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.

The information on the bulletin board is open and accessible to everyone. To add a new topic or to post a reply, you must be a registered user. Please note that you will be able to post both topics and replies anonymously even though you are logged in. All posts must abide by MRF posting policies.

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Carmon in NM's picture
Replies 5
Last reply 10/25/2010 - 9:47pm

Background: diagnosed 3b in 9/2008 with an upper left arm lesion. Clean scans through 11/2009. A sudden brain bleed 6/2010 turned out to be a metastatic tumor that hadn't shown on the 11/09 scans. An emergency craniotomy took care of the bleed and I had Gamma Knife Surgery 7/2010 for the primary tumor as well as one less than 4mm discovered at the same time. Full body scans done 6/2010 showed no other distant lesions.

S

Full body scans taken 9/2010 as a followup to Gamma Knife showed a new tumor on the right adrenal gland and we decided it was time for systemic therapy. We are waiting on the results of a biopsy taken 10/11/2010 and sent to France to see if I am c-kit positive and will qualify for a focused drug trial. Pathology done at the hospital (UNM Cancer Research Center) showed very sparsely scattered groups of 1 or 2 melanoma cells in the new tumor and my onc and I have decided to proceed with a Phase II trial of Carboplatin, Paclitaxel, and Temozolomide rather than wait the additional weeks for the c-kit analysis. If I am positive, I can always move on to that treatment.

I'll be getting the first infusion this coming Monday morning and I'm wondering if any of you who have experienced chemo have any suggestions or advice, things you wish someone had told you in advance. I'll be getting two 28-day courses before we do another set of scans. The goal is to find something this tumor will respond to, get it reduced in size, and then remove it surgically. I will have as many as six courses if we are seeing any improvement.

I have a great local Healing Team of a Dr of Chinese Medicine/Acupuncturist who is also an RN who has extensive experience with treating chemo side effects using needles. I also have a Homeopathic Doctor with advanced study and certification for using diet and supplements to assist with the side effects of chemo.

Some good news - a brain MRI done last Saturday showed the primary brain tumor (2 by3 centimeters originally) has reduced by 50% and the small one has stayed stable at less than 4mm and my onc feels it is most likely just a bit of scar tissue now.

Is there anything you found helpful to do before infusion? Eat or not eat? If eat, what was helpful? Anything that you brought that helped you to be more comfortable during a three hour infusion? How about the best things you found to do after treatment? Anything you can think of that you wish you had known will be greatly appreciate.

Thanks in advance - Carmon in NM

Carmon in NM: Stage IIIB 9/2008; Stage IV 6/2010 with brain and adrenal mets; NED since 4/13/2011. It’s not what happens to you, but how you react to it that matters. ~ Epictetus

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glewis923's picture
Replies 1
Last reply 10/25/2010 - 9:26pm
Replies by: Anonymous

Dear Fellow Mellas:    I've called some more #'s and found that I am in grevious error in what i thought i heard from a head research person from a major cancer center.  I've been under stress and a little hard of hearing (too much Rock-n-Roll and drum playing).  I was wrong, wrong, wrong and should never have put up something of that importance unless i was 1000% true!

Please accept my idiotcy.  

Love to ALL-  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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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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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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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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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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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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29 Sep 2010   

Patient-Specific Vaccines For Metastatic Melanoma May Induce Durable Complete Regression

Hoag Memorial Hospital Presbyterian recently announced encouraging clinical study results for patient-specific vaccine therapy to treat metastatic melanoma. The study is ongoing, but the report concludes that patient-specific vaccines can sometimes induce durable complete regression of progressing soft-tissue melanoma metastases, as demonstrated in one particular patient who participated in the trial.

The study report, entitled: "Durable Complete Response of Refractory, Progressing, Metastatic Melanoma after Treatment with a Patient-Specific Vaccine," will appear in the October issue of Cancer Biotherapy and Radiopharmaceuticals. Lead author of the report is Robert O. Dillman, MD, FACP, medical oncologist and cancer immunologist, as well as executive medical and scientific director at Hoag Cancer Institute. The study was sponsored by Hoag Hospital Foundation.

"Although we had previously shown that patient-specific vaccines can be associated with long-term disease control and survival despite previous recurrences of widespread metastatic melanoma, , , this is the first complete regression we have observed with a dendritic cell-based patient-specific vaccine therapy in patients with measurable metastatic melanoma," said Dr. Dillman.

The patient profiled in the study presented with cervical spine metastases and within the year had experienced local disease progression and, despite various therapies, metastases to the axilla, rectum, gall bladder, and multiple soft-tissue sites. She had previously received radiation therapy, combination chemotherapy, interleukin-2 plus interferon biotherapy, gamma knife radiosurgery, and undergone multiple surgical resections. At the time vaccine therapy was initiated, she had multiple new, measurable, soft-tissue metastases that were increasing in size.

The patient was treated with a vaccine consisting of autologous dendritic cells incubated with irradiated tumor cells from an autologous tumor cell line and suspended in GM-CSF, with s.c. injections once a week for three weeks and monthly for five months. There was evidence of disease regression by the completion of therapy. A few months later, a complete response was documented by radiologic scans, and subsequently reconfirmed at six-month intervals. She remains in complete remission more than 2.5 years after starting the vaccine, and more than two years after completing the vaccine, and survives more than four years after her initial presentation with bone, bowel, and lymph node metastases. This is the first time she has been in a complete remission since her initial diagnosis.

"These results are extremely encouraging for patients suffering from metastatic melanoma," said Dr. Dillman. "The promise of new therapies such as personalized cancer vaccines may help contribute to survival rates in these patients."

Source: Porter Novelli, Life Sciences
 

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ZymoGenetics Reports Favorable Survival Data From IL-21 Phase 2a Clinical Trial In Melanoma

ZymoGenetics, Inc. (NASDAQ:ZGEN) today announced positive survival data from a Phase 2a clinical trial in metastatic melanoma with recombinant Interleukin 21 (IL-21) as a single agent. Median overall survival was 12.4 months, and the percentage of patients surviving at 12 months was 53%.

"The median overall survival of 12.4 months in the Phase 2 study with IL-21 in advanced melanoma patients is very encouraging," said Eleanor L. Ramos, M.D., Senior Vice President and Chief Medical Officer of ZymoGenetics. "We look forward to further results from an ongoing IL-21 Phase 2b randomized clinical trial in melanoma."

The open-label, single-arm, multi-center Phase 2 study was conducted by the NCIC Clinical Trials Group in Canada. A total of 40 patients with Stage 4 melanoma were enrolled and treated with IL-21 using 3 dosing regimens. Previous results for the clinical trial were presented at the American Society of Clinical Oncology 2010 meeting. Overall response rate was 23% in 39 evaluable patients, and median progression-free survival was 4.3 months. Common adverse events were fatigue, rash, fever, myalgia, anorexia, chills and nausea. Responses were not dependent on B-Raf status.

About Interleukin 21 (IL-21)

Interleukin 21 (IL-21) is a cytokine that modifies the function of cells in the immune system. IL-21 activates several types of immune cells thought to be critical in eliminating cancerous or virally infected cells from the body. Specifically, IL-21 enhances the activity of natural killer cells and has multiple effects on cytotoxic T cells. This novel immunotherapy has demonstrated antitumor activity in multiple tumor types (metastatic melanoma, renal cell cancer and non-Hodgkin's lymphoma) as a single agent and in combination with other therapies. More than 250 patients have been treated with IL-21 in clinical trials. The lead indication is metastatic melanoma, where IL-21 has shown efficacy.

About the NCIC Clinical Trials Group

The NCIC Clinical Trials Group (NCIC CTG) is a cancer clinical trials cooperative group that conducts phase I-III trials testing anti-cancer and supportive therapies across Canada and internationally. It is one of the national programmes and networks of the Canadian Cancer Society Research Institute (CCSRI), and is supported by the CCSRI with funds raised by the Canadian Cancer Society (CCS). The NCIC CTG's Central Office is located at Queen's University in Kingston, Ontario, Canada.

Source:
ZymoGenetics

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ZymoGenetics Reports Favorable Survival Data From IL-21 Phase 2a Clinical Trial In Melanoma

ZymoGenetics, Inc. (NASDAQ:ZGEN) today announced positive survival data from a Phase 2a clinical trial in metastatic melanoma with recombinant Interleukin 21 (IL-21) as a single agent. Median overall survival was 12.4 months, and the percentage of patients surviving at 12 months was 53%.

"The median overall survival of 12.4 months in the Phase 2 study with IL-21 in advanced melanoma patients is very encouraging," said Eleanor L. Ramos, M.D., Senior Vice President and Chief Medical Officer of ZymoGenetics. "We look forward to further results from an ongoing IL-21 Phase 2b randomized clinical trial in melanoma."

The open-label, single-arm, multi-center Phase 2 study was conducted by the NCIC Clinical Trials Group in Canada. A total of 40 patients with Stage 4 melanoma were enrolled and treated with IL-21 using 3 dosing regimens. Previous results for the clinical trial were presented at the American Society of Clinical Oncology 2010 meeting. Overall response rate was 23% in 39 evaluable patients, and median progression-free survival was 4.3 months. Common adverse events were fatigue, rash, fever, myalgia, anorexia, chills and nausea. Responses were not dependent on B-Raf status.

About Interleukin 21 (IL-21)

Interleukin 21 (IL-21) is a cytokine that modifies the function of cells in the immune system. IL-21 activates several types of immune cells thought to be critical in eliminating cancerous or virally infected cells from the body. Specifically, IL-21 enhances the activity of natural killer cells and has multiple effects on cytotoxic T cells. This novel immunotherapy has demonstrated antitumor activity in multiple tumor types (metastatic melanoma, renal cell cancer and non-Hodgkin's lymphoma) as a single agent and in combination with other therapies. More than 250 patients have been treated with IL-21 in clinical trials. The lead indication is metastatic melanoma, where IL-21 has shown efficacy.

About the NCIC Clinical Trials Group

The NCIC Clinical Trials Group (NCIC CTG) is a cancer clinical trials cooperative group that conducts phase I-III trials testing anti-cancer and supportive therapies across Canada and internationally. It is one of the national programmes and networks of the Canadian Cancer Society Research Institute (CCSRI), and is supported by the CCSRI with funds raised by the Canadian Cancer Society (CCS). The NCIC CTG's Central Office is located at Queen's University in Kingston, Ontario, Canada.

Source:
ZymoGenetics

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ZymoGenetics Reports Favorable Survival Data From IL-21 Phase 2a Clinical Trial In Melanoma

ZymoGenetics, Inc. (NASDAQ:ZGEN) today announced positive survival data from a Phase 2a clinical trial in metastatic melanoma with recombinant Interleukin 21 (IL-21) as a single agent. Median overall survival was 12.4 months, and the percentage of patients surviving at 12 months was 53%.

"The median overall survival of 12.4 months in the Phase 2 study with IL-21 in advanced melanoma patients is very encouraging," said Eleanor L. Ramos, M.D., Senior Vice President and Chief Medical Officer of ZymoGenetics. "We look forward to further results from an ongoing IL-21 Phase 2b randomized clinical trial in melanoma."

The open-label, single-arm, multi-center Phase 2 study was conducted by the NCIC Clinical Trials Group in Canada. A total of 40 patients with Stage 4 melanoma were enrolled and treated with IL-21 using 3 dosing regimens. Previous results for the clinical trial were presented at the American Society of Clinical Oncology 2010 meeting. Overall response rate was 23% in 39 evaluable patients, and median progression-free survival was 4.3 months. Common adverse events were fatigue, rash, fever, myalgia, anorexia, chills and nausea. Responses were not dependent on B-Raf status.

About Interleukin 21 (IL-21)

Interleukin 21 (IL-21) is a cytokine that modifies the function of cells in the immune system. IL-21 activates several types of immune cells thought to be critical in eliminating cancerous or virally infected cells from the body. Specifically, IL-21 enhances the activity of natural killer cells and has multiple effects on cytotoxic T cells. This novel immunotherapy has demonstrated antitumor activity in multiple tumor types (metastatic melanoma, renal cell cancer and non-Hodgkin's lymphoma) as a single agent and in combination with other therapies. More than 250 patients have been treated with IL-21 in clinical trials. The lead indication is metastatic melanoma, where IL-21 has shown efficacy.

About the NCIC Clinical Trials Group

The NCIC Clinical Trials Group (NCIC CTG) is a cancer clinical trials cooperative group that conducts phase I-III trials testing anti-cancer and supportive therapies across Canada and internationally. It is one of the national programmes and networks of the Canadian Cancer Society Research Institute (CCSRI), and is supported by the CCSRI with funds raised by the Canadian Cancer Society (CCS). The NCIC CTG's Central Office is located at Queen's University in Kingston, Ontario, Canada.

Source:
ZymoGenetics

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Immunocore Announces Clinical Trials Of New Treatment For Advanced Melanoma In UK And USA
(NOTE: I believe one has to be positive for the HLA-2A haplotype -- but not sure// Hawaii Bob, Stage IIA)

Researchers at Immunocore Limited announced that IMCgp100, a targeted therapeutic for the treatment of advanced metastatic melanoma, has received regulatory and ethics approval and has opened enrolment for clinical trials in the UK and USA. IMCgp100 is the first clinical candidate originating from Immunocore's innovative ImmTAC technology platform and a new treatment could benefit many thousands of patients diagnosed with skin cancer each year.

Melanoma is a form of skin cancer that accounts for less than five per cent of cases but causes the vast majority of skin cancer deaths. The American Cancer Society estimates that 68,130 new melanomas will be diagnosed in the US during 2010 and 8,700 deaths from this disease will occur. 10,672 cases were diagnosed in the UK in 2007 and there were 2,067 deaths in 2008. Incidence rates for melanoma have increased in the last thirty years and, unlike other common cancers, melanoma has a wide age distribution.

Patients who are diagnosed early are treatable with surgical resection, although in many the disease will recur within a few years. If melanoma continues to the late stages and becomes metastatic the prognosis is poor, with average survival times of six to nine months. Chemotherapy is the most common treatment, but the response rate is very low so there is a high level of unmet need for more effective therapies.

In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) Medicines Division has approved a Phase 1 dose finding study in patients with advanced malignant melanoma. The two-part study will establish a tolerable intravenous dose of IMCgp100 and then assess the effect of this dose on pharmacodynamic markers when given repeatedly to a larger group of patients.

Recruitment for the clinical trial has commenced at three leading hospitals in Oxford, Cambridge and Birmingham and the first patient has received treatment.

Professor Mark Middleton of the NIHR Biomedical Research Centre, Oxford said: "We need new treatment options for patients with metastatic melanoma that not only extend lives but also improve quality of life. This clinical trial will generate the first data on this promising novel reagent IMCgp100".

Immunocore's ImmTAC technology platform builds on expertise with high affinity T cell receptors and has the potential to target a range of cancer and chronic viral diseases that are not accessible to conventional monoclonal antibodies. IMCgp100 is the first product in the pipeline to enter a clinical trial and the company has recently secured significant new investment to take additional programmes into the clinic.

Dr Bent Jakobsen, founder and chief scientific officer of Immunocore, said: "We have worked for over ten years trying to overcome immune tolerance to cancer. Tumour cells often express only very low levels of their signature antigens and thereby hide from the immune system. We take human T cell receptors which recognise specific cancer antigens, in this case gp100 for melanoma, and enhance their binding affinity so that they can target the cancer cells. The engineered T cell receptor is bound to an antibody fragment that redirects T cells to destroy the bound tumour cell. I am very excited to see the first candidate advance into clinical trials".

In the USA, the Food and Drug Administration (FDA) has approved a Phase 0 or Exploratory Trial. This study, in which the drug will be injected directly into melanoma tumours, is designed to complement the UK study by shedding light on how the drug works, and at what concentration.

"This is a novel approach to the challenge of mobilizing the immune system's ability to recognise and disable cancer cells. In this study we will assess their effectiveness by analysing tumour samples from melanoma patients for evidence of local immune stimulation," explains Professor Carl June, MD, director of translational research at the Abramson Family Cancer Research Institute (AFCRI) at Penn, which will conduct the US trial.

"The number of melanoma cases in the US is increasing and although early-stage melanoma can be treated surgically, we urgently need effective therapies to manage late stage metastatic disease," notes Leslie Fecher MD, assistant professor of Medicine and principal investigator on the trial. "As a novel targeted immunotherapy, IMCgp100 may be a promising new approach to tackle this intractable disease."

Note: The investigators in this study have no financial interest or other relationship with Immunocore Ltd, apart from their scientific collaboration in conducting laboratory experiments and planning human clinical trials.

Notes

About Metastatic melanoma

Melanoma is a form of skin cancer that accounts for less than 5% of cases but causes the vast majority of skin cancer deaths. The American Cancer Society estimates that about 68,130 new melanomas will be diagnosed in the United States during 2010 (about 38,870 in men; 29,260 in women) and 8,700 deaths from this disease will occur. 10, 672 cases were diagnosed in the UK in 2007 and there were 2,067 deaths in 2008. Incidence rates for melanoma have increased in the last thirty years and, unlike other common cancers, melanoma has a wide age distribution. In recent years, the increases have been most pronounced in young white women and older white men.

Patients who are diagnosed early are treatable with surgical resection, although in many the disease will recur within a few years. If melanoma continues to the late stages and becomes metastatic the prognosis is poor, with average survival rates of only six to nine months. Chemotherapy is the most common treatment for patients with metastatic melanoma but the response rate is very low. There is a high level of unmet need for more effective therapies.

About ImmTACs

IMCgp100 is a product derived from Immunocore's ImmTAC™ technology platform.

ImmTACs couple the unique ability of affinity enhanced T Cell Receptors (TCRs) to target cancer and virally infected cells based on intracellular antigens that cannot be treated using traditional antibody based approaches, with a highly potent anti-CD3 mediated T cell redirection system.

Immunocore has developed processes that allow it to isolate human TCRs specific for a target of interest and to create soluble versions whose affinity has been enhanced several million fold. These engineered, disease -specific, TCRs are fused to an antibody fragment that binds a cell surface protein called CD3 which is found on the surface of the killer T cells of the immune system. ImmTACs target the diseased cells and redirect any T cell touching them to kill, even if that T cell would normally only recognise the common cold.

Unlike traditional immunotherapies such as cancer vaccines or immune-stimulating agents such as anti-CTLA4 antibodies, Immunocore's ImmTACs have been specifically designed to overcome the antigen-down regulation that has limited the effectiveness of immunotherapies to date. Pre-clinical tests indicate that they can achieve potent T cell redirection against cancer cells that have lost almost all of their cell surface antigens through down-regulation.

About IMCgp100

IMCgp100 is an ImmTAC reagent specific for a peptide derived from the well validated target protein gp100, presented by HLA-A2; this target being present in approximately 50% of melanoma patients. IMCgp100 demonstrates potent activity against melanoma cells in vitro, including difficult to treat cancer stem cells

Source:
Immunocore Limited

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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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LynnLuc's picture
Replies 5
Last reply 10/22/2010 - 5:59am

I have a question maybe someone can help me with...Plans! You know...plan A, Plan B, etc etc...I have been going through mine and now I am stumped!

I know some people would say not to stress it...but it's melanoma and somehow I don't see an end to my plan making...Yes I am stage 4 NED...but the beast is a tough one to slay.

I am currently in a MDX 1106 (anti PD-1 ) trial plus injections of  proteins/peptides...my wish is that it keeps me NED...HOWEVER...given the current trend  of Melanoma ...I need more plans...

Currently the trials out there appear to exclude anyone who has used other immunotherapies...so what future options can I look at?? I think I am exhausted of reading studies and trials etc etc...no rest for the weary! -Lynn

Advocate for your own treatment.. Stage 4 Melanoma NED Surgery,Radiation, Temodar 300Mg July 2009-March 2010, then Thorocotomy...now "Phase I Study of Anti-PD-1 Human Monoclonal Antibody MDX-1106 and Vaccine Therapy"

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