To: 'Rosenberg, Steven A. (NIH/NCI) [E]'
Subject: FW: The Perfect Storm: Therapeutic use of Anti-CTLA-4 Blockage and IL-2 to enhance T-cell responses in vivo
Dr. Rosenberg, I wanted you to know about this because your Research has allowed me to put this puzzle together. Thank you for sharing your research.
Thanks for communicating with me over these years. Some researchers like to hold their cards close to their chest. I would rather show my hand to help find a cure/stabilization.
I know in your Research clinical trials you are approaching 50% complete response for HLA-02 positive patients. What does that calculate out to if you include the other subtypes?
I am hoping that the information that I have pulled together will benefit the whole Melanoma community. I know that my therapy was not a one off data point and that is why I am pursuing this combination theory to the max.
Thanks for lending me your ear.
By obtaining the above papers, I now have real evidence of what took place with my therapy as a Melanoma patient and why it worked. The paper that I wrote called Melanoma and the Magic Bullet (Monoclonal antibodies) was right on track. I did a little bit of hand waving early on, but NOW I have the evidence that the IL-2 timing plays a critical roll in the outcome of the clinical trials.
Also, I am now certain that the Anti-CTLA-4 blockage (Ipiilimumab or what I used Tremelimumab was the spark that started it all. “You Can’t Start a Fire Without a Spark!!” For the Anti-CTLA-4 Blockage did three things:
1. It blocked the B7 receptor causing the activated CD4+ T-cells to stay activated for a longer period
2. It pushes the balance of the CD4+ T-cell differentiation towards the Th17 lineage or also known as the THi cells which stands for inflammatory Cells. They generated the third signal “Danger Signal” which is one of three needed to activate the CD8+ T-cells. This base on research that Dr. Ribas has done.
3. It suppresses the Treg expansion/function tilting the immune response balance towards activation instead of Anergy.
CTLA4 blockade increases Th17 cells in patients with metastatic melanoma Ribas
According to Dr. Wolchok and investigating the dose of Anti-CTLA-4 blockage recently, the higher the dose the better the immune response.
The best overall response rate was 11•1% (95% CI 4•9—20•7) for 10 mg/kg, 4•2% (0•9—11•7) for 3 mg/kg, and 0% (0•0—4•9) for 0•3 mg/kg (p=0•0015; trend test).
10mg/Kg 11.1% response rate
3mg/Kg 4.2 % response rate
0.3mg/Kg 0% response rate
This data was base on Ipilimumab as a monotherapy
Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study
I did 15mg/Kg of Tremelimumab (one Dose) and got a COMEPLETE RESPONSE.
My guess is there is threshold that is needed to broken to tip the balance of tolerance to activation.
It all comes down to timing and the dose concentration.
Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo
IL-2 was giving in the contraction phase of the CD4+ T-cells and at the Maxiumum growth phase of the CD8+ T-cells. It is as I refer it as the “Perfect Storm”. This is all based on a paper by Dr. Itoh and colleagues in 1988.
Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor
Dr. Heryln’s Paper “Tumors as elusive targets of T-cell-based active immunotherapy.
Tumors as elusive targets of T-cell-based active immunotherapy
It is going to be a great 2010!!!!!
Take Care,
Jimmy B
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