MPIP: Melanoma Patients Information Page

The MPIP is the oldest and largest community of people affected by melanoma hosted through the Melanoma Research Foundation. It is designed to provide support and information to caregivers, patients, family and friends. Once you have been touched by melanoma—either as a patient or as a family member or friend of a patient—you become part of a community. It is not a community anyone joins willingly. But if you must be part of this group, you will find no better place to find the tools you need in your journey with this cancer, and the friends who can make that journey more bearable.

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Dear Fellow Mellos;

Just talked with VERY helpful folks at Eastabrooke cancer center in Omaha.  They told me the GSK 2118436 B-raf drug trial phase II (NCT 011537630) had been pulled (terminated?) by FDA nationwide.  MDAnderson cannot seem to give me an answer at all.  I waited 5 long weeks for MDA to lemme know i was B-raf positive.  Now my CT scan 2 days ago show 3 Nodules OVER 1 cm. as well as the continued others.  I completed 1 yr. I-feron 3 mths. ago.

Does ANYONE know of a viable active B-raf trial available via GSK, Novartis, Roche, Bayer?, anyplace anywhere?  

I know i could get IPI, but i'm just not too impressed with the stats on it- maybe i'm wrong.  At least the B-raf drugs showed miraculous results- albeit short term;  AND  traditional IL-2 shows Proven long term results on around 10% of people.  I really wanted to do B-raf drug to at least buy some somewhat guaranteed time.

Any suggestions or trial knowledge greatly appreciated!

Love, Shady-Grady.

I'm Here for Now, I've got the rest of my life to die; and if so, old age could be overated and God does exist.

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jim Breitfeller's picture
Replies 2
Last reply 10/25/2010 - 1:29pm
Replies by: bill58, Sharyn

This is a very good presentation from Dr. John M. Kirkwood for patients and care givers. Dated September 2010 held in Cleveland
Ohio.

Dr. Kirkwood give his honest opinion on the clinical trails to date and where they are heading in the future.

http://www.youtube.com/v/6EE5i8sSmyw?fs=1&hl=en_US

 

Please take an hour out of you day to view and listen, It may save you or your love one from doing the wrong therapy.

Best regards

Jimmy B

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bonnieb's picture
Replies 2
Last reply 10/24/2010 - 11:30pm
Replies by: Janner, Anonymous

But it just occured to me today that if only 7% of people have a second primary then why do we avoid the sun after diagnosis with the first?

Not that I am looking for an excuse to go tanning or anything but my Doctor seems so vague about everything and I just wondered about it. Does exposure to the sun increase the chance of melanoma returning?

Cheers,

BonnieB (diagnosed stage 1 Nov 09)

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fliberdy's picture
Replies 8
Last reply 10/24/2010 - 3:37pm
Replies by: fliberdy, Anonymous, Sharyn, teenagermom

I can not sleep and just discovered this site. I'm hoping to find some answers and encouragement here. I guess I don't really have a stage yet  The Dr thought  I was stage 1 but now they want to take more and do a sentinel node biopsy because the labs came back after surgery with rogue cells? Dr said my case is very odd, he has never seen this before. I am floundering here, anyone hear of something like this?

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Sherron's picture
Replies 5
Last reply 10/24/2010 - 12:28pm

Hello All - well, Jim went to the VA center in Denton, Tx. on Monday, Oct 18th..the doctor examined him...He is definitely Stage IV, which I had already figured that out...The doctor does not like the way his stomach felt, nor his coloring.  They did blood work on him...and have started him on pain medication.  They wanted him to wait until Dec 3rd to come in, but my daughter-in-law, bless her heart, is a good advocate for us...She told them that was not acceptable,  This was last Friday..Well, fortunately, they let him come in on Monday., the 18th.  They called my daughter-in-law because they could not reach my husband.  I was on my way to work on Tuesday morning, they said it was an emergency that I need to take to VA ER  now.  I turned the car around and met my daughter in law at the house, went in, woke him up and said you need to go the hospital...I thought there would be a huge argument over this...No, he agreed..His hemaglobin (sp) which last year was 18 was now 6.3....He needed a transfusion.  We drove to the VA across Dallas, got to the ER and they got him right in...by then, it was down to 5.3....they admitted him and gave him 4 units of blood over a period of 9 hours.  We were there for 2 days,...they released him last evening,   with it up to 9.8, which is still not good.  I have a feeling we might be doing this again soon.  I  have scheduled another appt in the VA center in Denton to check his blood on Nov 1st.  His liver enzymes are perfect.  The doctor thought they would be off the wall.  His color was awful.  He looks pinker now, but still not eating really good.  Of course, they wanted him to do a colonoscopy and upper GI, but of course Jim was not ready to do this.  The oncologist, said when it goes back down, he will give him another  transfusion...maybe by then Jim will be open to a colonoscopy..If it's Mel, maybe they can remove it and resesction...You all know  how hard it has been for me to get him to the doctor, so just getting him to the regular VA check-up for pain management was a big deal....and then the hospital....but he was so far down, he did not give me much trouble at all.  I was shocked...So, am hoping and praying that if his levels go down again that, he will be open to the colonoscopy.  They called his blood levels critical...The VA doctor also told us to go file an Agent Orange Claim right now.  So we will be doing that in the morning.  Please keep us in your prayers.

Take Care,

Sherron, wife to Jim

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Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology

Howard Streicher (CTEP, Bethesda, MD, USA) presented an overview of biomarkers useful for patient selection, eligibility, stratification and immune monitoring. CTEP sponsors more than 150 protocols each year across many types of new agents, so that this program is familiar with the need to prioritize trials selection using biomarkers. Biomarkers are important for 1) patient selection and stratification for the best therapy; 2) identification of the most suitable targets of therapy; 3) measurement of treatment effect; 4) identification of mechanisms of drug action; 5) measurement of disease status or disease burden and; 6) identification of surrogate early markers of long-term treatment benefit [1].

Examples of biomarkers predictive of immunotherapy efficacy (predictive classifiers) [4-7] are telomere length of adoptively transferred tumor infiltrating lymphocytes which is significantly correlated with likelihood of clinical response [8], serum levels of vascular endothelial growth factor (VEGF), which are negatively associated with response of patients with melanoma to high dose interleukin (IL)-2 administration [9] or K-ras mutations that predict ineffectiveness of cetuximab for the treatment of colorectal cancer [10]. Recently, the European Organization for Research and Treatment of Cancer (EORTC) reported a signature derived from pre-treatment tumor profiling that is predictive of clinical response to GSK/MAGE-A3 immunotherapy of melanoma. The signature includes the expression of CCL5/RANTES, CCL11/Eotaxin, interferon (IFN)-γ, ICOS and CD20 [11,12].

 

http://www.translational-medicine.com/content/7/1/45#B43

 

Take care

 

Jimmy B

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Has anyone heard how Jenna's doing. Lauren has not posted for awhile & I am worried. Thanks

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glewis923's picture
Replies 2
Last reply 10/23/2010 - 2:25pm
Replies by: glewis923

Sorry- I made typo and added extra "0" in previous post.  Guess the wonderful FDA considered this particular trial to be too compassionate!  Damn stinking beurocrats and trial lawyers!!!!!!!!!!!

I'm Here for Now, I've got the rest of my life to die; and if so, old age could be overated and God does exist.

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jross's picture
Replies 1
Last reply 10/23/2010 - 8:02am
Replies by: Fen

Does anyone have information on the long-term side effects of interferon. I am still here 6 years after my 45 weeks of regular injections. Have searched and can't find anything specific. AAny recommendations on search terms would be helpful since I have struck out using long term and chronic. Your assistance would be appreciated. JRoss

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Jim,
First of all thank you for replying to my post. I usually don’t get many replies. When I talk to my wife about this, within the first five minutes she is telling me “I am loosing her.” It has taken me close to three years to get to where my knowledge on melanoma and the immune system is today. I don’t mean to talk over patient heads. It is just the scientist in me. I worked at Eastman Kodak’s Research laboratories for 25 years.

Now to answer you first question:

You have said that the most effective durable treatment for advanced melanoma would consist of Ipilimumab combined with IL2 - is that correct?

Based on my research today, IL-2 and Anti-CTLA-4 (Ipilimumab) are most durable as we speak. A new phase I therapy is showing great promise with less side effects. That is anti-PD-1 Therapy. These therapies don’t need a specific HLA type to get into the trials.

There is also a very, very ,very new therapy that is still in translational stage. Translational research is a way of thinking about and conducting scientific research to make the results of research applicable to the population under study and is practised in the natural and biological, behavioural, and social sciences. It is usally conduted with animals like rats, mice, monkies.

Anyway this therapy combines the Anti-CTLA-4 and Anti-PD-1. It has shown syenergnic results.

 

If you have c-Kit or BRAF mutations, then targeted therapy may used but may not be durable.

If you are HLA-02 Positive, You have the option of ACT therapy with Dr. Rosenberg or Dr. Patrick Hwu at NCI or MD Anderson. They have gotten 72 % response rate with I think about 36 % complete response is I am not mistaken.

        Second Question:

There are no studies currently availble that combine Ipi and IL2, is that correct?
Define combine? There was a clinical study done by Dr. Rosenberg and colleages.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

As you can see in the graph above, IL-2 was added prior to the maximum propagation of the CD4+ T helper cells. IL-2 is known as a growth factor. So what I believe happened in this trial, they grew the Tregs.

IL-2 treatment during the expansion phase was detrimental to the survival of rapidly dividing effector T cells. In contrast, IL-2 therapy was highly beneficial during the death phase, resulting in increased proliferation and survival of Tumor-specific T cells. IL-2 treatment also increased proliferation of resting memory T cells in the host that controlled the disease. A tumor-specific T cell in chronically infected Host also responds to IL-2 resulting in decreased tumor burden. Thus, timing of IL-2 administration and differentiation status of the T cell are critical parameters in designing IL-2 therapies (Blattman et al., 2003).

So what I am trying to say is you do the Ipilimumab therapy first. Wash out for about 50 days, and then start IL-2 Therapy.

Take away:   It is a systemic combination with dosing and timing involved. Systemic Combinatorial Therapy.

Question 3:

If someone were to choose to do a combination treatment on their own (i.e. get IL2 following a course of Ipi through one of the clinical trials), would there be an advantage
to starting IL2 as soon as possible after stopping Ipi? Is there a time frame after which there would be no advantage to having received Ipi prior to taking IL2?

Base on papers from ITOH etal and others, 49 days after activation is at the maximum growth phase for the CD8- T-cells that mature into Cytotic T Lymphocytes.

<strong>Results: Graph setup</strong>

Kinetic Study of rIL-2-induced Expansion. In all 12 metastatic melanomas tested, a substantial proportion of TIL was present in tumor cell suspensions.
The ratio of lymphocytes to tumor cells ranged from 0.03 to 1.25 with an average ratio of 0.40 t 0.37. By fluorescence analysis,
TIL consisted of 78 days 11% CD3
T cells, 33 days 10% CD4+
<strong>T cells, 49 days 17% CD8+</strong>
Their CD4/CD8 ratio was 0.67.
(ITOH et al., 1988)

It was also reported that there is a time factor involved.
Our results show that T4 + human T cells differ substantially from T8 + cells with respect to their IL-2 responsiveness. T4 + cells cease to proliferate well before T8 + cells during a primary response. (GULLBERG AND SMITH et al.,1986)

<strong>Is there a time frame after which there would be no advantage to having received Ipi prior to taking IL2?</strong>

Yes, Ipilimumab has a half life of 15 days. So say you get one dose at 3.0 mg/Kg.

Days-- concentration
0-- 3
15-- 1.5
30-- 0.75
45-- 0.375
60-- 0.1875
75-- 0.09375
90-- 0.04687
105-- 0.02343
120-- 0.01171
135-- 0.00587
150-- 0.00292
165-- 0.00146
180-- 0.00073

It gets more complicated when you get multiple doses. Four dose regiment.

Days-- concentration
0-- 3
15-- 1.5
30-- 3.7
45-- 4.85
60-- 5.425
75-- 2.7125
90-- 1.35625
105-- 0.68
120-- 0.34
135-- 0.17
150-- 0.08
165-- 0.04
180-- 0.021

I am not sure where the limited threshold is but, at day 49 you have close to the maximum concentration of Ipilimumab in your body.

Since I used Tremelimumab with Half Life = 21 days and did 15mg/Kg

I had at day 50 approximately 2.17 mg/Kg anti-CTLA-4 level in my body

<strong>If I had to venture an educational guess, I would say after a four dose regime, you have 75 days to do the HD IL-2.</strong>

To back this theory up, we will use a chart from Dr. Wolchok experience the Ipilimumab.

It is a chart with the Absolute Lymphocyte count. (ALC). It is the CD4+ T-cells and CD8+ T cells combined.

 

 

 

 

 

 

 

 

 

 

 

 

As you can see from the graph, the maximum ALC was about week 7.
Week seven correlates to 49 days. That is when CD8+ T cells are at their maximum growth.

 

Question 4:

Last, is there any evidence that IL2's efficacy is enhanced by combining it with other agents (i.e. Biochemotherapy), either with or without first receiving Ipi?

This my take on the situation. You need the <strong>tumor-specific antigen</strong> to presented to the T-cells as signal 1. That could be a vaccine, radiation therapy or chemo to shed the antigen.
<strong>Secondly you need the costimulation of the CD28/B7 interface</strong>. By using Ipilimumab that blocks the CTLA-4 receptor from binding to the B7 molecule and shutting down the response.
Anti-CTLA-4 (ipilimumab) also blocks the CTLA-4 receptor on the Treg cells subduing their surpress function.

Third you need a “Danger Signal”  to get the cell to migrate to the tumor site. This may be done with inflammatory Cytokines like IL2, IL17, IL-1,IL-12,IFN gamma that act directly on the T-cells. This signal was found to optimally activate the Th1 differentiation and lead to the clonal expansion of the T-cells.
It has come to light recently that Ipilimumab helps also in the differentiation by tilting the balance towards Th17 cells. These cells secrete IL-17 which recruite the neutrophils. This all takes place at the tumor’s microenviroment. The neutrophils secrete chemokines that are chemoattractants.

These chemokines, MIP-1alpha, MIP-1beta, and MCP-1 are recently reported to serve as chemoattractants for Th1 cells. MIP-1alpha and MCP-1 are also reported to enhance antigen-specific (CTL) Cytotoxic T Lymphocyte induction. Studies revealed that MIP-1alpha /beta released from neutrophils are involved in recruitment of macrophages, T cells, monocytes, dendritic cells (DC), neutrophils and NK cells.
MIP-1 attracts predominantly CD8+ T cells while MIP-1 attracts CD4+ cells, although there is some overlap between subsets in response to both chemokines.
The other Chemokine MCP-1, binds to CCR2 to accumulate monocytes/macrophages, DC, T cells, and NK cells, thereby playing an important role in innate and adaptive immunity. CCR2 is Chemokine receptor that is key determinant of leucocyte trafficking.

IL-2 strongly upregulates expression of CCR2. With the MCP-1/CCR2 interface, the cells can traffic towards the tumor’s microenvironment. The trafficking of the cells and inflammatory cytokines present the perfect storm in the tumor’s microenvironment to induce the right immune response to eradicate the cancer, Melanoma.
So to answer your question, is there any evidence that IL2's efficacy is enhanced by combining it with other agents (i.e. Biochemotherapy), either with or without first receiving Ipi? yes if you know and take a systemic approach. You need to activate the t-cells before introducing IL-2. IL-2 can be the activator for small patient population.

As for Ipilimumab going it alone, like IL-2 can be the activator for small patient population. But when you do a systematic combinatorial therapy, there can be a synergetic result, complete response.

I hope I answered you questions, and please don’t hesitate to ask them. I do all this time by requesting reseach papers from around the world. Each question is a learning tool. There are no stupid questions. Knowledge is power to make an educated decision. Your Life may depend on it. There are many paths to take. Just follow the yellow brick road to complete response.

 

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

~Charles Darwin~
Take Care,
Jimmy B

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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EricNJill's picture
Replies 19
Last reply 10/22/2010 - 8:12pm

Due to progression and complications during our stay for a 2nd dose of Intralymphatic Vaccine, we are stopping treatment and searching for something new.  This was at the advice of professionals.  Eric has tested positive for BRAF and they are encouraging we find a trial for BRAF but since all Eric's tumors are either vascular and sub-cutaneous we are concerned about the return of melanoma after the 8-9 months with doing PLX4032. 

He's done the following treatments:

HD Interferon & LD Interferon

Clinical Trial of Abraxane, Avastin & Carboplatin

HD IL-2 (44 doses)

Clinical Trial - Dendric Cell Vaccine

Clinical Trial - Intralymphatic Vaccine

Does anyone have advice on what our next step should be? 

Thanks, Jill & Eric in OH

 

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This was recommended as an optional treatment alternative by Estabrooke Cancer Cent. in Omaha.  I know they are doing this study at Sarah Cannon Cancer Cent. in Nashville.

Would Love to know if anyone has done this protocal.  

 

Thanks & Love,  Shady-Grady.

I'm Here for Now, I've got the rest of my life to die; and if so, old age could be overated and God does exist.

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Napa K's picture
Replies 2
Last reply 10/22/2010 - 2:02pm
Replies by: Sherron, Linda/Kentucky

Hoping for and welcoming any input on any other potential protocol options for a fellow patient located in Central California.

 

*Stage IV, mom of two young children, diagnosed Fall '09.

*Has had surgery (spleen removed) failed PLX4032, high dose IL2 & Ipi ; has had WBR

*Has advancing brain mets (12 +) growing rapidly and rapid growing sub cue nodules

*As of yesterday she was given the last option of oral themolizide by her oncologist.

 

If you have any info to share, please let us know. And please include lovely Reese and her family in your prayers.

 

Be well-

Kari 

Hope is the most powerful drug

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Rebecca and Bob's picture
Replies 10
Last reply 10/22/2010 - 1:57pm

MRI and CTSCANS clear.  15 months NED hoping to keep hearing that news. Still on every 2 month but they said we can come back mid - January after the holidays... So happy, so happy.

Thanks everyone on this board for always being there!

Rebecca

Believe

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vickirs's picture
Replies 2
Last reply 10/22/2010 - 1:12pm
Replies by: vickirs, Sherron

On Sept 10 I had to have surgery because scans showed tumors invading colon and rectum.  Had to get colostomy and all visible tumors removed in pelvic area.  It was a very hard surgery.  Had to be in ICU for 6 days and recieve 2 units of blood.  Two weeks later developed naval orange size infection in pelvic so 8 more days in hospital and I am still draining and on antibiotics.  I had been on ym155 from may through sept. and failed that trial.  Thank God I had to have scans every 6 weeks because my surgeon told me that I would have been dead within a few weeks had I not had surgery.  Unfortunately he could not get the melanoma out of my liver so the surgery just bought more time.  My oncologist is waiting for me to heal all the way so that I can begin IPI.  My question is, has anybody else had to get a colostomy and how long does it take to feel better.  It has been a very long 6 weeks and I still feel week and tired with a lot of tail bone and pelvic pain.  I know 2 of my tumors there were bigger than 3 inches and I had some colon removed and the cancer had invaided the rectum.  After all of this shit it came down to this...  I went to my daughters football game last friday night (my first true outing since surgery) and my cheer leading, 15 year old daughter came up to me during half time as I was talking to friends and gave me a hug and kiss right in front of everyone.  If that doesn't make it all worth it I don't know what does.  How many 15 year old girls would actually want to be seen with their parents.  I am truly blessed for this extra time I have been given. 

melanoma is a word...not a sentence

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