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

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