Pittsburgh Trip (06/28/06) in detail:How my Melanoma Journey Began..Jim Breitfeller

Pittsburgh Trip (06/28/06) in detail:

We left Rochester 4:00 am and arrived in Pittsburgh about 9:00 am. It’s a 5 hour trip if there are no detours along the way and you have a lead foot. I was very anxious to find out what my four options were so we had a cup of coffee and a croissant at their café and then proceeded to the doctor’s office. It was now about 9:30 am and my appointment was for 10:00 am. You know me, I like to be early. My wife says I am always too early. We proceeded to check in, and they gave me the normal treatment. They took my height, weight and vital signs. But this time they make a big deal about my weight. I had loss 4 lbs. So she calls over another nurse to retake my weight again (SOP) standard operating procedure. It was still short 4 lbs. I am thinking great, I am finally getting my weight under control. So, I turned to the nurses and said, “If you gave out cookies, you would not have these problems.” From their point of view, if you lose weight the cancer is active. Meanwhile, I’m thinking to myself, “Of course I lost weight. I’ve been so nervous. . . And, I just drove 291 miles without my breakfast. And we did make a couple of stops along the way.

Anyway, within 15 minutes we were called into the exam room. I am thinking this is great. The temperature in the room must have been 55 degrees. I was told to strip down to my underwear and put on one of those gowns with the slit up the back. I’m thinking, if this is anything like the last visit, I will freeze to death before anyone sees me. So, I told my wife, “If within 30 minutes, no one shows up, I’m going to put my clothes back on.” She said to me, that she was so cold that she had to go to the bathroom. So here we are, I’m shivering and my wife is crossing her legs to hold it in. So we are sitting and waiting, sitting and freezing for about 20 minutes. I did put my shoes back on to keep my feet warm.

Finally, the physician assistant steps into the room and greets us with a big “Hello!!!! ” She proceeds to tell us a little bit about the options, but then stops abruptly. She said: “the doctor should fill you in with all the details.” She then takes a look at my back, and with her hand, finds the lumps and starts counting them. She said “Good they are all there.” I am thinking, where the hell would they go, maybe on vacation? Nahhhhhhhhhhhh!
Anyway, no new lumps to report. She leaves the room to get the doctor and my wife follows her to find the bathroom. Dee returns relieved, just in time here hear a knock at the door.

In walks Dr. Kirkwood who greets us with a big smile and a hand shake. He asks us if Melissa, the physician assistant, has filled us in with the option details and could we go over the details with him to make sure we understood them. My wife and I turned to each other and our faces must have looked white to him. We tried to regurgitate what little information she had shared, although, it was VERY brief and we had not taken any notes. Melissa had told us that the doctor was going to go over the details. Well, my quick thinking wife said that Melissa gave us a very, very brief overview and that at our last meeting with him, we got all of 5 minutes of his time. I guess Dr. Kirkwood did not realize that the last time he had talked to us was before he had the PET/CT scans results and the options were different.
Anyway, he began to draw us a flowchart of the options on the exam table paper. He was really getting into it.

He started with the options at the top, and continued with the first line, second line and third line of defense therapy. It looked like an ISO document. I could draw it for you, but you’d probably fall asleep reading it. The worse part is, you have to have the therapies done in a certain sequence or you can not move to the next line of defense. Another problem, you can not mix and or match. To make things even worse, one of the better lines of defense had to be removed because I have the wrong blood type for the vaccine therapies. I was hoping to use this as my third line of defense.

My wife and I just sat there staring at the flowchart for what seemed like hours. We both started to run different scenarios in our head. We came up with the same conclusion. We needed a therapy that would allow us to “work outside the box” and not “cuff my hands”. We wanted to have the Ticilimumab/ Tremelimumab (from Pfizer …anti-CTLA-4 therapy as my second line of defense. CTLA-4 seems to slow down the immune response, so blocking it with an anti-CTLA-4 antibody may make the immune response more active.

Soooooooooooo! I signed my life away for the phase I study of Patrin in combination with dacarbazine under our protocol 03-091, which is currently not a nationally available trial.


I also signed up to allow Tumor Biopsies. Hey why not. It is FREEEEEEEE!!!! And I get two tumors removed for the price of one. And they say nothing is free in the world anymore. They will remove one and study it before treatment, and then take another one out and see what effect the chemo had on it during the first cycle of therapy. You know me I am always looking for a bargain--and, I am always doing some sort of research.

That is it from my end to yours. That sounds gross. Anyway take care, and keep those messages coming.


If you want to follow my journey you can read it here or at Carepages.com with comments.

http://www.carepages.com/carepages/jimmyBreitfeller

We needed a therapy that would allow us to “work outside the box” and not “cuff my hands”. We wanted to have the Ticilimumab/Tremelimumab (from Pfizer …anti-CTLA-4 therapy) as my second line of defense. CTLA-4 seems to slow down the immune response, so blocking it with an anti-CTLA-4 antibody may make the immune response more active.

That was then, This is Now, NED!!!

"Think Outside the Box"


“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

What If you combine Therapies? Response from Dr. Keith Flaherty..Melanoma ..Jim Breitfeller

What If you combine Therapies? Response from Dr. Keith Flaherty

Jim,


Thanks for the note.




"It is actually critical “patient advocates” which obviously includes patients, as well as those who are motivated to advocate on behalf of patients get involved in this process. One of the very reasons why I thought that a consortium was important to form, so that there could at least a body of researchers to point to as a group jointly focused on this direction. You see, companies find it very easy to say no to individual investigators when it comes to “difficult” requests. We need to make it harder for them when it involves losing time that our patients don’t have."



A very obvious combination that we are trying to move forward now is PLX4032 with ipilimumab. There is unanimity among the academic researchers that this must be investigated. Both companies see the logic, but are reluctant with neither of their drugs yet being FDA approved. As you know ipilimumab (and tremelimumab) have not overwhelmed the FDA yet as they were told to show a response rate greater than 10% and neither drug could do so. Most melanoma researchers believe that there are additional patients who get real and long-term benefit without having their tumors shrink significantly in size, but the randomized trials are needed to show that. The worrying sign is the outcome of the tremelimumab randomized trial. So, now we are down to waiting for the results of the dacarbazine vs. dacarbazine plus ipilimumab phase III trial. If this is negative, we are in trouble as ipilimumab will have no clear path forward with the FDA. If it’s positive, then the idea of moving ahead with combinations becomes much, much easier. But, even it that trial is negative, we know that CTLA-4 blockade can induce phenomenal responses in some. So, in that case, we have to figure out (1) who those patients are and, (2) how to make those responses happen in more patients. The other way of thinking of #2 is that PLX4032 doesn’t work for as long as we would like and that making those responses more durable would be desirable.

The companies need to hear it from patients and all patient-advocates that fairly obvious directions need to be pursued to find multiplicative effects. For the first time in melanoma, we have the building blocks in front of us and scientific rationale to guide us for the next steps.


Best regards, Keith

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
Keith,


Base on my research, Ipi doesn’t work well is because it is lacking the tumor-specific antigens. DTIC+ Patrin-2, Irradiation, Oblimersen and others. We need the tumors to shed antigenic protein. To get the immune response into motion.


By using PLX-4032, my guess it will shed the protein needed. Then Anti-CTLA-4 Blockage comes in. It leaves the cd4+ T-cell activated and at the same time suppresses the Treg function allowing the CD8+ T-cells to get crossed primed and have them break though the tumor microenvironment. The HD IL-2 is added at the peak expansion of the CD8+ T-cells ( 50 days after Ipi is introduced into the host.). IL-2 is essential in the survival and function of the CTLs.


The above is my take on this combinatorial therapy. If you want, I can send you all the supporting papers of this theory.


Also, Can I get your permission to post your reply on my Blog?

Best Regards

Jim

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

What If you Combine three Therapies? PLX-4032 after remission, to let the tumor burden be low, Than add one dose of Anti-CTLA-4 Blockage. Wait 50 days so the CD8 T-cells would be at their maximum expansion. Then add two cycles of HD IL-2 to help grow and differentiate the CD8 T-cells into Cytotoxic T Lymphocytes (CTL's). You use the PLX-4032 to lower the tumor burden and shed the antigenic protein from the tumor.



For the patients that have the Braf mutation, use PLX-4032 to shed the antigenic protein and lower the tumor burden.

If you don't have the mutation, use radiation, chemo DTIC+ Patrin-2, Oblimersen and other small molecules to shed the antigenic protein.







Take Care,

Jimmy B

Tremelimumab Shows Low But Durable Response Rate in Advanced Melanoma..Jim Breitfeller

Tremelimumab shows low but durable response rate in advanced melanoma
FEBRUARY 18, 2010

"NEW YORK (Reuters Health) - In a phase II trial in patients with advanced refractory or relapsed melanoma, tremelimumab (CP-675,206) showed a 6.6% objective response rate, with these responses lasting more than six months, a multinational group of researchers report in the February 1 issue of Clinical Cancer Research."

Source:http://www.curetoday.com/index.cfm/fuseaction/news.showNewsArticle/id/13/news_id/2350

Tremelimumab shows low but durable response rate in advanced melanoma


As you can see, the response rate is low as a monothrapy, but if you can get the tumors to shed antigentic proteins by combining with chemotherapy, irradiation and other molecules to stop the repair of the tumor Cell DNA, then you have antigens to present on the the (APCs) Antigen Presenting Cells. Interluekin-2 can be added at the end of the T-cell expansion to help grow and maintain the (CTLs) Cytotoxic T Lymphocytes.





adapted from Henry Stewart Talks by Jim Allison



Take care

Jimmy B

Melanoma_Missionary


"Today might be the worst day of your life...but tomorrow could be the best. You just have to get there."
~Unknown~

First, how did I get the right antigen to be presented on the Antigen Presenting Cell (APC)?

There are three types of Antigen Presenting Cells:
• Macrophages
• Dendritic Cells
• B Cells

We will focus our attention on the Dendritic cells (DCs ) because I postulate that these cells played a major roll in help generating an immune response. Induced Dendritic cells go through a developental program call maturation, which transforms them into efficient antigen-presenting cells (APCs) and T-cell activators. They are the most potent of the three APCs.

So what really happened? Well, Dr. Kirkwood started me out on Dacarbazine with PaTrin-2. Dacarbazine is a chemotherapy agent, approved by the FDA for fighting Melanoma. Dacarbazine alkylates and cross-links DNA during the phases of the cell cycle, resulting in disruption of DNA function, causing cell cycle arrest, and apoptosis.17 The only problem is that the Melanoma Cells overexpresses this enzyme called MGMT.

Proteins known as DNA repair enzymes are present in cells to target damaged DNA and reverse the modifications caused by alkylating agents. One such enzyme is methylguanine methyltransferase (MGMT). MGMT directly reverses the chemical modification guanine, one of the four building blocks of DNA, allowing normal replication to take place.

The DNA-repair enzyme MGMT is a key factor in resistance to alkylating agents. This is one reason why the Dacarbazine therapy doesn’t have a very successful response rate. The MGMT enzyme repairs what the dacarbazine cross-links. So, PaTrin-2 was added to the trial. This drug is known to inactivate the MGMT activity. By inactivating the MGMT enzyme, it makes the tumors cells more susceptible to the chemotherapy.

This therapy was able to get the tumors cells to shed some antigenic Protein which I theorize and was used as the presenting antigen. This made the antigen “tumor-specific.”




Base on a paper by Dr. Olivera J.Finn called Cancer Immunology published in the New England Journal of Medicine in June 19, 2008, there are three ways for self antigens to become Tumor Antigens:


1. Mutation
2. over expression
3. Post-translational Modification

I postulate that some failure of the tumor cells to repair the DNA damage cause by the Dacarbazine in the present of PaTrin-2 resulted in a mutation causing the cancer cells to shed an antigenic peptide.


Well there is also anther protein that is overexpress in the cancer cells. It is the Bcl-2 protein. Bcl-2 has been implicated in disease resistance.


There is now a drug called Genasense®. Based on the clinical results. It also helps shed the right antigen. (The tumor-specific antigen)


Genasense®


If I am reading the data correctly, it is telling us that it to can be used with (DTIC) Dacarbazine to shed some antigenic protein. So If you combine the two, you are most likely will have the right antigen to present.


source:http://mct.aacrjournals.org/content/3/10/1215.abstract?ck=nck
Molecular Cancer Therapeutics



Take Care,

Jimmy B

You have questions for Me? Why DTIC & PaTrin-2?..Melanoma..Jim Breitfeller

Remember I went to United Kingdom virtually to scour the research papers Last year?

Introduction:

"Temozolomide is an alkylating agent that mediates its cytotoxic effect by forming O6-methylguanine (O6-meG) DNA adducts, which during DNA replication pair preferentially with thymidine. These O6-meG:T mispairs
can result in a G-to-A point mutation during a subsequent round of DNA replication but are also substrates for the postreplication mismatch repair pathway, which after a further round of DNA replication leads to apoptosis (1). O6-meG DNA adducts can be repaired by the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT), which removes adducts from the O6 position of guanine by accepting them onto a cysteine residue within its active site. Furthermore, fibroblasts and
bone marrow cells of MGMT knockout mice are significantly more sensitive to the toxic effects of temozolomide than those from MGMT wild-type mice (2).

The protective role of MGMT against the cytotoxic effect of temozolomide has been shown in human cell lines (3) and human xenograft models (4).

MGMT can be inactivated by free guanine base derivatives that have alkyl groups at the O6 position, which act as ‘‘pseudosubstrates.’’ O6-benzylguanine (5) and O6-(4-bromothenyl) guanine (PaTrin-2, Patrin, Lomeguatrib, KuDOS, Cambridge, United Kingdom; ref. 6) have been identified as the most promising MGMT inactivators. Compared with temozolomide used as a single agent, the combination PaTrin-2-temozolomide has been shown to significantly increase tumor growth inhibition in human melanoma
xenografts (7)."


Source:http://mct.aacrjournals.org/content/3/10/1215.full.pdf

Sensitization of a human ovarian cancer cell line totemozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferase


That is why, and I forgot to tell you that I did a trial with Patrin and DTIC Prior to CTLA-4 Blockage Therapy.

Take Care

Have a Great Weekend!!!!!

Jimmy B

6:00pm the PK Studies at Montifore Hospital

I arrived at Montifore about 5:45 pm for my pj party. I t was the night of the All Star Game. Perfect, I could watch the game and give blood at the same time. You have to learn how to multi-task. So, up to 8th floor I went and checked in with the nurse at the front desk. She said “Mr. Breitfeller, you are right on time.” She then led me to a room 847 N bed 2. “This is you home for the night. Get yourself comfortable.” So, I changed into my sexy shorts that I been wearing even before I got married. You know the ones, silky and has Kings Point printed on them. The most comfortable shorts I have ever encountered. I could tell you how I come to have them but, this a family channel.
So, I jumped into the bed and the nurse Beverly started to put lines in my left arm. One line was for the Chemo in the morning, and the other to draw blood.
At 8:00 pm I got my 400 mg dose of Patrin I think. In this part of the trial, I have a 50/50 chance of receiving the drug. It could be a glucose placebo. I think I might check it out with GC-MS to get the scoop if I can get it in at Kodak. All fair in war and games. Plus I would know if I am wasting my time an efforts. Hey! What would you do in my situation? Take advantage of what you have at your disposal.
Patrin™


The treatment of metastatic cancers present serious problems for clinicians. Many cancers are not discovered at all until they have progressed to this late stage and response rates to therapy are often very low in these cancers; for example, only around 15-20% of metastatic melanoma cases respond to the commonly used chemotherapies dacarbazine and temozolomide.

Such low response rates are the result of resistance. Cells become resistant due to the presence of AGT (O6-alkylguanine DNA-alkyltransferase). AGT detects and specifically removes alkylated base damage, effectively undoing the damage caused by alkylating chemotherapies.

Patrin™, an orally bioavailable small molecule, acts to increase the responsiveness of tumour cells to alkylating chemotherapy treatments by specifically inactivating cellular AGT, making cancer cells susceptible to the DNA damage caused by chemotherapy

Identifying new drugs and targets for melanoma therapy is critical, considering that melanoma, the most dangerous form of skin cancer, is resistant to currently available therapeutics. Much work has been focused on finding novel drugs and exploring different treatment options that could increase the overall survival of patients.

Anyway, Blood was drawn 0, 30 min., 1, 2,3,4,5,6 hours after taken Patrin . So, this part was over at 2:00 am . The next part was the dacarbazine was introduce and the blood drawn process started all over again. I did not get released until Wednesday at 3:30 pm.

My wife made the trip down to Pittsburgh and we drove back to Rochester last Night and arrived at 10:00 pm. We made a couple of stops along the way.

I am starting to see some of the side effects nausea and my blood sugar is on the rise. I will contact Heather Blair and Melissa DeMark from the Hillan Cancer Center. I’ll Let you know what they say.

That is it for now. Take Care

jimmy B.