IPI Warriors

The June 6 report showed that roughly 20-30% of patients taking IPI will get  a response from it. That might not sound like a lot, but for melanoma it is. Most of the people here who are taking IPI are on the compassionate use trial, which became available only this March. Some have completed the 4 infusions, others are halfway through and some just starting. The drug is said to have a delayed response, so it is still too early to know just how most people have responded.

The trial that led to FDA consideration didn't say a lot about remission, so response can mean many things. It did say that 23% of the people who were on the ipi arm, were still alive 2 years later. I believe there are a few people here who were on an earlier IPI or MDX (same thing) trial who reported major responses, perhaps NED.

My brother completed the trial in July and scans show very significant shrinkage in some areas, less in others, but still clearly a response. But he is not NED; his tumor burden was quite large, and only future scans will show if the immune response set loose by the IPI will continue to reduce the burden. That is the great unknown.

The June 6 report showed that roughly 20-30% of patients taking IPI will get  a response from it. That might not sound like a lot, but for melanoma it is. Most of the people here who are taking IPI are on the compassionate use trial, which became available only this March. Some have completed the 4 infusions, others are halfway through and some just starting. The drug is said to have a delayed response, so it is still too early to know just how most people have responded.

The trial that led to FDA consideration didn't say a lot about remission, so response can mean many things. It did say that 23% of the people who were on the ipi arm, were still alive 2 years later. I believe there are a few people here who were on an earlier IPI or MDX (same thing) trial who reported major responses, perhaps NED.

My brother completed the trial in July and scans show very significant shrinkage in some areas, less in others, but still clearly a response. But he is not NED; his tumor burden was quite large, and only future scans will show if the immune response set loose by the IPI will continue to reduce the burden. That is the great unknown.

Well ask me in about 1 1/2 weeks.  My husband is due to go back for his 3 month scans following his last Ipi tx.  His 12 week scans showed increased in size of mets but no new mets?  To be honest with you we really do not expect a possitive response due to the way his has felt and continues to feel.  We are unsure what our next option is as we are running out of them, possibly radiation depending on what next scans show.  He has only done the high dose IL-2 and Ipi.  Which we do not regret doing.  Just not sure Ipi is going to work for us.  He has not had surgery (due to the extent at diagnosis), any type of radiation or chemo, which I feel would be going backwards with the two treatments he has already had.  We have alot of decisions to be looking into in the next few weeks.  Then again…… he may choose no treatmen???  He has not felt good since Feb. 2010 and for somebody who was very active (hiking,bicycling,walking,gardening etc…) this has been a major change for him to accept.  I do continue to believe in miracles.  My God can supply ALL our needs!  Any ideas are certainly welcome from others as this next week of scanxiety kicks in…….

Thanks

Linda/Kentucky

Well ask me in about 1 1/2 weeks.  My husband is due to go back for his 3 month scans following his last Ipi tx.  His 12 week scans showed increased in size of mets but no new mets?  To be honest with you we really do not expect a possitive response due to the way his has felt and continues to feel.  We are unsure what our next option is as we are running out of them, possibly radiation depending on what next scans show.  He has only done the high dose IL-2 and Ipi.  Which we do not regret doing.  Just not sure Ipi is going to work for us.  He has not had surgery (due to the extent at diagnosis), any type of radiation or chemo, which I feel would be going backwards with the two treatments he has already had.  We have alot of decisions to be looking into in the next few weeks.  Then again…… he may choose no treatmen???  He has not felt good since Feb. 2010 and for somebody who was very active (hiking,bicycling,walking,gardening etc…) this has been a major change for him to accept.  I do continue to believe in miracles.  My God can supply ALL our needs!  Any ideas are certainly welcome from others as this next week of scanxiety kicks in…….

Thanks

Linda/Kentucky

I don't think remission is a correct term.

N.E.D and durable response are more appropriate with melanoma

A. Mouse

I don't think remission is a correct term.

N.E.D and durable response are more appropriate with melanoma

A. Mouse

Here's my story: I was diagnosed with MM in October of 2007 and had an LND to my right axillary. Three of the 25 lymph nodes were positive and I had extracapsulary extension in one of the nodes. That put me at stage 3C and I also had (and still do) an unknown primary. I followed up with 6 weeks of radiation and then decided on a clinical trial. It was a trial for those with stage 3 and 4 resected melanoma. It involved receiving iv infusions of 10kg/mg Ipilimumab and 3 peptide vaccines (which are made up of between 90-100% melanomas) which were injected in alternating thighs. I began the trial in March of 2008. Some of my white blood cells were collected to do a baseline on the level of immunity. Several months later more white blood cells were collected to determine if there was an immune response. To the delight of my doctor I had "big time" response. My immune response was at least 5 times over baseline and my doctor said he sees this kind of response in 10-20% of patients. The trial gave me a proliferation of dendritic cells. My doctor said, "These cells will remain active for years to come, thank goodness". I'm not sure how many years he's talking about but I'll take it as good news.

 I paid a price for the response with my pituitary gland swelling. I'm on a steroid as a hormone replacement. The long term responses are associated with major side effects like the kind I had

A subgroup of some of the earliest patients on Ipilimumab have been NED for 6 years. Doctors generally believe Ipilimumab will be more effective when used in combination with other drugs. If you google "Ipilimumab results" you will find this and more info. Some patients who wrote before the website changed said Ipi made their tumors disappear.

Anyway I've been NED since my LND which was almost 3 years ago and almost 2 years since I had to stop the trial ( I was able to get 4 infusions of Ipi). So right now I have a case of NED and Remission!!!  Hope this helps.

 God Bless,

 Jim M.

Here's my story: I was diagnosed with MM in October of 2007 and had an LND to my right axillary. Three of the 25 lymph nodes were positive and I had extracapsulary extension in one of the nodes. That put me at stage 3C and I also had (and still do) an unknown primary. I followed up with 6 weeks of radiation and then decided on a clinical trial. It was a trial for those with stage 3 and 4 resected melanoma. It involved receiving iv infusions of 10kg/mg Ipilimumab and 3 peptide vaccines (which are made up of between 90-100% melanomas) which were injected in alternating thighs. I began the trial in March of 2008. Some of my white blood cells were collected to do a baseline on the level of immunity. Several months later more white blood cells were collected to determine if there was an immune response. To the delight of my doctor I had "big time" response. My immune response was at least 5 times over baseline and my doctor said he sees this kind of response in 10-20% of patients. The trial gave me a proliferation of dendritic cells. My doctor said, "These cells will remain active for years to come, thank goodness". I'm not sure how many years he's talking about but I'll take it as good news.

 I paid a price for the response with my pituitary gland swelling. I'm on a steroid as a hormone replacement. The long term responses are associated with major side effects like the kind I had

A subgroup of some of the earliest patients on Ipilimumab have been NED for 6 years. Doctors generally believe Ipilimumab will be more effective when used in combination with other drugs. If you google "Ipilimumab results" you will find this and more info. Some patients who wrote before the website changed said Ipi made their tumors disappear.

Anyway I've been NED since my LND which was almost 3 years ago and almost 2 years since I had to stop the trial ( I was able to get 4 infusions of Ipi). So right now I have a case of NED and Remission!!!  Hope this helps.

 God Bless,

 Jim M.

First point – a pet peeve really – there are too many people who are "Anonomous" on this board.  Can't you give yourself some sort of handle to which others can refer?  It is very impersonal and not very respectful to the rest of us who post here with some regularity.

Anyway, I suspect you are the same "Anonomous" who asks lots of questions, but has little to offer in return (another pet peeve).  If you are not he/she/it, then I apologize.  I will answer briefly.  You apparently are not reading the literature, and prefer to solicit personal anecdotes.  Both are important, but not mutually exclusive in importance.

You should know well enough not to throw around such terms as "remission" or "cure" around here – don't you?  Those terms indicate a fundamental misunderstanding of melanoma treatment.  Regarding response, there a RANGE of responses, from progression (or no response) to partial response (slowing disease progression), to response (stopping or reversing progression).  These are 3 points on a continuum. 

As one of the posters above said, many of the people recieving Ipi this year will not be able to characterize how they are responding (or not) for some time yet.  The response to Ipi is usually slow, and not evident until 12 or even 24 weeks after treatment starts (which you would also know if you have read the literature).  There My be a few of the earliest patients to recieve Ipi on this board when it was call MDX who may be willing to post a response.

First point – a pet peeve really – there are too many people who are "Anonomous" on this board.  Can't you give yourself some sort of handle to which others can refer?  It is very impersonal and not very respectful to the rest of us who post here with some regularity.

Anyway, I suspect you are the same "Anonomous" who asks lots of questions, but has little to offer in return (another pet peeve).  If you are not he/she/it, then I apologize.  I will answer briefly.  You apparently are not reading the literature, and prefer to solicit personal anecdotes.  Both are important, but not mutually exclusive in importance.

You should know well enough not to throw around such terms as "remission" or "cure" around here – don't you?  Those terms indicate a fundamental misunderstanding of melanoma treatment.  Regarding response, there a RANGE of responses, from progression (or no response) to partial response (slowing disease progression), to response (stopping or reversing progression).  These are 3 points on a continuum. 

As one of the posters above said, many of the people recieving Ipi this year will not be able to characterize how they are responding (or not) for some time yet.  The response to Ipi is usually slow, and not evident until 12 or even 24 weeks after treatment starts (which you would also know if you have read the literature).  There My be a few of the earliest patients to recieve Ipi on this board when it was call MDX who may be willing to post a response.

I too would be interested in responses from those who have tried ipi in the past.  I don't know that it is really apples and oranges since many of the early anti-CTLA / MDX trials were pre-cursers (sp?) to the current BMS ipilumimab drug.  Many of those trials involved other elements as well.

But regardless I'd love to hear some personal stories of their experience (side effects, etc) and responses.  Off the top of my head I can think of various stories from several board members.

I may well be starting this soon and would welcome some 1st or 2nd hand experiences!

Thanks,

Amy

I too would be interested in responses from those who have tried ipi in the past.  I don't know that it is really apples and oranges since many of the early anti-CTLA / MDX trials were pre-cursers (sp?) to the current BMS ipilumimab drug.  Many of those trials involved other elements as well.

But regardless I'd love to hear some personal stories of their experience (side effects, etc) and responses.  Off the top of my head I can think of various stories from several board members.

I may well be starting this soon and would welcome some 1st or 2nd hand experiences!

Thanks,

Amy

Hi.  I started the MDX-010 Compassionate use (ipi)  trial in Aug 2008.  At the time of my first set of scans in Nov 2008 I had experienced about 75% shrinkage in the tumor markers they were tracking.  At the completion of all 4 initial doses in the trial, I had experienced even more shrinkage so that in Feb 2009 I was allowed to start maintenance.  I had one dose in Feb 2009.  As of my Sept 2010 scans (some 18 months after my maintenance dose)  I now have one sub-cm lung spot showing on my CT scan and they believe it's dead.  So I have no active disease.  I went from 2 page CT reports prior to taking ipi to a single page report that's not even a full page.  So far, this treatment has worked for me…your results may vary.

PS – continue to ask questions, anon or not…it's the way we all learn.

Hi.  I started the MDX-010 Compassionate use (ipi)  trial in Aug 2008.  At the time of my first set of scans in Nov 2008 I had experienced about 75% shrinkage in the tumor markers they were tracking.  At the completion of all 4 initial doses in the trial, I had experienced even more shrinkage so that in Feb 2009 I was allowed to start maintenance.  I had one dose in Feb 2009.  As of my Sept 2010 scans (some 18 months after my maintenance dose)  I now have one sub-cm lung spot showing on my CT scan and they believe it's dead.  So I have no active disease.  I went from 2 page CT reports prior to taking ipi to a single page report that's not even a full page.  So far, this treatment has worked for me…your results may vary.

PS – continue to ask questions, anon or not…it's the way we all learn.

My brother in law is about to begin the third IPI treatment.  Scans reported increased tumor size on lung tumors. Patient anemic and weak since IPI begian.  We are holding out big hoped that the response begins.  For those that had a response, when did they see it? After which session? What were the side effects?

Any recommendations on combinationtherapy with IPI?

My brother in law is about to begin the third IPI treatment.  Scans reported increased tumor size on lung tumors. Patient anemic and weak since IPI begian.  We are holding out big hoped that the response begins.  For those that had a response, when did they see it? After which session? What were the side effects?

Any recommendations on combinationtherapy with IPI?

Here is my story with Anti-CTLA-4 Blockage. It starts back in 2005.

 The Orchestration of an Immune Response Unrehearsed

In 2006, after two fail attempts (Interferon and Dacarbazine with Patrin) to stop the progression of my melanoma, I was able try CTLA-4 Blockage. It was one of my first choices, but due to protocol, I had to try the FDA approved therapy first. I had researched this monoclonal antibody. On 10-24-2005when I was first diagnosed with melanoma, I contacted Dr. Luis H. Camacho who was currently at MD Anderson.

Subject:Paper on  Antitumor Activity

“Luis Camacho, My name is Jim Breitfeller and I have recently been diagnosed with melanoma will need some sort of Ontological therapy after my surgery. I ran across an abstract of yours (Antitumor activity in Melanoma and anti-self responses in Phase 1 trials with the anti-Cyctotoxic T Lymphocyte-Associated Antigen 4 Monoclonal Antibody CP-675,206) in the Journal of Clinical Oncology. Is it possible to get a copy of your paper? It can be emailed to the address below.”

Camacho response:

Dear James,
Thank you for your note. The CTLA4 antibodies in melanoma are currently under development and completing the approval process with the FDA (Phase II and Phase III). The overall response rates in my mind will be near 20-30% with a good number of patients attaining long term remissions. However, none of the programs are currently oriented to patients rendered NED (Stage III or IV). They are in fact for patients with advanced disease.  From your brief introduction, I think your best options are to obtain an HLA typification and go for an adjuvant trial.

Please feel free to page me if you need further information. Pager is 713.404-5319
Best,

Luis

CP-675,206, a novel monoclonal antibody, enlists the immune system to fight advanced melanoma

Some Positive Test results of the CTLA-4

Early testing of an experimental human monoclonal antibody showed a striking benefit in patients with advanced melanoma, say researchers at The University of Texas M. D. Anderson Cancer Center, who presented their findings at the annual meeting of the American Society of Clinical Oncology. Of 39 patients given a single injection of CP-675,206 (known as CP-675), tumors disappeared in three patients, shrunk in a fourth patient, and cancer stopped growing in five other patients. These responses have remained since their initial treatment, which ranged from 13 to 28 months ago.

Most of the patients in the trial had advanced melanoma, which has a median survival of less than a year, says the study's principal investigator, Luis Camacho, M.D., MPH, assistant professor in the Department of Melanoma Medical Oncology.

"We were very pleasantly surprised to find such objective antitumor responses in a Phase I clinical trial, which is designed to find the ideal dose and to look for side effects," says Camacho. "These results are very early, but they are encouraging to us because there are no good agents available to treat melanoma once it has spread."

Source:  Laura Sussman from (ASCO) American Society of Clinical Oncology

At the time of the request, I was not at the correct stage but I knew that this might be the path of the future. I did contact him and we discussed my options at that time. I was just learning the ropes.

On 9/3/06I contacted Dr. Rosenberg just in case I needed a back up plan if the CTLA-4 blockage did not work. At that time I did not know I was the wrong HLA-02 type for Rosenberg’s trials.

“I am Contacting Dr. Steven A. Rosenberg at the National Cancer Institute in Bethesda, Maryland.

He is the lead the researcher on the Gene Therapy Trials.
Log onto the CBS website for the story!!!!!!
http://www.cbsnews.com/stories/2006/08/31/health/main1955526.shtml

The research team recently applied to the Food and Drug Administration (FDA) to try the new cells in about 100 patients. The FDA is expected to respond to the request by mid-September.

Dr. Rosenberg, I just got the news of your Gene Therapy Experiments. The initial results look somewhat promising. I applauded you and your team for making great strides in the cure for melanoma cancer.

I am a cancer patient (48 yrs. old) under the care of Dr. John Kirkwood at the Hillman Cancer Center at the University of Pittsburgh. I have gone through a wide incision, lymph nodes removal, Interferon therapy, and Dacarbazine therapy without success. I am presently on track to start a clinical trial with CTLA-4 monoclonal antibodies September 13, 2006. I have some tumors on my right side of my back and some in each lobe of my lungs. I would like to be considered for your next round of Gene Therapy in the coming months if I have no response to the CTLA-4 treatment. Please let me know if you would need a copy of my medical records to date.

Thanks again for the great work you are doing and I hope to hear from you in the near future.

Best Regards,
Jim Breitfeller

On 9/5/06 I received a call from Dr. Rosenberg’s office this morning while I was at Dr. Marino’s office. Kathy Morton (Research Nurse) contacted me by phone and asked a few questions about my health. She went on to say if I go with the CTLA-4 therapy, it would take about 2 months to washout before I could try the Gene Therapy. They would also have to do a colon biopsy to check the colon for any adverse conditions from the CTLA_4. She then gave me her direct phone number if I want to pursue the gene therapy at a later date.

So, on 9/13/06(day 1)I had my first and only infusion of anti-CTLA-4 monoclonal antibodies. A dose of 15 mg/kg on Day 1. This was done as an outpatient procedure. Anti-CTLA4 monoclonal antibodies block the ability of CTLA4 to down-regulate T cell proliferation. The theory behind this therapy is that by decreasing the inhibitory signal, there will be a subsequent increase in the number of activated T-cells available, to improve the ability of the T-cells to recognize melanoma cells as non-self.

Before we can go any further, we need to know the clinical pharmacokinetics (pk)of anti-CTLA-4 monoclonal antibodies. Base on published papers, the predicted half-live of the antibody is around 3 weeks.¹¹ This means your body will eliminate half the dose that was infused in you in about 21days. So, in 42 days or there about, the drug is completely gone from your system.

I started my CTLA-4 treatment at 9:15 am at 100 ml/hr and I had 500 mls hanging on my rack (Miss Daisy). I call the rack Miss Daisy because I have to take it with me where ever I go which includes the bathroom. I am driving Miss Daisy!! This will take us to 3:15 pm and then they draw blood fora pk study an hour later. So, we won’t get out until about 4:30 pm and home until 10:00 pm.

Day 7 –9/19/06  “Along with the fatigue, my muscles ache like they have lactic acid in them”. Is this an indication of something? All immune cells begin as immature stem cellsin the bone marrow.

Day 15 –9/27/06 about half the CTLA-4 antibodies are depleted. It appears that the CTLA-4 has stimulated my immune system. In the pass week, I noticed that there was redness around the area where my tumors are located. Also it is becoming quite tender in that area. This is Great news!!!!! It appears that the treatment my have kick started my immune system. The only way we will know for sure is another CT scan. That is not scheduled until November 23^rd.

I sure hope this isn’t a false positive. Anyway, they gave me an antibiotic just in case it is an infection.

This inflammatory response provides a third signal that acts directly on T cells, referred to as the “danger signal”. “This signal was found to optimally activate T_H1 differentiation and lead to clonal expansion of T cells¹².

With this clonal expansion of the T cells and the secretion of IL-2, The Immune system is gearing up to make an assault on the foreign invaders, the tumors.

In 1988,a paper was published Autologous Tumor Specific Cytotoxic Lymphocytes in the Infiltrate of Human Metastatic Melanomas  Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor  by Itoh  and Colleagues.⁴  In their studies, they propagated (TILs) Tumor infiltrate lymphocytes cells from 12 Metastatic Melanoma patients. They preformed kinetic growth studies in IL-2 and even broke it down three Surface markers (CD3,CD4 and CD8). The results are as follows:

The average maximum propagation was 43 days. (N=12)

The average maximum propagation for (lung, Axilla) was 40 days (n=3)

The average maximum propagation for (CD3) was 78 +/- 11 days (n=12)

The average maximum propagation for (CD4) was 33 +/- 10 days (n=12)

The average maximum propagation for CD4 (lung, Axilla) was 26 days (n=3)

The average maximum propagation for (CD8) was 49 +/- 17 days (n=12)

The average maximum propagation for CD8 (lung, Axilla) was 57 days (n=3)

Base on the above data, it would take about 49 days for my activated T cells to reach maximum propagation.

Day 29– 10/11/06, A couple of days ago, Dee noticed two new growths on my back. I
was hoping for the best. Anyway, we got confirmation from the Hillman Center that it is 2 new tumors growing. This really stinks. I think it is time to take out the “Weed be Gone”. This is not what I was hoping to hear. It was decided that the CTLA-4 blockage therapy was to be terminated. My CD4⁺T cells were just about at maximum propagation.

Dr. Kirkwood, decided that the next line of defense would be Interleukin-2 (IL-2).

Results of early PROLEUKIN® IL-2 Clinical Trials
Year received FDA Approval 1998
Number of Patients 270 patients
Number of Trials 8
Response In 16% of the patients, tumors shrank or disappeared as a result of PROLEUKIN® IL-2 therapy.

In 6% of the patients, the tumors disappeared completely.
Results From these trials, it was determined that a patient whose tumors completely disappeared from the treatment remained cancer-free for a median of 4.9 years.

I needed to washout the CTLA-4 blockage and have some test run before I would be accepted into the next trial. We know from the PK studies that it would take 42 days to eliminate the antibodies from my system.

Day 43-10/25/06, I got the results back from the Scans and it wasn’t good. The cancer is spreading in my lungs quite rapidly according to the CT scans. There are now over 40+ nodules ranging from 15 mm down to < 5 mm. No wonder I been having shortness of breath. I thought it was my lack of exercise. Dr. Pandya gives my prognosis a poor rating. I guess I will have to sit in the corner. (CTLA-4 Antibodies are gone from my body.) The cancer has made its way to the “Escape Phase” and is now out of control. This is also the average maximum propagation time of the cultured T-cells.

Day 50– 11/1/06, the first cycle of High dose Interleukin-2 (IL-2). It just so happen to be the maximum propagation of the CD8+ T cells. All of the anti-CTLA-4 is washed out. We also, most likely have the most CD4+ T reg cells.These are the cells that help regulate the immune response so it doesn’t go into overdrive and cause an autoimmune response.

If we reset the clock for the second therapy (LI-2), then we can follow the activation of the CD8+ T-cells. My body has become a big Erlenmeyer flask. Erlenmeyer flasks are used in microbiology for the preparation of microbial cultures.

So on day 50- 11/1/06, we innocuated my body with IL-2 – a growth factor. So based on the Itoh study,  I should be activating the CD8+ T-cells  into a mature state (TILs and LAK  cells.) It should take  roughly 50 days they would be at there maximum growth phase.

In Itoh’s study the cultures were supplemented every 5 days by replacing half the cultured medium with fresh medium containing (IL-2) as one of the supplements. My

IL-2additions were every 21days. (600,000IU/kg for high dose IL-2)

On78^th day 11/29/06, the second cycle of IL-2was administered. I t was pushed back a week due to the Thanksgiving Holiday. I completed 8 doses which is the average that patients can withstand.

On day 93 12/14/06, I have another CT scan. I am trying to recover between cycles.

On day 98 12/19/06we got the CT Scan Results: What a Christmas Present!!!!!! The tumors were shrinking!!!!!!!

Melissa’s  Note:

I'm Christmas shopping…..but Heather called me with the results….I AM SOOOOO HAPPPY FOR YOU!!!!!!!!!!!!!

YIPPPPPEEEEEE!!!!!!!

Hope you have a wonderful holiday, and I'll see you soon 🙂 🙂 🙂 🙂 Melissa

As you can see, the timing and the players of this Orchestration all fell into place. A single Bullet of Monoclonal antibodies started a chain reaction with a whole sequence of events which lead to the restarting of my immune system. Without that bullet, there would have been no "Danger Signal"

Take care

Jimmy B

"Melanoma and the Magic Bullet (Monoclonal Antibodies)

http://www.box.net/shared/kjgr6dkztj

Here is my story with Anti-CTLA-4 Blockage. It starts back in 2005.

 The Orchestration of an Immune Response Unrehearsed

In 2006, after two fail attempts (Interferon and Dacarbazine with Patrin) to stop the progression of my melanoma, I was able try CTLA-4 Blockage. It was one of my first choices, but due to protocol, I had to try the FDA approved therapy first. I had researched this monoclonal antibody. On 10-24-2005when I was first diagnosed with melanoma, I contacted Dr. Luis H. Camacho who was currently at MD Anderson.

Subject:Paper on  Antitumor Activity

“Luis Camacho, My name is Jim Breitfeller and I have recently been diagnosed with melanoma will need some sort of Ontological therapy after my surgery. I ran across an abstract of yours (Antitumor activity in Melanoma and anti-self responses in Phase 1 trials with the anti-Cyctotoxic T Lymphocyte-Associated Antigen 4 Monoclonal Antibody CP-675,206) in the Journal of Clinical Oncology. Is it possible to get a copy of your paper? It can be emailed to the address below.”

Camacho response:

Dear James,
Thank you for your note. The CTLA4 antibodies in melanoma are currently under development and completing the approval process with the FDA (Phase II and Phase III). The overall response rates in my mind will be near 20-30% with a good number of patients attaining long term remissions. However, none of the programs are currently oriented to patients rendered NED (Stage III or IV). They are in fact for patients with advanced disease.  From your brief introduction, I think your best options are to obtain an HLA typification and go for an adjuvant trial.

Please feel free to page me if you need further information. Pager is 713.404-5319
Best,

Luis

CP-675,206, a novel monoclonal antibody, enlists the immune system to fight advanced melanoma

Some Positive Test results of the CTLA-4

Early testing of an experimental human monoclonal antibody showed a striking benefit in patients with advanced melanoma, say researchers at The University of Texas M. D. Anderson Cancer Center, who presented their findings at the annual meeting of the American Society of Clinical Oncology. Of 39 patients given a single injection of CP-675,206 (known as CP-675), tumors disappeared in three patients, shrunk in a fourth patient, and cancer stopped growing in five other patients. These responses have remained since their initial treatment, which ranged from 13 to 28 months ago.

Most of the patients in the trial had advanced melanoma, which has a median survival of less than a year, says the study's principal investigator, Luis Camacho, M.D., MPH, assistant professor in the Department of Melanoma Medical Oncology.

"We were very pleasantly surprised to find such objective antitumor responses in a Phase I clinical trial, which is designed to find the ideal dose and to look for side effects," says Camacho. "These results are very early, but they are encouraging to us because there are no good agents available to treat melanoma once it has spread."

Source:  Laura Sussman from (ASCO) American Society of Clinical Oncology

At the time of the request, I was not at the correct stage but I knew that this might be the path of the future. I did contact him and we discussed my options at that time. I was just learning the ropes.

On 9/3/06I contacted Dr. Rosenberg just in case I needed a back up plan if the CTLA-4 blockage did not work. At that time I did not know I was the wrong HLA-02 type for Rosenberg’s trials.

“I am Contacting Dr. Steven A. Rosenberg at the National Cancer Institute in Bethesda, Maryland.

He is the lead the researcher on the Gene Therapy Trials.
Log onto the CBS website for the story!!!!!!
http://www.cbsnews.com/stories/2006/08/31/health/main1955526.shtml

The research team recently applied to the Food and Drug Administration (FDA) to try the new cells in about 100 patients. The FDA is expected to respond to the request by mid-September.

Dr. Rosenberg, I just got the news of your Gene Therapy Experiments. The initial results look somewhat promising. I applauded you and your team for making great strides in the cure for melanoma cancer.

I am a cancer patient (48 yrs. old) under the care of Dr. John Kirkwood at the Hillman Cancer Center at the University of Pittsburgh. I have gone through a wide incision, lymph nodes removal, Interferon therapy, and Dacarbazine therapy without success. I am presently on track to start a clinical trial with CTLA-4 monoclonal antibodies September 13, 2006. I have some tumors on my right side of my back and some in each lobe of my lungs. I would like to be considered for your next round of Gene Therapy in the coming months if I have no response to the CTLA-4 treatment. Please let me know if you would need a copy of my medical records to date.

Thanks again for the great work you are doing and I hope to hear from you in the near future.

Best Regards,
Jim Breitfeller

On 9/5/06 I received a call from Dr. Rosenberg’s office this morning while I was at Dr. Marino’s office. Kathy Morton (Research Nurse) contacted me by phone and asked a few questions about my health. She went on to say if I go with the CTLA-4 therapy, it would take about 2 months to washout before I could try the Gene Therapy. They would also have to do a colon biopsy to check the colon for any adverse conditions from the CTLA_4. She then gave me her direct phone number if I want to pursue the gene therapy at a later date.

So, on 9/13/06(day 1)I had my first and only infusion of anti-CTLA-4 monoclonal antibodies. A dose of 15 mg/kg on Day 1. This was done as an outpatient procedure. Anti-CTLA4 monoclonal antibodies block the ability of CTLA4 to down-regulate T cell proliferation. The theory behind this therapy is that by decreasing the inhibitory signal, there will be a subsequent increase in the number of activated T-cells available, to improve the ability of the T-cells to recognize melanoma cells as non-self.

Before we can go any further, we need to know the clinical pharmacokinetics (pk)of anti-CTLA-4 monoclonal antibodies. Base on published papers, the predicted half-live of the antibody is around 3 weeks.¹¹ This means your body will eliminate half the dose that was infused in you in about 21days. So, in 42 days or there about, the drug is completely gone from your system.

I started my CTLA-4 treatment at 9:15 am at 100 ml/hr and I had 500 mls hanging on my rack (Miss Daisy). I call the rack Miss Daisy because I have to take it with me where ever I go which includes the bathroom. I am driving Miss Daisy!! This will take us to 3:15 pm and then they draw blood fora pk study an hour later. So, we won’t get out until about 4:30 pm and home until 10:00 pm.

Day 7 –9/19/06  “Along with the fatigue, my muscles ache like they have lactic acid in them”. Is this an indication of something? All immune cells begin as immature stem cellsin the bone marrow.

Day 15 –9/27/06 about half the CTLA-4 antibodies are depleted. It appears that the CTLA-4 has stimulated my immune system. In the pass week, I noticed that there was redness around the area where my tumors are located. Also it is becoming quite tender in that area. This is Great news!!!!! It appears that the treatment my have kick started my immune system. The only way we will know for sure is another CT scan. That is not scheduled until November 23^rd.

I sure hope this isn’t a false positive. Anyway, they gave me an antibiotic just in case it is an infection.

This inflammatory response provides a third signal that acts directly on T cells, referred to as the “danger signal”. “This signal was found to optimally activate T_H1 differentiation and lead to clonal expansion of T cells¹².

With this clonal expansion of the T cells and the secretion of IL-2, The Immune system is gearing up to make an assault on the foreign invaders, the tumors.

In 1988,a paper was published Autologous Tumor Specific Cytotoxic Lymphocytes in the Infiltrate of Human Metastatic Melanomas  Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor  by Itoh  and Colleagues.⁴  In their studies, they propagated (TILs) Tumor infiltrate lymphocytes cells from 12 Metastatic Melanoma patients. They preformed kinetic growth studies in IL-2 and even broke it down three Surface markers (CD3,CD4 and CD8). The results are as follows:

The average maximum propagation was 43 days. (N=12)

The average maximum propagation for (lung, Axilla) was 40 days (n=3)

The average maximum propagation for (CD3) was 78 +/- 11 days (n=12)

The average maximum propagation for (CD4) was 33 +/- 10 days (n=12)

The average maximum propagation for CD4 (lung, Axilla) was 26 days (n=3)

The average maximum propagation for (CD8) was 49 +/- 17 days (n=12)

The average maximum propagation for CD8 (lung, Axilla) was 57 days (n=3)

Base on the above data, it would take about 49 days for my activated T cells to reach maximum propagation.

Day 29– 10/11/06, A couple of days ago, Dee noticed two new growths on my back. I
was hoping for the best. Anyway, we got confirmation from the Hillman Center that it is 2 new tumors growing. This really stinks. I think it is time to take out the “Weed be Gone”. This is not what I was hoping to hear. It was decided that the CTLA-4 blockage therapy was to be terminated. My CD4⁺T cells were just about at maximum propagation.

Dr. Kirkwood, decided that the next line of defense would be Interleukin-2 (IL-2).

Results of early PROLEUKIN® IL-2 Clinical Trials
Year received FDA Approval 1998
Number of Patients 270 patients
Number of Trials 8
Response In 16% of the patients, tumors shrank or disappeared as a result of PROLEUKIN® IL-2 therapy.

In 6% of the patients, the tumors disappeared completely.
Results From these trials, it was determined that a patient whose tumors completely disappeared from the treatment remained cancer-free for a median of 4.9 years.

I needed to washout the CTLA-4 blockage and have some test run before I would be accepted into the next trial. We know from the PK studies that it would take 42 days to eliminate the antibodies from my system.

Day 43-10/25/06, I got the results back from the Scans and it wasn’t good. The cancer is spreading in my lungs quite rapidly according to the CT scans. There are now over 40+ nodules ranging from 15 mm down to < 5 mm. No wonder I been having shortness of breath. I thought it was my lack of exercise. Dr. Pandya gives my prognosis a poor rating. I guess I will have to sit in the corner. (CTLA-4 Antibodies are gone from my body.) The cancer has made its way to the “Escape Phase” and is now out of control. This is also the average maximum propagation time of the cultured T-cells.

Day 50– 11/1/06, the first cycle of High dose Interleukin-2 (IL-2). It just so happen to be the maximum propagation of the CD8+ T cells. All of the anti-CTLA-4 is washed out. We also, most likely have the most CD4+ T reg cells.These are the cells that help regulate the immune response so it doesn’t go into overdrive and cause an autoimmune response.

If we reset the clock for the second therapy (LI-2), then we can follow the activation of the CD8+ T-cells. My body has become a big Erlenmeyer flask. Erlenmeyer flasks are used in microbiology for the preparation of microbial cultures.

So on day 50- 11/1/06, we innocuated my body with IL-2 – a growth factor. So based on the Itoh study,  I should be activating the CD8+ T-cells  into a mature state (TILs and LAK  cells.) It should take  roughly 50 days they would be at there maximum growth phase.

In Itoh’s study the cultures were supplemented every 5 days by replacing half the cultured medium with fresh medium containing (IL-2) as one of the supplements. My

IL-2additions were every 21days. (600,000IU/kg for high dose IL-2)

On78^th day 11/29/06, the second cycle of IL-2was administered. I t was pushed back a week due to the Thanksgiving Holiday. I completed 8 doses which is the average that patients can withstand.

On day 93 12/14/06, I have another CT scan. I am trying to recover between cycles.

On day 98 12/19/06we got the CT Scan Results: What a Christmas Present!!!!!! The tumors were shrinking!!!!!!!

Melissa’s  Note:

I'm Christmas shopping…..but Heather called me with the results….I AM SOOOOO HAPPPY FOR YOU!!!!!!!!!!!!!

YIPPPPPEEEEEE!!!!!!!

Hope you have a wonderful holiday, and I'll see you soon 🙂 🙂 🙂 🙂 Melissa

As you can see, the timing and the players of this Orchestration all fell into place. A single Bullet of Monoclonal antibodies started a chain reaction with a whole sequence of events which lead to the restarting of my immune system. Without that bullet, there would have been no "Danger Signal"

Take care

Jimmy B

"Melanoma and the Magic Bullet (Monoclonal Antibodies)

http://www.box.net/shared/kjgr6dkztj