm

NCI: Melanoma

http://www.cancer.gov/cancertopics/types/melanoma

CDC: Skin Cancer

http://www.cdc.gov/cancer/skin/




“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

A Melanoma Story,.. Read the Comments. BMS denies Compassionate Care to a dying patient.. Jim Breitfeller

A Melanoma Story,.. Read the Comments. BMS denies Compassionate Care to a dying patient. It is an EYE OPENER!!!!!!

-And-thats-all-I-know


Read the 62+ comments from the comments link at the top of the page.

Bristol Myer Squibb should be held accountable for it's actions.

“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

Alarmins Initiate Host Defense against Melanoma, Let the war games begin..Melanoma ..Jim Breitfeller

The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. These signals are generated by molecules call Alarmins.
In response to infection and/or tissue injury, cells of the host innate immune system rapidly produce a variety of structurally distinct mediators that not only function as potent effectors of innate defense but also act to alarm the immune system by promoting the recruitment and activation of host leukocytes through interaction with distinct receptors. One of these Alarmins is the High mobility group box 1 (HMGB1).

(HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders, but our case, it is the molecule that sends the red flag up to the immune system, stating there is a problem.

This Alarmin (HMGB1) is capable of activating antigen-presenting cells (APCs) and enhancing the development of antigen-specific immune responses.

The interaction of high mobility group box 1 protein (HMGB1) released from dying tumor cells with Toll-like receptor 4 (TLR) on dendritic cell was required for the crosspresentation of tumor antigens and the promotion of tumor specific cytotoxic T-cell responses.



Under stress conditions, such as injury or infection, HMGB1 is released and promotes inflammation. (Danger Signal) HMGB1 is passively released by Death of cells or tissues through injury or disease (necrotic) but not apoptotic death. Disintegration of cells into membrane-bound particles that are then eliminated by phagocytosis or by shedding of normal cells and actively secreted by a variety of activated immune and non-immune cells.
Through the TLR4, HMGB1 activates NFκB inducing a wide range of host changes that include activation of the innate immune system (neutrophils, NK cells, dendritic cells) and secretion of proinflammatory cytokines and mediators.

There is growing evidence that the relationship between the inflammatory process and cancer is complex. Our understanding of this relationship as it relates to Danger Signal development and or progression of malignancy is still limited. Further evaluation in patients is clearly needed if we are to truly understand whether there is therapeutic potential in targeting Pro-inflammation, “The Danger Signal”.

HMGB1 as a DAMP released into the tumor microenvironment plays a central role in the recruitment and activation of innate immune cells.

This emergent understanding of the danger signals also called alarmins or damage associated molecular patterns (DAMPs) is fueling new research that may be beneficial to finding a cure.

This ability of dendritic cells to recreate the environment associated with necrosis via the regulated secretion of HMGB1 represents a successful evolutionary strategy and places HMGB1 at the crossroads between innate and adaptive immunity.



Once T-cells are activated, RAGE and HMGB1 are upregulated during cellular activation, consistent with a role of the RAGE axis in pro-inflammatory immune responses.

So how do we cause tumor cells to die? We don’t need to kill them all at once, that would be nice, and we need to a portion so that HMGB1 is secreted. Or do we inject a mixture of naturally occurring Cytokines that act as the pro-inflammatory cytokines, (the Danger Signal)?



.
A little known company is just doing that. The company is IRX Therapeutics.

Irx Therapeutics, Inc
2350 Broadhollow Road
Farmingdale, NY 11735-1006


Dr. John W Hadden founded the company in 1994 and holds the patent on the cytokine mixture called IRX-2.

The cytokine components of IRX-2 (includes IL-1, IL-2, IL-6, IL-8, IFN-γ, TNF-α, G-CSF and GM-CSF) are known to promote both T lymphocyte and dendritic cell development and function and monocyte function.

I believe the natural cytokine mixture (NCM). The NCM includes 1L1, IL2, IL6, IL8, IL10, IL12, .delta.IFN, TNF.alpha. and G- and GM-CSF could play a pivotal role in activation of the T-cells (CD4+ and CD8+). This mixture that is in the patent (20030206885) is what I would call the Proinflammatory Cytokines, the “Danger Signal”.

The natural cytokine mixture is missing MCP-1, MIP-1 alpha and beta which is very important to attract immune cells to the tumor’s microenvironment.


CCL3/MIP-1 alpha acts as a chemoattractant to a variety of cells including monocytes, T cells, Dendritic cells, B cells and eosinophils

CCL4/MIP-1 beta is expressed primarily by T cells, B cells, and monocytes after antigen or mitogen stimulation. The functional receptor for MIP-1 beta has been identified as CCR5.

CCL4, also known as macrophage inflammatory protein 1 beta (MIP1β)
is a 7.8 kDa β chemokine that is secreted at sites of inflammation by activated leukocytes, lymphocytes, vascular endothelial cells.

CCL4 attracts a variety of immune cells to sites of microbial infection as well as to other pathologic inflammation.

Monocyte chemoattractant protein-1 (MCP-1) is important in attracting monocytes to sites of inflammation. Besides induction of monocyte recruitment, MCP-1 can also affect chemotactic response of endothelial cells.


I speculate by combining Radiation, Chemotherapy, Ipilimumab, IRX-2, and IL-2 in a systematic way, we can induce an immune response against Melanoma and win most of the Battles. Let the war games begin. Who will take on this challenge and be the first to CURE Melanoma? We shall see.

A clue: This is from a patient that is receiving Ipilimumab (Yervoy)

“The Dr. says it's possible the swelling is caused by the tumors starting to respond. My back and leg tumors did become inflamed before they receded, so it's possible the same is happening in the brain. I could also be having a delayed reaction.”




From a paper of Dr. Meenhard Herlyn.

Inflammation is the key to the Danger Signal which can be produced by dying Tumor cells or Ipilimumab differentiating T-cells into Th-17 Phenotype or by injecting a pro-flammatory cytokine mixture. Let the War on Melanoma Begin!!!!!


“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

BMS denies any wrongdoing. Is this what we have to look forward to with Yervoy (Ipililumab) Melanoma..Jim Breitfeller

Commentary:
BMS denies any wrong doing, but this was not it's first offence and may not be it's last. As the patent waterfall nears close with Plavix, is BMS trying to make up for it's loss of revenue?
Mesothelioma and Cancer Patients Who Received Certain Chemotherapy Drugs May be Eligible for Reimbursement



I am anticipating that BMS will try to inflat the cost of production of Ipilimumab (Yervoy) and try to pass it along to the patients that desperately need it. It is a shame that the drug companies have come down to greed and screw the consumer. BMS needs desperately to clean house again and go through some Ethics training, Big time!!!

I am all for paying a fair price, but not to get gouged to the point that the insurance won't pay and pass the copay onto the patients. It is not right.





Bristol Myer Slogan:

"What sets us apart? We believe it's our commitment to patients with serious diseases, our focus on finding innovative medicines that combat those diseases, and our dedication to extending and enhancing human life."

So we can deplete your life savings for the good of the company and line our pockets!!!!




“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