Combinatorial Therapy Will Revolutionize Cancer Therapy ...Just wait until ASCO 2015!!

Bristol-Myer Squibb Pharmaceutical Research Institute
Attention: Elliott Sigal
Route 206, Provinceline Road
P.O. Box 4000
Princeton, New Jersey 08543 U.S.A...

 Date: 3-10-2010

Dear Dr. Sigal:
I want to thank you for responding to my emails over the last few months. I know I can be candid and straight to the point sometimes. By reopening the compassionate Drug Use (ipilimumab) you and your company gave the Melanoma Patients “The Last Chance of HOPE”. You don’t know how much this means to us. If we haven’t passed the “Lethal Tumor Burden” we still have a chance of survival. I believe you have done your company justice and showed your compassion. My faith in the Company’s Ethics has been restored.

Now we need to prove to the world that this drug may be one of the most important discoveries in the last twenty years of Cancer. By taking the “Brakes off the Immune System” we can harness our own immune system to battle cancer. Granted we may have to use the drug in combinatorial therapy to rid the host of the cancer once and for all. I hope you and your company can collaborate together with all the major players in this exciting field of Oncology. See it took millions of years for our immune system to evolve, so why do we think that one drug can do it all. We need to approach the Beast arm to arm, to block all the pathways so it can’t escape. This can only be done by using one’s own immune system.

Can you imagine working out a protocol that will vaccinate the patient with the patients own tumor–specific antigen? And Ipilimumab (Anti-CTLA-4 Blockade) is at the center of this revolutionary therapy/protocol. Please if you get a chance, listen to some of the lectures and symposiums from the like of Dr. James Allison, Dr. Jedd Wolchok, Dr. Antonio Ribas, Dr. Jeffery Weber, Dr Keith Flaherty and others. You will be amazed at their accomplishments in the clinical setting. But they need more. They need access to the entire drug arsenal that is available across companies. We now know that timing and dose concentration plays a major roll in setting up an immune response. There are feedback loops. It is like dominos. You have this elaborate step-up. It may take weeks to build. Once you set it in motion, the chips begin to fall. There are different pathways, cytokines, T-cells, receptors, etc that need to be taken into account get the right immune response. This immune response can only be generated if you have all the keys to unlock the response. We need yours and other Pharmaceuticals to work together for the good of the cancer patients. We need to take down all the red tape which also includes the FDA.

“Our Life depends on it.”

Thanks again.
Sincerely,
Jim Breitfeller

 

 

“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

Radiation Blast May Turbocharge Bristol-Myers Melanoma Drug, Report Shows..Jim Breitfeller

Radiating one tumor can trigger the immune system to wipe out tumors in other parts of the body and may boost the effectiveness of Bristol-Myers Squibb Co. (BMY)’s cancer drug Yervoy, doctors have shown.
Source: Radiation Blast May Turbocharge Bristol-Myers Melanoma Drug



Recent evidence shows that the anti-tumor immune response elicited by radiation therapy or chemotherapy is due to the release by dying tumor cells of HMGB1, which acts on TLR4/MyD88 on dendritic cells.

It has been known that if radiation kills the outer most cells of the tumor, it can shed tumor specific peptides/antigens that are picked up and display on the DCs. It can also get the cells to secrete HMGB-1 which binds to the TLR4 and activates the macrophages which in turn secrete IL-12 and other cytokines and chemoattractants to get the right immune response.



Dr. Rosenberg uses whole body radiation prior to the adoptive cell therapy. He has seen higher responses.

The Immune System needs three Signals:

The role of the CD8+ T cells is to monitor all the cells of the body, ready to destroy any that express foreign antigen fragments in their class I molecules.

Three major events must occur to Activate CD8+ T cell mediated response against melanoma.

First, the T-cell receptor (TRC) must be triggered by a (or multiple) self antigen–derived peptide MHC class I complex. This event depends entirely on appropriate antigen presentation, which is most efficiently provided by mature dendritic cells. Once properly activated, may serve as tumor-specific effector T cells.

Second, simultaneously with T-cell receptor triggering, a distinct second costimulatory signal must be delivered, mediated by IL-2, B7-1, or B7-2, which engage IL-2 receptors and CD28 on the surface of the T cell, respectively . A source of these cofactors for effective CD8+ T-cell stimulation can be provided by CD4+ T cells that release critical amounts of IL-2, or by mature dendritic cells that display an increased level of B7-1/B7-2 costimulatory molecules on their cell surfaces.

Third, inflammatory cytokines, including IL-1, IL-6, IL-12, and IFN-γ provide a third signal that acts directly on T cells, referred to as the “danger signal”. This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells.

Without the tumor derived debris(Tumor-specific antigens), the immune system doesn't know what to go after.No Immune response will occur.

new-melanoma-treatment-a-turning-point-against-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 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

Hope over new skin cancer therapy..Melanoma ..Jim Breitfeller

Hope over new skin cancer therapy

By Pallab Ghosh
Science correspondent, BBC News
Scientists have presented results of an experimental new drug which in early stage trials has significantly shrunk skin cancer tumours.

US rearchers from Memorial Sloan-Kettering Hospital in New York said their results were "unprecedented".

While not a cure, the study of 31 patients with late-stage skin cancer suggested the therapy could improve the quality of life and extend lifespan.

Larger scale trials will now be needed to test the drug, PLX4032, further.

In the study, which has been unveiled at a major cancer conference in Berlin, researchers treated patients where cancer had spread throughout their system.


We've seen responses in patients who didn't respond to chemotherapy before

Dr Paul Chapman, lead researcher
They were given a new drug that blocks the activity of a gene thought to be involved in the spread of skin cancer, the so-called BRAF gene.

Within two weeks they noticed what they described as a "rapid and dramatic" shrinking of the tumours in the cancer patients:

Lead researcher Dr Paul Chapman said: "We've seen responses in patients who didn't respond to chemotherapy before. So far 70 per cent of patients have responded. So that is unprecedented for us."

New treatments can often seem promising to begin with - but have disappointing results in later larger trials.

However, the doctors involved in the trial - and those at the European Cancer Organisation who have organised the conference - have never seen a cancer drug act so quickly on such a high proportion of patients.

SKIN CANCERS: THE FACTS



Skin cancers: In-depth UK data, symptoms, treatments and causes
The drug, PLX4032, is the latest in a new generation of cancer drugs that block the action of cancer causing genes.

The most successful of these so far has been Glivec (imatinib), which is used to treat myloid Leukaemia and gastric cancer.

Professor Alexander Eggermont, president of the European Cancer Organisation, said: "The new drug is the equivalent of Glivec in terms of the effect its having in advanced melanoma."

'It's fantastic'

One of those to receive the treatment was Mikhail Lvovsky, a dentist from New York.

A year ago he stopped work because he was so ill. He asked his doctor to take him off his previous medication because he could not bear the side effects. Now six months after taking the new drug he is back at work.

He said: "The first thing I did six months ago was to call the funeral director and pay for my funeral. Now I'm thinking of going back to work. It's beyond exciting. It's fantastic."

Dr Lvovsky's cancer is so serious it is unlikely for the new treatment to hold it back for very much longer longer.

But if the drug is shown to be effective in larger trials it has the potential to help people whose cancer is less advanced to live healthier and longer lives.

Alexander Eggermont, president of the European Cancer Organisation, described the trial as "simply spectacular".

He said it showed the benefits of targeting treatment.

The news would transform melanoma work into "a very exciting field instead of a graveyard", he said.

Dr Toby Chave, a consultant dermatologist at Derriford hospital in Plymouth, said: "Up to this point advanced melanoma has been extremely difficult to treat and does not respond well to any existing chemotherapy or radiotherapy.

"Prognosis is very poor. The new study shows that there is some response to the treatment which is very encouraging. Even giving patients the hope of a few extra months of life is significant for them."

However Dr Chave stressed that the new treatment was not a cure.

He added: "Any hope of long-term cure for advanced melanoma is still a long way off."

Hope over new skin cancer therapy

Source:http://news.bbc.co.uk/2/hi/health/8268719.stm
http://news.bbc.co.uk/1/hi/health/8269797.stm

Take Care,

Jimmy B

Inherent Complexities in Melanoma Research..Jim Breitfeller

Inherent Complexities in Melanoma Research

NCI Conference Highlights Promising Advances in Immunotherapy
EASTMAN, PEGGY

Oncology Times:
25 October 2008 - Volume 30 - Issue 20 - p 32-35


Still challenging researchers and slowing progress in the field of cancer immunology and immunotherapy are the inherent complexities of immunity, said other speakers at the meeting.
Regulation of T-cell responses is a lot more complex than we had initially thought, noted James P. Allison, PhD, Director of the Ludwig Center of Cancer Immunotherapy and Chairman of the Immunology Program at Memorial Sloan-Kettering Cancer Center.


Dr. Allison said that one reason there have not been more successful clinical strategies to mobilize the immune system to attack cancer cells is that until recently not enough attention has been paid to the multiple inhibitory mechanisms that serve to shape the immune response and minimize harm to normal tissues.

These mechanisms, he said, are a collective obstacle that can frustrate generation of effective anti-tumor responses.
His research has shown that the prototype of these inhibitory pathways is CTLA4, which limits T-cell proliferation. We have shown that blockade of CTLA4 can greatly enhance anti-tumor responses in a number of experimental tumors in mice, he said, noting that the CTLA4 blocker ipilimumab is now being developed by Medarex, Inc., and Bristol-Myers Squibb.

The results of clinical trials in more than 3,500 patients [for ipilimumab] have demonstrated objective, durable responses in a subset of melanoma, renal, ovarian, and prostate cancer patients. Thus for the first time we have objective responders, which he called exciting.

James C. Yang, MD, Senior Investigator in NCI's Surgery Branch, said that one immunotherapy combination of special clinical interest is ipilimumab plus interleukin-2 (IL-2). Dr. Yang, who chaired a symposium session, noted that in a Phase I/II study of 36 melanoma patients who received dose-escalating ipilimumab with a high-dose bolus of IL-2, the overall response rate was 22%. Long-term follow-up shows that six of the eight responders achieved ongoing complete responses with durations all exceeding four years.


Anti-CTLA4 antibodies have also been tried with other cancers, said Dr. Yang. He added that to extend the role of anti-CTLA4 therapy to a broader array of cancers, it will likely be necessary to combine it with other immunological manipulations, a combination approach which will hopefully boost the host immune response to cancer.


Take Care,

Jimmy B

Remember I said Blame it on The Tregs??Melanoma..Jim Breitfeller

OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis.

Published online May 4, 2009
doi:10.1084/jem.20082205
The Journal of Experimental Medicine, Vol. 206, No. 5, 1103-1116
The Rockefeller University Press, 0022-1007 $30.00
© 2009 Hirschhorn-Cymerman et al.


Hirschhorn-Cymerman Daniel; Rizzuto Gabrielle A; Merghoub Taha; Cohen Adam D; Avogadri Francesca; Lesokhin Alexander M; Weinberg Andrew D; Wolchok Jedd D; Houghton Alan N

The Journal of experimental medicine 2009;206(5):1103-16

Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

"Expansion and recruitment of CD4(+) Foxp3(+) regulatory T (T reg) cells are mechanisms used by growing tumors to evade immune elimination. In addition to expansion of effector T cells, successful therapeutic interventions may require reduction of T reg cells within the tumor microenvironment. We report that the combined use of the alkylating agent cyclophosphamide (CTX) and an agonist antibody targeting the co-stimulatory receptor OX40 (OX86) provides potent antitumor immunity capable of regressing established, poorly immunogenic B16 melanoma tumors. CTX administration resulted in tumor antigen release, which after OX86 treatment significantly enhanced the antitumor T cell response. We demonstrated that T reg cells are an important cellular target of the combination therapy. Paradoxically, the combination therapy led to an expansion of T reg cells in the periphery. In the tumor, however, the combination therapy induced a profound T reg cell depletion that was accompanied by an influx of effector CD8(+) T cells leading to a favorable T effector/T reg cell ratio. Closer examination revealed that diminished intratumoral T reg cell levels resulted from hyperactivation and T reg cell-specific apoptosis. Thus, we propose that CTX and OX40 engagement represents a novel and rational chemoimmunotherapy."

Abstract on PubMed

By depeting or changing the Treg ratio/compared to the CD8+ Tcells, one can theoretically shift the balance of the immune system to initiate an immune repsonse.

I will try to ge a copy of this paper


Take Care,

Jimmy B

Melanoma Update: Highlights of research presented at ASCO and an update on vaccines trials.Melanoma..Jim Breitfeller

Issue Number:
Volume 17 - Issue 3 - March 2009
author:
John Otrompke, Contributing Editor
Mixed Melanoma Trial Results Point to Need for Tailored Studies

"Effective melanoma therapies may be inching forward, with a number of the new class of potential therapeutics in the pipeline entering Phase III trials, and researchers presenting some of the first published data on other agents at this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

But with mixed results, some disappointing, some surprising, some researchers say clinicians and clinical trial designers must rethink development strategies, including patient selection, if some of the new class of biological therapeutics for melanoma are to make significant headway.

“The problem with melanoma is that, other than surgery, there really are no very good effective therapies. The chemotherapies that are out there are not curative but palliative treatments,” explains David Solit, MD, Elizabeth and Felix Rohatyn Chair and Assistant Attending Physician, Department of Medicine, Sloan-Kettering Cancer Center.

But medical science is progressing, says Dr. Solit, who spoke at the ASCO conference. “We actually know a lot of the genetic alterations that cause the cancer. In 2002 there was a mutation in a protein called BRAF that was identified, and the mutation is found in the tumor in 50% to 70% of patients with melanoma. Then there’s a protein called NRAS, which also gets mutated in 15% to 20% of melanoma patients. But when you have an NRAS mutation, you don’t have a BRAF mutation. In total, between 60% and 90% of patients have one of the two,” says Dr. Solit, who gave the presentation, “Genetic Predictors of RAF/MEK Dependence.”

But the news at ASCO was not all good for the new therapies.

Early Promise, Mixed Results

Some of the most important new strategies for treating advanced melanoma focus on the patient’s immune system.

“Two of the strategies use anti-CTLA 4 and anti-PD1 agents to take the brakes off the patient’s immune system. Both are receptors on a patient’s T-cells, which are part of the normal braking system, which is a good thing at most times, but not a good thing in regards to a cancer cell,” says Walter Urba, MD, PhD, Director of Cancer Research at the Earle A. Chiles Research Institute in Portland, Oregon.

“The other two strategies use antibodies 41BB or OX 40. At ASCO this year, we saw some late clinical trial results with the anti-CTLA 4 product, and the first published results with anti-41BB and anti-PD1,” says Dr. Urba, who also discussed very early results with his own institution’s investigational agent, OX 40.

A disappointing trial of a new potential therapeutic agent was a head-to-head trial of an agent called a MEK inhibitor, which was tested against temozolomide, a standard pre-existing chemotherapy for melanoma. There was no significant difference between the standard arm and the MEK inhibitor (AZD 6244 by Astra Zenaca), according to the trial results.

However, patient selection may be the problem. “Genetic differences are relevant, because the BRAF mutation found so often in melanoma patients, activates a protein called MEK. “If you have a RAF mutation, you may respond a lot better to a MEK inhibitor,” explains Dr. Solit, noting that in addition to the Astra Zenaca drug, another MEK inhibitor in research is a drug from Pfizer called PD 0325901. The Astra Zenaca drug, which encountered the disappointing result, is in Phase II trials, whereas the MEK inhibitor from Pfizer is only in Phase I.

“The problem with the Astra Zenaca trial is that they didn’t look for BRAF-mutated patients. It’s possible temozolomide is as good or better than AZD 6244 in unselected patients, but five of the six responders in the MEK inhibitor arm had BRAF mutations,” Dr. Solit says. “There is technology out there already to start looking for these mutations, and it has already become routine in lung cancer for other genes.”

There were some positive, surprising results presented as well, however. A Phase II trial of ipilimumab, an investigational immunomodulatory agent from Bristol Meyers Squibb, which is in late Phase III trials, was studied in a population of 115 patients in combination therapy with Budesonide, a currently existing therapy. “Our primary endpoint was to see whether in a randomized trial we could reduce the amount of diarrhea that occurs as a side effect of the Budesonide, and our primary endpoint was not successful, but ironically, the clinical results were outstanding. Our median survivals were over a year,” says Jeffrey Weber, MD, PhD, Director of the Donald A Adam Comprehensive Melanoma Research Center and Professor of Oncologic Sciences at the University of South Florida.

Updated survival data of three Phase 2 studies of ipilimumab in patients with metastatic melanoma (Stage III or IV) who had previously been treated were presented at the European Society for Medical Oncology in Stockholm. Study results show that approximately half of patients who received ipilimumab (10 mg/kg) remained alive beyond 1 year. The results are based on follow-up of the patient population from studies 008, 022 and 007 treated with 10 mg/kg of ipilimumab (induction and maintenance) and show a consistent 1-year survival rate between 47% and 51%.

Combination Therapies of the Future, Today

Another promising strategy offering hope to advanced melanoma patients is to stimulate the patient’s immune system, by mimicking signal’s sent naturally by the body.

“We have learned from studying patients with melanoma just how powerful the immune system can be, but we need to supplement the response, and free it from some of its limitations,” says Robert H. Vonderheide, MD, Assistant Professor of Medicine at Abramson Cancer Center at the University of Pennsylvania.

The immune response in melanoma patients can be so pronounced that in rare cases, tumors even shrink in the face of it, says Dr. Vonderheide.

Dr. Urba agreed. “The immune response in melanoma is different from other cancers,” he explains. “One of the thoughts is that melanoma tumors are more immunogenic. Sometimes the response occurs after disease progression. In a couple percent of every patient population, the patient comes in and looks for all the world like they’re having tumor progression, and they end up having the tumor go away in response. The rationale is, that maybe it takes time for an immune response to build up and eliminate tumor cells following these investigational therapies,” he says, noting that these delayed responses can occur 8 or 12 weeks following therapy.

To attempt to take advantage of melanoma’s unique immunogenicity, Pfizer has developed an investigational agent that acts on an immune receptor called CD40, according to Dr. Vonderheide. “This is an antibody that binds to CD40 and mimics the signal sent to activate the immune system.”

The CD40 agonist has been tested by itself and in conjunction with standard chemotherapy drugs carboplatin and paclitaxel. The first clinical trial with the agent started about 4 years ago, and was reported 2 years ago at ASCO. Though the drug is only in Phase I trials, “taking it to Phase II is definitely warranted,” notes Dr. Vonderheide. “In the second study, we saw clinical activity: one patient has regressed, and remained in remission for years.”

In another study, the CD40 agonist will be given, along with chemotherapy, every 3 weeks, and the trial is enrolling as many as 30 patients, according to Dr. Vonderheide.

With some of the therapies, lack of experience in testing them may lead to unpredictable future results; in others, the sheer longevity of their period in trials can lead to skepticism.

“Anti-CTLA 4, an anti-inhibitory drug, has probably been in clinical trials for about 7 years, whereas anti-PD1, which is also an anti-inhibitory drug, has probably not been in trials for much more than a year,” says Dr. Urba, noting that the 41BB has also been in trials for 2 years.

For some drugs, clinical trials have enrolled hundreds of patients over the years, while other novel agents have only been tested in a few dozen humans. “The delayed response phenomenon, for example, has not been seen with other agents besides ipilimumab and tremilimumab, but with the other agents, the number of patients who have been treated is so small I’m not sure if we would have seen it,” he adds.

Still, the novel agents, whether young or old, often offer the only hope for advanced melanoma patients to hold onto.

“Nonetheless, it’s probably going to be a long series of trials to figure out which are the patients who are going to benefit. It’s a targeted therapy, and it doesn’t work for everybody. But we have insight into who it would work in, and we need to incorporate that information into our clinical trial design,” Dr. Solit says."


source: http://www.skinandaging.com/content/melanoma-update-highlights-research-presented-asco-and-update-vaccines-trials

Melanoma Update: Highlights of research presented at ASCO and an update on vaccines trials


Take care
Jimmy B