Pearls of Wisdom: Melanoma ..Jim Breitfeller

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

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


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


Advanced Stage III/Stage IV resectable disease

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

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


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

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


Standard therapies for metastatic disease

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


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

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


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


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

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



Cytotoxic chemotherapy

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

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



Promising Therapies


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



•Anti-PD-1 therapy:

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

•Anti-PD-1 + Yervoy therapy:

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



References

1.

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

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

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

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


5.

Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. The New England journal of medicine 2011;364:2507-16.     “It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
 Take Care,
Jimmy B

Interview With Michael B. Atkins, MD Immunotherapies in Melanoma.Jim Breitfeller

Interview With Michael B. Atkins, MD Immunotherapies in Melanoma: Taking Stock
 Alice Goodman, MA; Michael B. Atkins, MD

 Posted: 07/02/2012

 Editor's Note: Immunotherapy is the only treatment that can produce durable tumor regression in patients with metastatic melanoma. With novel molecularly targeted agents also being developed for metastatic melanoma, the hope is to learn how to combine and sequence these therapies and improve survival for patients with this once universally fatal disease. At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO®), Dr. Michael B. Atkins, Deputy Director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, chaired an educational session on immunotherapy in advanced melanoma.

 Medscape caught up with Dr. Atkins to ask him to put into perspective the emerging data on immunotherapy and what questions still need to be answered.

IL-2 Opens the Door Medscape:
 What was the first immunotherapy to show an effect in metastatic melanoma?

Dr. Atkins: High-dose interleukin (IL)-2 received US Food and Drug Administration (FDA) approval for the treatment of patients with metastatic melanoma in 1998. A number of durable responses were observed and 11% of patients were alive at 5 years.[1] More recent studies have shown that patients with elevated lactate dehydrogenase (LDH) levels are much less likely to respond to IL-2, with about a 6% response rate in patients with elevated LDH (all partial responses) and about 21% in those with normal LDH levels.[2] Analysis of molecular profiles shows that a significantly larger proportion of patients with BRAF- and NRAS-mutated tumors respond to IL-2 than those who do not have these mutations. Also, we now have information suggesting that tumors with an inflamed phenotype and immune infiltrates have a 2- to 3-fold improved chance of response relative to those with a noninflamed gene expression pattern.

Michael B. Atkins, MD
Medscape: Has IL-2 been combined with other immunotherapies?

Dr. Atkins:
 IL-2 has been combined with vaccine therapy. Results of a randomized trial found that the combination of IL-2 plus vaccine produced response rates of 22.1% compared with 9.7% with IL-2 alone, and a trend was observed toward improved overall survival.[3] Median survival was 17.6 months with the combination of IL-2 plus vaccine vs 12.8 months with IL-2 alone. Very few relapses were seen beyond 2 years in responding patients, a hallmark of effective immunotherapy. However, lower-than-expected response rates were reported for the IL-2-alone group, calling into question how much of an advance this treatment is. Some questions remain: Is this a proof of concept that the immune response can be focused by a vaccine? Will the findings be relevant with novel immunotherapies? Ipilimumab: A Check-Plus for a Checkpoint Inhibitor Medscape: More recently, ipilimumab, a different type of immunotherapy, was approved by the FDA for the treatment of metastatic melanoma. This drug is referred to as the first checkpoint inhibitor, meaning that it interferes with an important downregulatory property of the immune response.

How does this drug work, and what kinds of outcomes does it achieve?

Dr Atkins: The monoclonal antibody ipilimumab blocks CTLA-4, which serves as a coregulatory protein that shuts off the immune response when it binds to a protein on antigen-presenting cells. Blocking CTLA-4 restores immunity. Ipilimumab has been evaluated in a variety of clinical trials. It is administered intravenously once every 3 weeks for 4 doses on an outpatient basis. Its side effects result primarily from induction of immune reactions against normal tissues, but in general, it produces fewer inflammatory systems (eg, fever, chills, hypotension) than those associated with high-dose IL-2. A recent trial compared ipilimumab plus gp100 vaccine vs ipilimumab alone vs the vaccine alone.[4] In both ipilimumab-containing arms, survival was prolonged. One-year survival was 46%, 44%, and 26% for the 3 arms, respectively. Two-year survival was 22%, 24%, and 14%. Few deaths occurred in the ipilimumab-treated patients after 30 months.

Medscape: What about the safety profile of ipilimumab and patient selection?

Dr Atkins:
The toxicities of ipilimumab are related to activation of the immune system and include colitis, dermatitis, endocrine effects, and hepatitis. In clinical trials, all subgroups benefitted from ipilimumab, with the possible exception of patients with elevated LDH. One feature of ipilimumab is apparent disease progression early in the course of treatment followed by a major response, so we have learned that the effect of treatment is not seen immediately. Pooled data from clinical trials suggest that about 25% of patients with metastatic melanoma have long-term benefit from ipilimumab therapy, and the benefit might be greater with a higher dose of the drug. Also, there is a potential role for maintenance therapy with this agent.

Medscape: Has ipilimumab been studied in combination therapy?

Dr Atkins:
A study was conducted in previously untreated patients with metastatic melanoma in which the patients were randomly assigned to dacarbazine alone or dacarbazine plus ipilimumab.[5] Some experts expected better results than were achieved in this first-line setting, and it is possible that dacarbazine may have compromised outcomes.

Medscape: What are the take-home messages about ipilimumab for metastatic melanoma?

Dr. Atkins:
Ipilimumab enables an immune response and antitumor responses in some individuals. This agent is powerful enough to work in the central nervous system and overcome concurrent immunosuppression. The response to ipilimumab may be associated with autoimmunity. Activity of the drug is seen in patients previously treated with IL-2. This drug is an option for most patients with advanced melanoma. Optimal timing of therapy and severe autoimmune toxicities should be considered. We don't know the answers to all of the questions about how to use ipilimumab. Should it be combined with dacarbazine? Should it be used as first-line or second-line treatment? What is the optimal dose and schedule? Does it have a role in maintenance therapy? What is its role in the adjuvant setting? What combinations should be studied? Some possible combination partners are bevacizumab, GM-CSF [granulocyte-macrophage colony-stimulating factor], high-dose IL-2, and the novel PD-1 antibody. PD-1 Inhibitor: New Kid on the Block Medscape: At the 2012 annual meeting of ASCO®, we heard exciting preliminary reports about a second checkpoint inhibitor called MDX-1106, a PD-1 antibody.

 How does this immunotherapy work, and what are preliminary observations?

 Dr. Atkins:
On activated T-cells, PD-1 serves as the receptor for PD-L1, which is expressed on tumor cells. When PD-L1 binds to PD-1 inside the tumor microenvironment, it paralyzes T-cell immune function. Blocking the interaction between PD-L1 and PD-1 with an antibody provides a specific way to activate the immune system within the tumor microenvironment. It is hypothesized that this would provide a less toxic and more potent means of activating the immune system. Several presentations at ASCO® on this novel immunotherapy showed exciting preliminary results. A large phase 1 study evaluated MDX-1106 given every 2 weeks for up to 2 years in patients with melanoma, renal, and non-small cell lung cancer.[6] Durable responses were seen in all 3 malignancies. In the melanoma patients, about half had tumor shrinkage and some responses were quite significant. This novel therapy will move forward in clinical development for patients with melanoma, either as a single agent or in combination. A number of PD-1 and PDL-1 blockers are under development. Which Patients Are Right for Immunotherapy?

Medscape: How do you select patients for treatment with immunotherapy?

 Dr Atkins: Patients with metastatic melanoma are not all the same. There are 2 basic phenotypes: noninflamed and inflamed. Data suggest that the second phenotype is associated with a better prognosis; that is, the greater the percentage of immune cells within a tumor, particularly CD8+ T cells, the better the prognosis. As mentioned previously, patients with tumors expressing an immune signature are more likely to respond and to exhibit a longer progression-free survival than those with tumors that do not have this signature. Studies suggest that PDL-1 expression appears to be associated with benefit, because patients without PD-L1 expression were less likely to respond to PD-1 antibody.[6-8] Sequencing: Which Therapy, and When? Medscape: What is the current thinking on sequencing of therapies? Dr Atkins: In addition to immunotherapies, several new targeted therapies are on the horizon. Vemurafenib, which targets tumor containing a BRAF V600E mutation, is approved for the treatment of patients with metastatic melanoma, and other BRAF and MEK inhibitors are being studied. These therapies may be able to be used in combination with immune therapies to improve outcomes. Most patients would like a chance to be cured. Immune therapies are the only curative therapies for advanced melanomas. Thus, if patients can receive an immune therapy, it may be better to give it first. For BRAF wild-type tumors (those without the BRAF V600E mutation) and even for the BRAF-mutated tumors, it might make sense to give patients an immunotherapy first to try to produce long-term benefit and reserve the use of a BRAF inhibitor for those patients who don't respond to immunotherapy. Data suggest that giving an immunotherapy first does not reduce the ability to respond to a BRAF inhibitor. On the other hand, patients who progress on vemurafenib do not appear to respond to ipilimumab. In fact, in a small study of 32 patients whose disease progresses on vemurafenib, 50% were dead within 4 months.[9] Only 3 of the 32 patients were alive longer than 1 year, and all of them were back on a BRAF or a MEK inhibitor. These preliminary data suggest that a BRAF inhibitor may not be the best initial therapy for some, if not most, patients with BRAF V600E mutations. A prospective trial is needed to study this question. A sequencing study is being planned by ECOG that has 2 arms: ipilimumab with crossover to vemurafenib at time of progression vs vemurafenib with crossover to ipilimumab at time of progression. The primary endpoint will be overall survival at 2 years. The study should tell us which is the best initial therapy for patients with BRAF mutant metastatic melanoma.

More Work to Be Done Medscape: Are there any potential downsides to combining immunotherapy and targeted therapy?

Dr Atkins: By combining immunotherapy and targeted therapy, the hope is to get the benefits of both worlds. But there are potential problems. Studies suggest that dacarbazine interferes with the immune effects of ipilimumab; however, preliminary data suggest that BRAF inhibitors might increase immune infiltration into tumors, converting the microenvironment from a noninflamed state to an inflamed state. Theoretically, this might mean that the combination of a BRAF inhibitor with immunotherapy might produce synergistic antitumor benefits. Medscape: What can you say to sum up where we are with melanoma immunotherapy in 2012? Dr Atkins: We have IL-2 and ipilimumab, and there are novel immunotherapies on the horizon, including the PD-1 antibody. We will need studies to refine optimal patient selection and identify the best combination treatments, including a BRAF inhibitor either alone or in combination with MEK inhibitors. The field has advanced, and in 2012 it is no longer futile to treat metastatic melanoma. There is a glimmer of hope on the horizon, but there is still a lot of work to be done.

Source: http://www.medscape.com/viewarticle/766473?src=mp&spon=38

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

~Charles Darwin~

Take Care,

Jimmy B

 

A very Happy Father's Day from a stage IV Melanoma Survivor..Jim Breitfeller

I want to thank all the people that has made this day a very special Day.


As a stage IV Melanoma Survivor, I never dreamed that I would be here today to witness my children spread their wings and learn to fly. My daughter was just entering college when I was first diagnosed and my son, Chris was a sophmore in High School. Today, I am preparing to help my son relocate to Connecticut. He just landed an engineering job at an areospace company. My daughter, Jessica is globe-trotting around the world working on her dual Masters in "International Affairs" and "Natural Resources & Sustainable Development". This day, marks Dee and I as offically "Empty Nesters".

This all was made possible by entering a journey that entailed four clinical trials along with the best and internationally renowned medical team that makes climbing Mt. Everst apiece a cake. And you , My carepage friends that kept me on the "Yellow Brick Road". I have won the "lottery of life."

Many Thanks

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

Take Care,

 Jimmy B
 

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

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

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

Dr. Steven Rosenberg is using engineered T-cells that secrete IL-12 to stimulate Th cells to secrete Th1 cytokines. This sets in motion the positive feed back loop needed to initiate an immune response. His therapy is show great promise. “It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” ~Charles Darwin~ Take Care, Jimmy B

Why Does Yervoy need to be systematically combined with IL-2? Melanoma..Jim Breitfeller

Yervoy therapy acts upon the T-cells by blocking the CTLA-4 receptor, making it unable to engage. By doing this blockade, the CD28/B7 complex can engage and the signaling to activate, secrete and multiply is allowed. Cytokines produced by activated cells can stimulate or inhibit the production of other cytokines by the same cells in an autocrine manner or those present in the vicinity by a paracrine mechanism. Thus, a complex network of cell interactions is established, with positive and negative feedback controls, regulating cytokine production. For example,
TNF-a induces the synthesis of both IL-1 and IL-6 in macrophages. In contrast, IL-10, which is also synthesized by macrophages, inhibits the synthesis of TNF-a, IL-1 and IL-6. Both IFN-g and TNF-a can activate macrophages, which subsequently synthesize TNF-a and IL-1. What I am trying to elude to is that depending on the microenvironment which contains many cytokines, the pattern of cytokines matters whether the macrophages are activated or not.

This does not take into account the suppressiveness of the Tumor’s activity. Melanoma tumors can secrete TGF-b and IL-10 and other suppressive molecules. These suppressive cytokines (IL-10) can block the activation of the tumor associated macrophages (TAMs) which in turn inhibits the secretion of other cytokines and chemoattractants into the Tumor’s microenvironment. This inhibition suppresses the “Danger Signal” needed to alarm the immune system of foreign invaders (Tumor cells).
Th1 cells promote macrophage activation by producing IL-2 and IFN-g. What if the Th1 cells are not producing enough or there are many Tregs in the tumor’s microenvironment recruited by the tumors themselves? The Tregs, Th1 and the CD8+ T-cells are all competing for the IL-2 for survival. There could be a shortage of IL-2 to satisfy all the cells leading to a less than robust response. It has been greatly accepted that macrophage activation by IL-2 is essential for tumor regression. et al Masztalerz
So administration of HD IL-2 during the peak propagation of the (ALC) Absolute Lymphocyte Count (7 weeks or 49 days) may be synergetic to Yervoy.








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

~Charles Darwin~
Take Care,

Jimmy B

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

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




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



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

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

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

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



“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

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

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



A picture is worth a thousand words.






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







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


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






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

~Charles Darwin~

Take Care,

Jimmy B

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

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

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


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

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




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

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


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


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


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

This is why Combinatorial Therapy is a Must to CURE Melanoma

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

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





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

~Charles Darwin~
Take Care,

Jimmy B

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

Hi everyone

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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



Kind regards

willtolive

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


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

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

Both Vicky and I did some IFN therapy first.



Vicky’s Treatment timeline:

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


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






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

~Charles Darwin~

Take Care,

Jimmy B

Researchers at UCLA's Jonsson Comprehensive Cancer Center Discover Way To Amp Up The Power Of Killer T Cells..Melanoma ..Jim Breitfeller

Researchers at UCLA's Jonsson Comprehensive Cancer Center Discover Way To Amp Up The Power Of Killer T Cells

Article Date: 10 May 2011 - 1:00 PDT
Source: http://www.medicalnewstoday.com/articles/224693.php

Researchers with UCLA's Jonsson Comprehensive Cancer Center have discovered a way to amp up the power of killer T-cells, called CD8 cells, making them more functional for longer periods of time and boosting their ability to multiply and expand within the body to fight melanoma, a new study has found.

The study, done in mouse models of metastatic melanoma that had spread to the brain, has important clinical implications, as the method could boost the cancer-killing power of experimental immunotherapies being tested now in various cancers, including deadly glioblastoma and metastatic melanoma, both of which are very difficult to treat successfully.

Study senior author Dr. Robert Prins, an associate professor of neurosurgery and a Jonsson Cancer Center scientist, said the killer T cells also were better able to recognize and traffic to the cancer, which is crucial as the immune system often fails to identify malignant cells as invading enemies.

The study is published in the May issue of the peer-reviewed the Journal of Immunology.

The process Prins and his team used sought to mimic the way the T cells in the immune system recognize and fight viruses in the body, stimulating what is called the innate immune system. The innate immune system is comprised of cells that immediately defend the body from infection and frequently is not stimulated in the presence of cancer, Prins said. However, the innate immune cells can be tricked into thinking a virus is present by treating with compounds that activate Toll-like receptors (TLR).

Prins' group had previously demonstrated that TLR agonists, such as imiquimod, could synergize with dendritic cell vaccines, both in mouse models and patient clinical trials. Interleukin 12 (IL-12) is one of the predominant cytokines released when TLR are activated. In this study, they wanted to see how IL-12 would affect the CD8 T cells.

Graduate student Dominique Lisiero, first author of the study, said CD8 T cells come in a large variety of "flavors" and can be stimulated in differing ways. However, what signals and which stimuli work best to prime the cells to fight cancer was unclear. Lisiero added IL-12 to the CD8 T cells in culture, before the cells were transferred into mice with established brain tumors.

"We wanted to see if we could make these cells become better at either recognizing the tumor or killing tumor cells," she said. "We didn't know what expect, but what we found was that when we programmed these cells in the presence of IL-12, we saw that the tumors decreased in size and the mice with brain metastases survived longer. In fact, Prins said that the mice treated with killer T cells primed in the presence of IL-12 lived about 2.5 times longer than those not receiving the IL-12.


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To better understand the mechanisms by which priming killer T cells in the presence of IL-12 really enhanced their function, the team focused on how these T cells responded to a different cytokine, Interleukin 2 (IL-2). IL-2, which is instrumental for the body's natural response to infection and recognition of foreign invaders, often is included in adoptive transfer immunotherapies to help the T cells survive, but it has to be given in high doses that frequently cause significant toxicity to patients. Prins and Lisiero wanted to know if adding IL-12 would enhance the sensitivity of IL-2 signaling inside the T cells.

"T cells that were primed in the presence of IL-12 had a higher expression of the IL-2 receptor, meaning the T cells had an enhanced ability to respond to the IL-2. This, we believe, allowed the killer T cells to expand and survive after being transferred into mice with brain tumors. " Lisiero said. "Because the IL-12 stimulates the IL-2 receptor, we can give much lower doses of IL-2 and still get the same anti-tumor function from the killer T cells. In patients, this may translate to reduced toxicity. Clinical trials, however, would be required to prove that this priming with IL-12 would have similar effects."

Lisiero also tested the new process on human T cells, culturing them in either IL-2 or IL-12, and studying their function in the lab. The function of the cells programmed in IL-12 was dramatically increased, Prins said, validating the work in the mouse models. Their findings are already influencing how T cells are grown in the lab, he said.

The findings also are translational to the clinic, since metastatic melanoma patients in clinical trials often are removed from the protocol when the cancer appears in their brain. Many oncologists and scientists still believe that T cells can't access the brain because of its immune privilege. This study, however, has proven in a pre-clinical model that these tumors in the brain can in fact be effectively targeted.

"The in vitro priming of mouse tumor-specific CD8 T cells in the presence of IL-12 induced a diverse and rapid anti-tumor effector activity while still promoting the generation of memory cells," the study states. "Importantly, the IL-12-primed effector T cells dramatically reduced the growth of well-established tumors and significantly increased survival to highly immune resistant, established intracranial tumors."

The study was funded by the National Institutes of Health, the Philip R. and Kenneth A. Jonsson Foundations and STOP Cancer.

Source:
UCLA's Jonsson Comprehensive Cancer Center


In my studies, If naive T-Cells differentiate in the presence of IL-12,(secreted from dendritic cells and Macrophage, the cells differentiate into the TH1 phenotype).












“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

Understanding cancer immunotherapy..Melanoma ..Jim Breitfeller

Understanding cancer immunotherapy
By Dr. NG SOO CHIN

The basic premise of cancer immunotherapy involves enhancing the body’s own immune system to fight off cancer. It sounds logical and simple in concept, but the practice is complicated.

THE need for more effective and targeted therapy for cancer has always been in the minds of researchers and doctors who treat cancer. The traditional methods of treating cancer, ie surgery, radiation, and chemotherapy, have obvious limitations. Surgery would not be effective in disseminated or widespread diseases, while radiation and chemotherapy cause “collateral damage” due to effects on normal cells while killing off cancer cells. Certainly, a treatment modality utilising and enhancing our immune system to prevent or fight off cancer is a sound and attractive concept, hence the basic premise of cancer immunotherapy (CI).

The traditional methods of treating cancer, i.e surgery, radiation, and chemotherapy, have obvious limitations, hence the surge in interest in cancer immunotherapy. There is a general belief that failure of “immune surveillance” is a main contributory cause of cancer arising in an individual. There is also evidence that in many cancer patients, the immune system slows down the growth and spread of tumours. This means we need a competent immune system to prevent cancer, and to prevent it from spreading once cancer has started. The basis of CI, ie enhancing the body’s own immune system to fight off cancer, sounds logical and simple in concept. Unfortunately, like most things in life, the real scenario proves to be far more complicated, and the quest for effective cancer immunotherapy has taken a long time. But slowly and surely, we are unraveling the mysteries.

What are the ‘tools’ of CI?

To battle cancer cells with immunotherapy, we can either stimulate our immune system, or transfer antibodies or T cells from an outside source. Certainly, immunotherapy involving certain cytokines and antibodies has now become part of standard cancer treatment. Other examples of immunotherapy, especially those involving cellular therapy, remain largely experimental. Although many clinical trials of new forms of immunotherapy are in progress, an enormous amount of research and clinical trials need to be done before the findings can be widely applied.

What are the different types of CI available now?

The cytokines and monoclonal antibodies used are not called drugs or medication, but are labeled as biological immune response modulators (BIRMs), which include cytokines such as interferons, interleukins, colony-stimulating factors and monoclonal antibodies, plus cancer vaccines. We can further categorise them as below:

I. Immunostimulants

Immunostimulants are non-specific agents that tune-up the body’s immune defences. There have been some success with interleukin-2 (IL-2), a potent growth factor for T cells, which have been used in kidney and malignant melanoma, while alpha-interferon (IFN) are used for the treatment of chronic myeloid leukaemia and hairy cell leukaemia.

II. Monoclonal antibodies

Monoclonal antibodies are identical because they are produced by one type of immune cell – all clones of a single parent cell. Currently, most of the antibodies used are produced by recombinant DNA technology. The basis of monoclonal therapy is that different tumours have unique tumour antigens on their surfaces, and the identification of such antigens, such as CD20 on lymphoma cells, and the production of anti-CD20 antibody, ie rituximab, enables a targeted hit on the tumours. This will result in selective killing of lymphoma cells. Indeed, the advent of rituximab has changed the landscape of lymphoma treatment, with improvement in response and survival of patients. Similarly, other monoclonal antibodies such as herceptin (breast cancer), bevacizumab (lung cancer), and alemtuzumab (chronic lymphocytic leukaemia) are making waves in cancer treatment.

III. Immunotoxins and radioimmunotherapy

Monoclonal antibodies can be modified for delivery through toxin, radioisotope, cytokine or other active conjugates. Many such conjugates have been tried with some success. Mylotarg was licensed by the US Food and Drug Administration (FDA) for treatment of acute myeloid leukaemia (AML). Myelotarg is a combination of anti-CD33 and calicheamicin (a cytotoxic compound). However, it was recently withdrawn from the market due to potential severe liver damage. Monoclonal antibodies against tumour antigens can also be coupled to radioactive atoms. The goal with these agents is to limit the destructive power of radiation to those cells (cancerous) that have been “tagged” by the attached monoclonal antibody. Zevalin is a monoclonal antibody against the CD20 molecule on B cells (and lymphomas) conjugated to the radioactive isotope yttrium-90 (90Y). The results in treating B cell lymphoma with radioimmunotherapy are encouraging, though the delivery of such an agent is somewhat cumbersome.

IV. CI with T Cells (allografts or autografts of T cells)

T lymphocytes such as cytotoxic T lymphocytes (CTL) are capable of killing target or tumour cells. How to prime them to act appropriately, ie to kill tumour cells and not other normal cells, remains the challenge. The main reason why allogeneic bone marrow transplants (allografts) work is because of the the post transplant continual attacks on the tumour cells by T cells (graft versus tumour effect) seen in many patients. However the accompanying graft versus host reaction can be severe enough to result in significant mortality and morbidity to the transplant recipient. The same effect of such immunological attacks on tumour cells can be harnessed by donor lymphocyte infusion. This is a double edged sword and needs to be used with extreme caution. Infusion of own or autologous T cells or genetically modified T cells have been attempted with limited success.

V. Cancer vaccines

The response of the patient’s own immune system – immune surveillance – has clearly failed in cancer patients. The purpose of cancer vaccines is to elicit a more powerful active immunity in the patient. Several approaches are being explored. The name “cancer vaccines” is somewhat misleading, as these vaccines are developed to cure cancer and not to prevent it. Dendritic cells (DC) are the most potent antigen-presenting cells. They engulf antigens, process them into peptides, and “present” them to T cells. The making of the vaccine entails, firstly, harvesting DC from patients and exposing them to tumour specific antigens. By injecting the “stimulated” DC back to the body, they may be able to elicit a strong immune response and attack the tumour, utilising the stimulated cytotoxic T lymphocytes. On April 29, 2010, the FDA approved the first anti-cancer vaccine, a patient-specific dendritic cell vaccine for use against advanced prostate cancer. Tumour-antigen specific vaccines are used to immunise the patient with an antigen universally expressed by tumours of that type (but not by normal cells), mixed with some form of adjuvant that will enhance the response. Unlike patient-specific vaccines, these vaccines can be mass-produced for use in anyone with the appropriate tumour.

What are the strengths of immunotherapy?

The most appealling point of CI is that potentially, this is a targeted therapy, and hence the side effects to normal cells would be considerably less. Some chronic myeloid leukaemia patients with relapsed disease post-bone marrow transplant managed to attain long term survival after donor lymphocyte infusion. CI is a very powerful tool indeed, if only we know how to apply it optimally, but we are still grappling how best to titrate the graft versus leukaemia response. Because the side effects are different from conventional chemotherapy, the combination of cytotoxics and immunotherapeutic agents such as rituximab has improved the outcome in lymphoma patients without additional side effects. Because of the favourable safety profile, CI can be given in repeated courses, unlike cytotoxics, which are limited by their cumulative toxicities.

What are the weaknesses or problems of immunotherapy?

The main problem is likely to be the need for time for the immune system to respond to CI, and in some patients with cancer which behaves like a runaway train, eg Burkitt’s lymphoma, time is what the patients do not have. CI is unlikely to work in a large volume tumour, and the tumour needs to be debulked (reduced in size) before CI has a chance to work. CI is costly, and the price is not likely to go down in the near future. Monoclonal antibodies are fabulously expensive. This is even so for a personalised vaccine. For patients who have financial constraints, money is not everything – it is the only thing! Hence, it is likely that such treatment may not be available to those who need it, unless some assistance programme is forthcoming. It is unlikely that CI alone can cure a cancer in the setting of cancer patients whose immune systems have failed them in the first place. We need to learn and strategise how to put different treatment modalities, ie chemotherapy, CI, radiotherapy, in a winning treatment combination. The answer can only come with more painstaking research and careful clinical trials.

Is immunotherapy devoid of side effects?

A resounding NO. Any form of treatment can potentially give rise to side effects. Even taking paracetamol can cause severe allergic reactions, although rarely. Rituximab commonly gives rise to infusion reactions, which are manageable. In 2006, in one of the phase 1 trials of a T cell stimulatory monoclonal antibody called TGN1412 in England, all six of the volunteers were nearly killed, and ended up with multiple organ damage due to unrestrained generalised T cell stimulation. So forget about the no side effects talk. I believe the side effects of immunotherapy are different from conventional treatment like chemotherapy, and we have to learn about them (both short term and long term), and deal with them accordingly. For instance, we now know that the use of chemo-immunotherapy in treating non-Hodgkin’s lymphoma can cause potentially fatal hepatitis B virus activation. This problem is prevented by concurrent antiviral therapy. How does CI fit into a patient’s treatment plan? Can a patient ask for immunotherapy first before following established treatment or can CI be the sole form of treatment? I feel the best person to answer the question is the oncologist/haematologist who is looking after the patient. CI with monoclonal antibodies can be used in induction (initial treatment) or to consolidate the treatment, and in some instances, to remove any minimal residual disease. Cell-based immunotherapy remains experimental and is likely to be offered in a setting of clinical trials. Very rarely is CI used as the sole form of therapy. I honestly feel that clinicians should make the decision. Using inappropriate therapy results in loss of valuable time in tackling the cancer, not to mention the accompanying financial toxicity!

What are the basic questions to ask when one checks out immunotherapy?

The patient really needs to know what he or she is in for. Is the centre a reputable one, and is the treatment approved by authorities such as the FDA or EU (European Union)? Is the treatment potentially curative or merely palliative? Are there other treatment options which may work just as well? What does the procedure entail and what are the potential side effects? The patient, together with the attending doctor, should weigh the benefit versus risk equation, and also the cost effectiveness of the planned treatment. In other words, one should go into any treatment only with eyes widely open. When a treatment sounds too good to be true, it usually is.

Is CI ready for prime time?

It is important to keep our feet firmly on the ground and not be taken by sales propaganda. In some forms of CI, such as monoclonal antibodies treatment, many lives are prolonged and saved, and monoclonal antibodies is now an established treatment modality. We need to tread far more carefully in cell based therapy. To date, the FDA has only approved one, and only one, cancer treatment vaccine, i.e. Provenge (sipuleucel-T). The vaccine is designed for men with advanced prostate cancer who have limited treatment options. Patients will have immune cells purified from their blood, and then combined with a specific protein (an antigen) that stimulates the immune cells to recognise and kill prostate cancer cells. The custom created vaccine is given intravenously in three doses, two weeks apart. Potential reactions include fever and flu-like symptoms. Before we get carried away, the new treatment resulted in a very modest 4.1 month improvement in median survival compared to the placebo group.

Why the surge in interest in CI?

According to the American Cancer Society, immunotherapy, especially cancer vaccines, is still a small field which hasn’t yet proven itself to be better than other types of cancer treatments. However, it’s one that researchers say holds a lot of promise and “many future advances against cancer will probably come from this field”. Interestingly, Time magazine voted in two cancer researchers, Dr Larry Kwak and Dr Doug Schwartzentruber, for its 2010 list of 100 most influential people in the world. Both of them are in the forefront of cancer vaccine research. Dr Kwak is involved in BiovaxID patient-specific vaccine for follicular lymphoma while Dr Schwartzentruber is researching a melanoma vaccine. Both vaccines had good phase 3 trial results and may make their way to bedside use soon. Is there a need for regulation of CI in Malaysia? The answer has to be yes. Unfortunately, we have no shortage of entrepreneurs, and for new therapies, whether it’s stem cell based or cell based, medical supervision is necessary to protect our patients. We don’t want to make news for the wrong reasons. At the end of the day, we should heed Hippocrates’ wise words – to cure sometimes, to comfort always, and not to cause any harm to our patients. This article is contributed by The Star Health & Ageing Panel, which comprises a group of panellists who are not just opinion leaders in their respective fields of medical expertise, but have wide experience in medical health education for the public.

The members of the panel include:

Datuk Prof Dr Tan Hui Meng, consultant urologist; Dr Yap Piang Kian, consultant endocrinologist; Datuk Dr Azhari Rosman, consultant cardiologist; A/Prof Dr Philip Poi, consultant geriatrician; Dr Hew Fen Lee, consultant endocrinologist; Prof Dr Low Wah Yun, psychologist; Datuk Dr Nor Ashikin Mokhtar, consultant obstetrician and gynaecologist; Dr Lee Moon Keen, consultant neurologist; Dr Ting Hoon Chin, consultant dermatologist; Prof Khoo Ee Ming, primary care physician; Dr Ng Soo Chin, consultant haematologist.

For more information, e-mail starhealth@thestar.com.my. The Star Health & Ageing Advisory Panel provides this information for educational and communication purposes only and it should not be construed as personal medical advice. Information published in this article is not intended to replace, supplant or augment a consultation with a health professional regarding the reader’s own medical care. The Star Health & Ageing Advisory Panel disclaims any and all liability for injury or other damages that could result from use of the information obtained from this article.

Source: http://thestar.com.my/health/story.asp?file=/2011/4/3/health/8389839&sec=health

“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

“Schedule and Dose for Combination Therapy,” Melanoma.. 2011 Scientific Colloquium of the Cancer Immunotherapy

“Schedule and Dose for Combination Therapy,”
2011 Scientific Colloquium of the Cancer Immunotherapy Consortium
• Thursday, March 17, 2011 7:00 AM - Saturday, March 19, 2011 1:30 PM
Eastern Time


First Speaker: Dr. Rafi Ahmed
Director of the Emory Vaccine Center

"As a basic immunologist, EVC Director Dr. Rafi Ahmed studies immunological memory – the ability of the immune system to “remember” a particular antigen and respond accordingly. Dr. Ahmed and his colleagues have made significant discoveries about how immune memory cells are created and how long they survive; understanding these mechanisms is crucial to the development of vaccines for HIV and other infectious agents. In addition to contributing vitally to vaccine science, Dr. Ahmed’s findings are being applied to research into therapies for the treatment of cancer and the prevention of organ rejection."




Dr. Rafi Ahmed is now being introduced by Johannes Vieweg, & highlighting his work on immunological memory

Dr. Ahmed is sharing how lessons from immune memory development in chronic viral infection can inform cancer immunotherapy field

Ahmed: wait 30-60 days to boost in vaccination produces better immune responses for many types of viral vaccines. Same for cancer?JimmyB :Why 30 to 60 days? Because this is the time factor that it takes for the CD4+ and CD8+ T-cells to grow and differentiate into effector T-cells. (See Graph)




Fig-1

Dr. Rafi Ahmed is now being introduced by Johannes Vieweg, & highlighting his work on immunological memory Dr. Ahmed is sharing how lessons from immune memory development in chronic viral infection can inform cancer immunotherapy field Ahmed: wait 30-60 days to boost in vaccination produces better immune responses for many types of viral vaccines. Same for cancer?
Fig-2

Ahmed: Synergy we've seen combining PD-1 with IL-2 (negative + positive signal) in viral infection therapy have been astonishing.

Jimmy B:Imagine if you combine CTLA-4 + PD-1 and IL-2. The Holy Grail of Immuno therapy I believe.Ahmed raises point that mTOR inhibition may enhance vaccine-induced memory CD8 T-cells. Role for combining with cancer vaccines?

Much audience Q&A for Dr. Ahmed - when see exhaustion clinically, is it inhibition, effect of dose of IL-2, and role of autophagy?

Source: Cancer Research on Twitter

http://twitter.com/#!/search?q=%23cic11












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

Jimmy B

The Accelerator..IL-2 Therapy..Melanoma Cancer..Jim Breitfeller

The Food and Drug Administration this year approved a “cancer vaccine” for prostate cancer called Provenge, so-called because it trains the immune system to attack the patient’s tumors. Most such vaccines focus on a single type of cancer, or are even tailored to individual patients.

Ipilimumab, by contrast, is a more general immune booster. It blocks a protein called CTLA-4 that acts as a brake on T cells, the soldiers of the immune system. It is already also being tested against lung and prostate cancer.

Still, if a tumor does not elicit a strong immune response to begin with, then just keeping the response going longer would not help much, just as lifting one’s foot from the brake usually will not make a car go faster if the accelerator is not pressed. The accelerator needed is Interluekin-2 (IL-2.

IL-2 induces inflammation at tumor sites(Danger Signal) with three predominant secondary effects:

1)activation of antigen-presenting monocytes.

2) massive production of chemoattractants that may recruit other immune cells to the tumors.

3) activation of cytolytic mechanisms in monocytes (calgranulin, grancalcin) and NK cells NKG5, NK4.

The take away; systemic combinatorial therapy is one of the best ways to utilize the immune system to induce an immune response to Melanoma Cancer.





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

Take Care,

Jimmy B

The Future of Immunotherapy.. Emerging concepts in biomarker discovery.Melanoma.Jim Breitfeller

Emerging concepts in biomarker discovery!!!!!2009

Take away: Get your blood and tumors profiled for Biomarkers. It could lead you to the right therapy to do.

A table of:
Emerging biomarkers potentially useful for the immunotherapy of cancer.

A Table of:
Emerging biomarkers potentially useful for the immunotherapy of cancer.



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



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



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

Dr. Kirkwood talks about autoimmunity through out the presentation
NIH Scientists Discover Secrets Of Helper T Cells Involved In
Autoimmunity.... Th17 cells!!!!!!









“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

Questions and Answers from Jim In Denver Co..Melanoma..Jim Breitfeller

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, monkeys.



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

Results: Graph setup

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+
T cells, 49 days 17% CD8+
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)

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

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

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.

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 tumor-specific antigen to presented to the T-cells as signal 1. That could be a vaccine, radiation therapy or chemo to shed the antigen.
Secondly you need the costimulation of the CD28/B7 interface. 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