Ultimate fate of cellular immune responses is determined by the balance between positive & negative signals delivered by T-cells..Melanoma ..Jim Breit

ICOS Expression,To secrete and what to secrete is the question.







My research has taken me to the costimulators and coinhibitors of the T-cell activation. The Delicate balance between the costimulators and coinhibitors render the right immune response at the right time. One of these costimulators is the ICOS. But if there is to much ICOS, then there is a down regulation of the the immune response by the secetion of IL-10 into the tumor's microenviroment.

The level of ICOS surface expression regulates the magnitude of the in vivo Th1/Th2 ratio, perhaps by influencing Th2 differentiation. This regulation plays a major role in the differentiation of the T-cells.


The linkage between low ICOS expression and “early” cytokines, and between intermediate/high ICOS expression and “late” cytokines is intriguing and could mean that ICOS is gradually up-regulated in the course of progressing T cell differentiation.

ICOS-low-cells were found to be loosely associated with the early cytokines interleukin (IL)-2, IL-3, IL-6, and interferon (IFN)-gamma.

ICOS-medium cells, the large majority of ICOS_ T cells in vivo, were very tightly associated with the synthesis of the T-helper type 2 (Th2) cytokines IL-4, IL-5, and IL-13, and these cells exhibited potent inflammatoryeffects in vivo.

In contrast, ICOS-highT cells were highly and selectively linked to the antiinflammatory cytokine IL-10.

The strength of the effector response of Th cells is regulated by the control of ICOS expression.

Overall, this data seem to indicate that ICOS cell surface density serves as a regulatory mechanism for the release of cytokines with different immunological properties.

We want the low expression of ICOS which seems to differeniate the niave T-cells towards the TH1 T-cell phenotype. We can accomplish that with Yervoy (Anti-CTLA-4). STAT5 signaling is found in both the Th2 and Treg pathway.It just so happens Yervoy causes the phosphorylation of STAT5 to decreased significantly with increasing concentrations . Yervoy skews the T-cell differentiation towards the Th1/Th17 phenotype which we want.

Another coinhibitor which surpresses the immune resonse is (PD-1) Program Death 1.

Blockade of PD-1 by monoclonal antibodies specific to its ligands (PD-L1 and PD-L2) results in significant enhancement of proliferation and cytokine (gamma interferon [IFN-gamma] and interleukin-2 [IL-2]) secretion by tumor-specific CTLs. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Tregs.

So by do a combinatorial therapy with Yervoy and PD-1 antibodies, It would most likely have a synergistic immune response.



This why on 9-20-2011, Bristol Myer Squibb expanded it's deal with Japan's Ono Pharmaceutical Co. Ltd. BMS now knows that they have an monopoly on T-cell activation and can be applied to many other cancers besides Melanoma. They are collecting the "String of Pearls". It would not surprise me they will go after the rest of the costimulators and coinhibitors on the T-cells. Only time will tell.

My hope is that Bristol Meyer Squibb uses it for the cure of cancer one day and not just monetary gains.

“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

Bristol's String of Pearls are Shining!!

FDA NEWS RELEASE
For Immediate Release: Sept. 25, 2009

Media Inquiries: Karen Riley, 301-796-4674, karen.riley@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

FDA Approves New Drug to Treat Psoriasis

The U.S. Food and Drug Administration today approved Stelara (ustekinumab), a biologic product for adults who have a moderate to severe form of psoriasis.

Plaque psoriasis is an immune system disorder that results in the rapid overproduction of skin cells. About 6 million people in the United States have plaque psoriasis which is characterized by thickened patches of inflamed, red skin, often covered with silvery scales.

“This approval provides an alternative treatment for people with plaque psoriasis, which can cause significant physical discomfort from pain and itching and result in poor self-image for people who are self-conscious about their appearance,” said Julie Beitz, M.D., director, Office of Drug Evaluation III, in the FDA’s Center for Drug Evaluation and Research.

Stelara is a monoclonal antibody, a laboratory-produced molecule that mimics the body’s own antibodies that are produced as part of the immune system. The biologic treats psoriasis by blocking the action of two proteins which contribute to the overproduction of skin cells and inflammation.

Three studies of 2,266 patients evaluated the biologic’s safety and effectiveness.

Since Stelara reduces the immune system’s ability to fight infections, the product poses a risk of infection. Serious infections have been reported in patients receiving the product and some of them have lead to hospitalization. These infections were caused by viruses, fungi, or bacteria that have spread throughout the body. There may also be an increased risk of developing cancer.

The FDA is requiring a risk evaluation and mitigation strategy or REMS for Stelara that includes a communication plan targeted to healthcare providers and a medication guide for patients.

Stelara is manufactured by Centocor Ortho Biotech Inc. of Horsham, Pa., a wholly-owned subsidiary of Johnson & Johnson of New Brunswick, N.J.

Well Medarex is the partner who developed the antibody, (ustekinumab).

We shall soon hear about Ipilimumab, I hope

Bristol-Meyer Squibb just bought out Medarex in what I would call a give away by the Board of Directors and the Top Management of Medarex.

My guess, Bristol had information on Stelara proir to buying out Medarex.

The Pearl Neckace Lives On!!!!!!!!

I believe each pearl represents an antibody or Drug that is commercialized and FDA approved.

commercialized.. Definition --To apply methods of business to for profit.

BMY will get some royalites that can fund their war chest.

Check Mate!!!!!!!

Take Care,

Jimmy B

Note to Bristol-Meyer Squibb,,Subject: TimeLine for compassionate drug use Ipilimumab.Melanoma.Jim Breitfeller

Subject: TimeLine for compassionate drug use Ipilimumab

It, has been over a year now that the compassionate drug use Ipilimumab was terminated due to production problems. As a chemist working in the field of biologics, I know it only takes about 3 months to generate Human Monoclonal antibodies. So why is it taking so long? I know you are trying different production protocols, but patients are loosing hope and their lives waiting for this drug. Will the compassionate use be reinstated soon? You say in your mission statement that:

“What sets us apart? We believe it's our commitment to patients with serious diseases, our focus on finding innovative medicines that combat those diseases, and our dedication to extending and enhancing human life.”

We need you Help Now!!!

Response:

Dear Mr. Breitfeller,

Thank you for your email.

As you are aware, Bristol-Myers Squibb and Medarex had to suspend enrollment of new patients into the compassionate use program and single patient exemptions to ensure treatment is not interrupted for patients currently receiving ipilimumab and to provide supply for ongoing clinical studies.

The manufacturing cycle time and testing of a biologic such as ipilimumab is complex. However, we are working through this process and continue to carefully manage the supply to enable the potential re-opening of compassionate use at the earliest possible time and when continuous supply is available. The companies recognize the great unmet medical need for patients with metastatic melanoma and remain committed to the development of ipilimumab.


Regards,


Bristol-Myers Squibb

Something doesn't seem right here. There is something going on. A year to get your Protocol in place that was already in place.

It doesn't smell right!!!!


I bet you it has something to do with the string of Pearls!!!!!!!!

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