Targeted therapy for metastatic melanoma: From bench to bedside..Jim Breitfeller

Targeted therapy for metastatic melanoma: From bench to bedside
Author: Wen-Jen Hwu, MD, PhD

Malignant melanoma is well known for its aggressive clinical behavior, propensity for lethal metastasis and therapeutic resistance. However, in the last decade, considerable excitement has been generated by the identification of genetic mutations in various components of signaling pathways involving melanoma initiation and progression, particularly those involved in the MAP and PI3 pathways. Most recently, clinical trials of pharmacological targeting of relevant molecular targets have demonstrated dramatic response even in patients with late-stage melanoma.

The emerging insights into the mechanisms of activation and negative regulation of innate and adaptive immunity to tumors have provided another breakthrough in melanoma therapy. A new family of immune-based agents of monoclonal antibodies that exert their functions by tampering with immune system cell molecules causing an enhancement of antitumor immune responses has entered clinical trials. In general, these new antitumor agents are designed to break down the barriers to tumor tolerance/immunity. This new group of agents holds promise for at least additive effects with conventional therapies, as well as signal transduction pathway targeted therapies.

Targeting signal transduction pathways

Several key genetic lesions governing melanoma initiation and progression have been identified, the earliest and most common being a point mutation (T1799A) in the BRAF proto-oncogene, which is detected in approximately 60% of metastatic melanoma. BRAFT1799A encodes BRAFV600E, a constitutively active protein serine kinase that elicits sustained activation of the BRAF® MEK1/2® ERK1/2 MAP kinase pathway.

In addition to BRAF, RAS oncogene (rat sarcoma viral oncogene homolog) is another constituent of the MAP kinase pathway. RAS mutations (in one of three isoforms) are found in approximately 20% of metastatic melanoma. RAS is capable of turning on several downstream pathways, including BRAF and other components of MAP kinase pathways, the PI3 kinase pathway, and the RAL-GDS pathway. In general, if a RAS mutation is present, there will be no BRAF mutation. However, the combination of mutated BRAF and silencing of PTEN expression is common in human melanoma (~20%). Dankort and colleagues have demonstrated in a preclinical model that “BRAFV600E cooperates with PTEN loss to induce metastatic melanoma.”

The prevalence of RAS/RAF alterations in human cancer has prompted significant efforts in the development of drugs targeting the MAP kinase pathway. Many of these are currently in clinical trials in patients with metastatic melanoma. Studies with the broad spectrum RAF inhibitor sorafenib (Nexavar, Bayer) as a single agent in patients with BRAF mutated melanoma have proved disappointing. What was unclear from these studies was whether the lack of efficacy was because BRAF was not a critical target or because of incomplete blocking of BRAF by sorafenib.

Since 2005, several BRAF inhibitors have entered clinical trials. These inhibitors are grouped in two categories: BRAF selective inhibitors, and broad spectrum multiple kinases inhibitors with high potency against BRAF.

BRAF inhibitors

PLX4032 (Plexxikon, also known as RO5185426) is a selective BRAF inhibitor and is the first of its kind tested in advanced melanoma. A response rate of 70% in 32 BRAF mutated melanoma patients was reported in the phase 2 study. In general, PLX4032 is well tolerated and most common toxicities include mild-to-moderate skin rash, sun sensitivity, fatigue, arthralgia and keratoacanthoma. Currently, there are two ongoing PLX4032 trials.


Wen-Jen Hwu

The first is a phase 2 study of PLX4032 as a single agent in BRAF mutated melanoma patients who have failed standard therapy for metastatic disease. This study will hopefully confirm the high response rates observed in previous phase 1/2 studies. The second is a phase 3 trial comparing PLX4032 with dacarbazine (standard chemotherapy) in chemotherapy-naive patients with BRAF mutated metastatic melanoma. Seven hundred patients will be enrolled; the primary endpoint is OS.

Another BRAF selective inhibitor is GSK2118436 (GlaxoSmithKline). This drug has already shown promising antitumor activity in the phase 1 portion of a study. The phase 2 portion is ongoing. The impressive high level of antitumor activity of BRAF selective inhibitors indicates that both PLX4032 and GSK2118436 have single-agent activity; BRAF is an important target in melanoma.

Currently, there are at least two nonselective BRAF inhibitors. XL281 (Bristol-Myers Squibb) and RAF265 (Novartis) are in phase 1 testing. Results are expected in the near future.

MEK is a kinase and is immediately downstream of BRAF. It is never mutated in cancer but is activated by BRAF and, in turn, activates the rest of the MAP kinase pathway. In the laboratory, MEK inhibitors have shown activity in a number of BRAF mutated cancers. Currently, there are many MEK inhibitors in clinical trials.

AZD6244 (AstraZeneca) is a MEK inhibitor that has been evaluated most extensively in melanoma. A phase 2 study comparing AZD6244 with temozolomide (oral chemotherapy) has found an objective response rate of 12% among 45 BRAF-mutated patients. However, patients in this study who received temozolomide had a similar response rate and PFS.

Melanomas from acral lentiginous, mucosal and chronic sun-damaged sites frequently harbor activating mutations and/or increased copy number in the KIT tyrosine kinase receptor gene, which are very rare in more common cutaneous melanomas. Multiple case reports and early observations from clinical trials suggested that targeting mutant KIT with small molecule KIT inhibitors such as imatinib (Gleevec, Novartis) and/or dasatinib (Sprycel, BristolMyersSquibb) is efficacious.

Although the dramatic clinical activity of BRAF selective inhibitors is a major breakthrough in the treatment of this disease, there are many hurdles to overcome to optimize this targeted therapy approach. Many of the patients who initially responded to PLX4032 have subsequently progressed with a median duration of response of approximately 8 months. The mechanisms that cause resistance are largely unknown.

Recently, a number of preclinical studies have demonstrated that BRAF inhibitors activate MEK and MAP kinases in melanoma cell lines with wild-type BRAF, including cell lines with mutant NRAS. These studies suggest at least one potential mechanism of resistance is through continued activation of the RAS-RAF-MEK-ERK signaling pathway. Thus, combination agents that target multiple components of this pathway have great potential to overcome drug resistance. Several ongoing clinical trials using the combination of BRAF and MEK targeted agents will be able to test this hypothesis.

Targeting tumor immunity barriers

Since the discovery of monoclonal antibodies in the late 1970s, it has become clear that these antibodies, which are of defined specificity and can be produced in large amounts, had potential for the management of various diseases, including malignancies.

The key property of antibodies to be used as therapeutic tools is their behavior as high-avidity ligands to protein or glycoprotein. Most recently, a new group of monoclonal antibodies that enhance the cellular immune response against cancer have entered clinical trials. These agents bind molecules on the surface of immune system cells. They either provide activating signals to lymphocytes and antigen presenting cells or block the action of receptors that normally down-regulate the immune response.

A humanized monoclonal antibodies (MDX-010, Medarex) against cytotoxic T-lymphocyte antigen 4 (CTLA-4) is the first to reach clinical trials. CTLA-4 is only expressed on the cell surface of activated T cells and regulatory CD4+ CD25+ T cells. In murine models, systemic treatment with transplantable immunogenic colon carcinoma cells with anti-CTLA-4 monoclonal antibodies induced complete tumor regression of established tumors through an immune response found to be critically dependent on the activity of cytotoxic T lymphocytes.

Various phase clinical studies have been conducted on the two anti-CTLA-4 monoclonal antibodies, ipilimumab (Bristol-Myers Squibb) and tremilimumab (Pfizer), as monotherpy, in combination with vaccines or other immunotherapies, and in combination with chemotherapies. Blockade by the T-cell inhibitory molecule CTLA-4 results in antitumor response with overall response rates from 10% to 20%. Most adverse events involve autoimmune toxicities, such as dermatitis, uveitis, colitis/enterocolitis, hepatitis and hypophysitis.

4-1BB (CD137) is a surface glycoprotein that belongs to the TNF receptor family. It is expressed by activated, but not resting, T and NK cells. A humanized anti-4-1BB monoclonal antibody (Bristol-Myers Squibb) has been tested in clinical trials. However, the phase 2 study in refractory melanoma was discontinued in May 2009 due to unusually high incidence of grade-4 hepatitis.

Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance and immunopathology. In vivo studies have shown B7-1 (CD80) is also a binding partner for PD-L1, and their interactions can lead to bidirectional inhibitory response in T cells.

PD-L1 is expressed on many tumors including melanoma and is a component of the immune suppression by the tumor microenvironment. Phase 1/2 experience of the anti-PD-1 monoclonal antibody, MDX-1106 (Medarex, Ono-4538), in refractory or relapsed malignancies was presented at the 2009 ASCO Annual Meeting. Clinical activity against melanoma was observed and, more importantly, no MDX-1106 related severe adverse events were noted.

In 2009, at M.D. Anderson Cancer Center, we participated in a phase 1 study of anti-PD-L1 monoclonal antibody (MDX-1105, Medarex) in refractory metastatic melanoma. MDX-1105 has been tolerated by all patients. Most adverse events were mild and were related to inflammatory responses in the tumors, not immune-related toxicity. Clinical responses were observed at all dose levels (1 mg/kg to 10 mg/kg every 2 weeks). Durable partial responses and stable disease were noted in patients whose disease had progressed after at least one, and as many as five, prior systemic therapies. Based on the low toxicity and impressive clinical activity, a phase 2 study of MDX-1105 in advanced melanoma is warranted.

In summary, the treatment of metastatic melanoma is changing rapidly due to the great success in translational research from bench to bedside. Although such studies, to date, have focused on the treatment of advanced metastatic disease, the approaches of targeting signal transduction pathway, as well as targeting tumor immunity barrier, hold great promise to the development of preventive strategies and personalized therapies in malignant melanoma.

Wen-Jen Hwu, MD, PhD, is a professor in the department of melanoma medical oncology at The University of Texas M.D. Anderson Cancer Center and is a member of the HemOnc Today Editorial Board.

Source:http://www.hemonctoday.com/article.aspx?rid=65856


“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

Effective Immunotherapy for Patients with Metastatic Melanoma..Jim Breitfeller

Steven A. Rosenberg, MD, PhD
Chief of Surgery, National Cancer Institute
National Institutes of Health, Bethesda, MD

Immunotherapy has emerged as the most effective treatment for patients with metastatic melanoma. Much of the information concerning the immune response to melanoma has come from the study of tumor-infiltrating lymphocytes (TIL), immune cells that infiltrate into the stroma of the growing tumor and can be grown in vitro in the cytokine IL-2.1 TIL have been used to identify dozens of antigens that are presented on melanomas.2 Some antigens such as MART-1 and gp100 are shared by both melanomas and normal melanocytes, whereas others, such as NY-ESO-1, can be expressed on melanomas, but on no other adult tissue except the testes.

Most studies of immunotherapy for melanoma patients have been directed at those with metastatic disease. Although multiple trials of cancer vaccines have been performed in patients with resected lymph nodes at high risk of recurrence, none of these clinical trials have convincingly demonstrated prolonged survival.3 Some controversy exists surrounding the use of interferon alpha for the treatment of stage 3 melanoma; prolonged follow-up of patients in prospective randomized trials has yielded ambiguous results, and many oncologists are concluding that the toxicities of highdose interferon are not warranted given the lack of conclusive evidence of effectiveness in this setting.

Substantial progress has been made, however, in the treatment of patients with metastatic melanoma. It is now possible to cause complete regressions of widely metastatic melanoma at multiple sites in the body utilizing immunotherapy approaches. Immunotherapy Approaches To Metastatic Melanoma Approaches to the treatment of patients with metastatic melanoma fall into three major categories, which are summarized in Table 1 at Effective Immunotherapy for Patients with Metastatic Melanoma


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~

Immune System, White Blood Cells, T-Cells, Cancer Cells..Melanoma Jim Breitfeller

How cells activate and produce immune response .

Search for a Cancer Vaccine Beginning to Show Promise..Melanoma ..Jim Breitfeller

Search for a Cancer Vaccine Beginning to Show Promise

As Reported by TIME. 2009 Sept 14

The search for an effective cancer vaccine has been elusive until now, but positive results for separate vaccines against melanoma and lymphoma were finally reported this past June. Although the theory behind a cancer vaccine seems logical—enlist the immune system to seek and destroy cancer cells—it also contains an inherent problem, specifically, that cancer cells aren’t foreign pathogens, such as bacteria or viruses, but cells from a person’s own body. Getting a vaccine to work against cancer requires a deep understanding of how the immune system works and how malignant cells evade detection. A feature article in the September 14 issue of TIME, written by Alice Park, explains the quest thus far for cancer vaccines.

Defining a cancer vaccine

The Food and Drug Administration has approved vaccines against cervical cancer and liver cancer, but both of these diseases are caused by a virus (human papillomavirus and hepatitis B virus, respectively). Thus, the vaccines are actually targeting the virus. Nonviral cancers attributed to genetic mutations, environmental exposures, and other factors would require a vaccine that can accomplish primary prevention or prevention of recurrence. Such vaccines would need to prime the immune system to find every last cancer cell.

Cancer vaccines that didn’t work, but might

A vaccine for melanoma seemed on the horizon when researchers used extracts of melanoma tumors in developing Canvaxin. More than 1500 patients received the vaccine following treatment with surgery and chemotherapy, but the study was terminated after interim analysis showed that survival was no better for the vaccinated patients than for the nonvaccinated patients. Addition of interleukin-2, however, improved the rate of tumor shrinkage. Researchers working on a vaccine for follicular lymphoma took the combination approach one step further, by adding GM-CSF to a vaccine developed from each patient’s cancer cells. This combination extended disease-free survival by 47% over that achieved by patients who received a nonindividualized vaccine. Experience with this vaccine also indicated that the best time to administer the vaccine was when patients were in remission.

Creating a “foreign” tumor

Various strategies to manipulate a tumor to cause it to become more “foreign” are being investigated. One technique is to make the tumor look like a virus to the immune system. Another is to inhibit immune suppressors that tumors secrete. Along the lines of the bone marrow transplantation approach, some studies have used in vitro techniques to develop immune system cells, taken from the cancer patient, that will target those specific cancer cells; the newly sensitized immune cells are then reinfused back into the patient. In melanoma, this approach has caused 70% of tumors to regress.

The final analysis

Regardless of how effectively a vaccine causes tumor regression, patients and their physicians are most interested in its effect on survival. Also important is how use of a vaccine compares with the targeted therapies that have been developed. For cancer to become a truly chronic condition, manageable over the long term, a vaccine or treatment must be safe. Vaccines, as it turns out, are generally less toxic than chemotherapy or targeted agents. Immune-based treatments for cancer are still in their infancy, but if they are ultimately proven successful, their development would be well worth the effort.

Source:http://www.oncologystat.com/news-and-viewpoints/what_patients_are_reading/Search_for_a_Cancer_Vaccine_Beginning_to_Show_Promise.html

My take:Creating a “foreign” tumor

If you can get the tumor to shed antigenic peptide and then activate the T-cells using anti-CTLA-4 Blockage, I believe you will see the Melanoma survival rate expand and that Melanoma will become just a "chronic condition,manageable over the long term."






Take Care,

Jimmy B

As I Continue my Quest, I have come to another Windmill..Melanoma..Jim Breitfeller

As I Continue my Quest, I have come to another Windmill.

Anti-CTLA-4 Blockage maybe coming back to compassionate care or better yet,may be getting ready to seek FDA approval.

I have stumble upon another Review Article by Dr. Kim Margolin from 2008.

"Moving forward with immunotherapy: the rationale for anti-CTLA-4 therapy in melanoma."

Source:http://www.communityoncology.net/journal/articles/0507367.pdf
Moving forward with immunotherapy: the rationale for anti-CTLA-4 therapy in melanoma

If you look closely at the tables, you know why Brisol-Meyer Squibb aquired Medarex for their "String of Pearls".

This is the quote I like the Best:

"The preliminary results of these trials are encouraging, considering most patients were previously treated for advanced melanoma. The possibility that anti-CTLA-4 antibodies, used as single agents, will be superior to proven therapies, ie, dacarbazine or IL-2, will be tested in phase III trials. Of greater promise may be the combination of these agents in carefully timed sequence with cytotoxic or other immunotherapeutic strategies."

See , I believe that the combination therapies Hold the greatest Promise.
I can vouch for that. NED FOR OVER 25 MONTHS AND STILL COUNTING!!!!!

Please seek out this therapy if you need it. It could extend or even save your life.



Take Care,

Jimmy B

Is Triple Therapy more effective than Single Agent Therapy? Melanoma..Jim Breitfeller

Is Triple Therapy more effective than Single Agent Therapy?

Base on my knowledge there are at least five things you need to accomplish before an immune response can be generated:

1. You need the correct antigen to be presented by the (APC) Antigen presenting cell at the TCR T Cell receptor
2. You need to Activate the CD-4 + T-cell
3. You need to co-stimulate the CD28 receptor
4. You need to suppress the Treg cells
5. You need to a growth factor (IL-2) to grow your army of Cytotoxic Cells

Once activated, you need all the players to help orchestrate the immune response. This can not be done by single agent alone. The immune response has checks and balances that it must pass through. It is like opening a deposit box at the bank. You need the master key to open the first gate. Then you need two different keys to gain access to the deposit box. Plus there is a sequence of events that must be followed to gain access. If you only have one key, you will fail to open the box.

Each Drug company has a key to solving the problem. In order to get the tumor specific response the drug companies must work together.




Take Care,

Jimmy B

I am Not going to tender my Shares of Medarex to Bristol Meyer Squibb. Melanoma..Jim Breitfeller

I am Not going to Tender my Shares of Medarex to Bristol-Meyer Squibb. BMY low balled the tender and Medarex would be better off as a separate company. Here why.

Therapeutic Monoclonal Antibody Production Is More Profitable Than Small Molecule Drugs

New study has suggested that therapeutics based on monoclonal antibodies (mAbs) are fare more likely to be commercially successful than their small molecule predecessors. According to a study completed by // consultancy Propagate Pharma, about half the mAbs launched so fare appear to be profitable. That means mAbs are recouping more in revenues than their estimated $1 billion to $1.8 billion cost of development and marketing. By comparison, the study estimates that only 30% of conventional small molecule drug launches ever recover their costs. Drug is likely to be profitable if peak revenues pass the $300 million mark. So far, of the 17 mAbs launched in the US, eight have achieved this benchmark. And of these, four have become blockbusters earning over a billion dollars a year.

Of 57 mAbs launched so far, 16 have become blockbusters, 14 have at least recouped their costs, and the other 27 are either question marks or failures. The high success rate of biotherapeutics is due to low levels of competition in the markets they address, says Jo Collett, author of the Propagate study. There are signs that the tail end of a biotherapeutics products life cycle might be more profitable than that of a small molecule drug. However, this high level of success may be difficult to sustain as competition increases, especially in the cancer market, says Propagate’s Collett. “It’s not going to be quite as easy as it was for the pioneers,” she prophesies.

There are more than 150 mAbs in development worldwide, over 100 of which are in phase 2 or phase 3 trials. Nearly 40% of these are in the oncology field; 18 are in development for breast cancer alone. Collett predicts that companies launching the next generation of mAb therapeutics will have to be more commercially acute with a better understanding of their products positioning that the pioneers of the field were. Although there is respectable data showing that obtaining regulatory approval tends to be easier for antibodies than for other drug classes, he warns it is too early to make firm predictions. “The mid and longer term future may look quite different in terms of competitive threats, so past performance is not necessarily a guide”.

Source: Nature Biotechnlogy.




Date:10/8/2005


http://www.bio-medicine.org/medicine-news/Therapeutic-Monoclonal-Antibody-Production-Is-More-Profitable-Than-Small-Molecule-Drugs-5161-2/



Take Care,

Jimmy B

Bristol-Meyer Squibb is Stealing the Pearl Necklace!!!Monoclonal Antibodies FDA approval over the last 10 years..Melanoma..Jim Breitfeller

Monoclonal antibodies used to treat cancer MAb Name
Trade Name
Used to Treat:
Approved in:

Rituximab
Rituxan
Non-Hodgkin lymphoma
1997

Trastuzumab
Herceptin
Breast cancer
1998

Gemtuzumab ozogamicin*
Mylotarg
Acute myelogenous leukemia (AML)
2000

Alemtuzumab
Campath
Chronic lymphocytic leukemia (CLL)
2001

Ibritumomab tiuxetan*
Zevalin
Non-Hodgkin lymphoma
2002

Tositumomab*
Bexxar
Non-Hodgkin lymphoma
2003

Cetuximab
Erbitux
Colorectal cancer
Head & neck cancers
2004
2006

Bevacizumab
Avastin
Colorectal cancer
Non-small cell lung cancer
Advanced breast cancer
2004
2006
2008

Panitumumab
Vectibix
Colorectal cancer
2006



*conjugated monoclonal antibodies

Two types of monoclonal antibodies are used in cancer treatments:

Naked monoclonal antibodies are those without any drug or radioactive material attached to them.
Conjugated monoclonal antibodies are those joined to a chemotherapy drug, radioactive particle, or a toxin (a substance that poisons cells).

http://www.cancer.org/docroot/ETO/conten...

Think what Our 40+ Antibodies in the pipeline of the Medarex Company are worth.

We have been sold out by Pien and Company!!!!

Bristol-Meyer Squibb is stealing the Pear Necklace from the Medarex Shareholders.

The Boards of Both Companies should be Investigated along with the CEO's

Take Care,

Jimmy B

Here is what Anti-CTLA-4 blockage can do!!!! Melanoma..Jim Breitfeller

Source:FORBES.COM

On The Cover/Top Stories

Targeting Melanoma

Robert Langreth 10.15.07, 12:00 AM ET

A new arsenal of therapies is aimed at a widespread and lethal skin cancer.




"Until recently researchers had little clue what molecular changes drive melanoma's rapid growth. But that has changed in a flurry of basic biology findings. "In terms of understanding what makes melanoma tick, in the past five years there has been an utter revolution," says Keith Flaherty, a physician at the University of Pennsylvania.

In 2002 gene researchers in the U.K. discovered that two-thirds of melanomas have a mutation in a growth-promoting gene inside skin cells called BRAF. The mutation causes the BRAF protein to become stuck in the "on" position, so it constantly sends a signal to the nucleus that it is time to proliferate. BRAF blockers are now in early-stage human trials at Novartis and separately at Roche, which works with partner Plexxikon. AstraZeneca is in midstage trials with 180 melanoma patients for a drug that hits a related target called mitogen-activated protein kinase kinase. "Every company I know of is interested in this," says Plexxikon Chief Executive Peter Hirth.

Therapies that trick the immune system into attacking melanoma are further along. Such immune system boosters have the potential to treat many types of cancer, but melanoma is one of the prime initial targets because it is one of the few cancers known to go into spontaneous remission on its own, indicating a possible immune response at work. The immune system activator interleukin-2 helps 15% of advanced melanoma cases and cures a few, but it produces such devastating side effects that patients must be hospitalized.

Pfizer's drug tremelimumab and Bristol-Myers Squibb's ipilimumab are antibodies to a protein called CTLA-4 (cytotoxic T-lymphocyte antigen-4) that acts as an emergency brake to prevent killer T cells from attacking healthy tissue. The antibodies bind to the CTLA-4, found on a cell's surface, and shut off the brake. Killer T cells then attack the cancer cells. Both drugs are in final-stage trials on hundreds of melanoma patients.

Much credit for the concept goes to immunologist James Allison, now at Sloan-Kettering. In the mid-1990s he theorized that CTLA-4 might prevent the immune system from mounting an effective response against tumors. Others were skeptical. But Allison showed in 1996 that he could shrink tumors in mice by injecting them with antibodies to CTLA-4.

Both Pfizer and Medarex, a biotech firm in Princeton, N.J., subsequently produced human antibodies to CTLA-4 and began testing them in patients a few years later. In 2005 Bristol-Myers Squibb paid Medarex $50 million in cash plus up to $480 in payments contingent on the success of Medarex's antibody.

At a meeting of cancer specialists last June Bristol-Myers and Medarex reported their drug shrank tumors in 46, or 13%, of 356 melanoma patients. The Pfizer antibody shrank melanomas in 7 of 84 patients in a midstage trial. The success rates were modest, but cancer doctors say that some patients may have had delayed responses. In some people tumors started to regress months after they had been declared treatment failures, says Bristol-Myers Vice President Renzo Canetta.

UCLA's Ribas calls the response rates "very low" and cautions that the anti-CTLA-4 drugs are just a first step. But even if the drugs improve survival only minimally, they are likely to be approved, he says. Bristol-Myers and Medarex are expected to finish key trials this fall. RBC Capital Markets analyst Jason Kantor pegged the odds of disappointing results "relatively high" in a recent report and rated Medarex an underperform; if the response rate is under 10%, it would make near-term approval "iffy", he says. Side effects of the drugs can include inflammation of the colon, thyroid or pancreas, or other autoimmune problems.

One reason for the limited response rate may be that some patients' T cells do a poor job of recognizing melanoma. To improve this situation, researchers are combining new antimelanoma vaccines with anti-CTLA-4 drugs. The idea is that the vaccines will train T cells to spot cancer, while the antibody will make sure the T cells remain activated long enough to do their dirty work.

Sharon Belvin was one of the first to try such a combination therapy. In May 2004, just a week before her wedding, she had developed a melanoma metastasis in her left lung. Belvin was only 22. The tumor grew through her chest cavity underneath her collarbone. Various chemo drugs and interleukin-2 produced nerve damage and other nasty side effects and didn't solve the problem. By June 2005 she had tumors in both lungs and could barely breathe or walk. Then Wolchok put her in a trial testing ipilimumab with an experimental Medarex vaccine. After only four treatments the tumors started to melt away. They were gone by mid-2006. The Jamesville, N.C. resident has been off therapy for a year and is pregnant with her first child, a girl due Feb. 10 2008."




By the Numbers

59,940 annual cases of melanoma in the U.S.

8,110 annual deaths.

99% five-year survival rate, localized disease.

15% five-year survival rate, widespread disease.

Source: American Cancer Society



Take Care,

Jimmy B

Medarex and Lonza Sign Collaboration Agreement for the Supply of Antibody-Based Products.Melanoma..Jim Breitfeller

Medarex and Lonza Sign Collaboration Agreement for the Supply of Antibody-Based Products.

I believe that they are gearing up for a full marketing Blitz.

Lonza:
"As one of the frontrunners in the contract manufacture of monoclonal antibodies and recombinant proteins from mammalian cell culture, Lonza produces the essential ingredients for tomorrow’s life-saving medicines with four state-of-the-art cGMP multi-product facilities. One of these facilities is in the UK in the Thames Valley technology corridor, which focuses on process development and clinical trial supply (including small-scale manufacture of licensed products). The second is in the USA, just outside Boston, Massachusetts, focusing on large-scale manufacture for late-stage clinical trials and in-market supply. The third is in Northern Spain, and the fourth is currently under construction in Singapore. We are hard at work developing the world’s most advanced biotechnology manufacturing processes."

"Lonza is the world's leading contract manufacturer of monoclonal antibodies and recombinant proteins. Lonza undertakes highly specialized development and manufacturing services for the pharmaceutical and biotechnology industries based on more than 25 years of experience in mammalian cell culture and proprietary technology for large-scale manufacture of innovative biopharmaceutical products"

Source:http://www.lonza.com/group/en/products_services/custommanufactoring/mammalian.html

Now all we have to wait for is the FDA Approval. As far as I know,Ipilimumab has not been submitted to the FDA for approval at this time.



Take Care,

Jimmy B