Study Start Date: February 2003
• Determine the maximum tolerated dose (MTD) of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-CTLA4) in combination with high-dose interleukin-2 (IL-2) in patients with metastatic melanoma. (Phase I is closed to accrual as of 4/13/2004).
• Determine the activity of MDX-CTLA4 administered at the MTD with high-dose IL-2 in these patients.
• Determine whether the administration of IL-2 alters the pharmacokinetics of MDX-CTLA4 in these patients.
• Determine the safety and adverse event profile of this regimen in these patients.
OUTLINE: This is an open-label, dose-escalation study of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-CTLA4).
• Phase I: Patients receive MDX-CTLA4 IV on days 0, 21, and 42. Patients also receive high-dose interleukin-2 (IL-2) IV over 15 minutes every 8 hours for up to 15 doses beginning on days 22 and 43. Treatment repeats every 63 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients with an ongoing partial response and no greater than grade 1 toxicity may receive additional courses of therapy. Patients who require discontinuation of MDX-CTLA4 due to toxicity may continue receiving IL-2 at the discretion of the investigator.
Cohorts of 3-6 patients receive escalating doses of MDX-CTLA4 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. (Phase I is closed to accrual as of 4/13/2004).
• Phase II: Patients receive treatment as in phase I at the MTD of MDX-CTLA4. Patients who achieve a partial or complete response and later develop recurrent or progressive disease may be retreated at the same dose.
Patients are followed at 3 weeks, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.
PROJECTED ACCRUAL: A total of 3-51 patients (3-18 for phase I and 19-33 for phase II) will be accrued for this study within 1 year. (Phase I is closed to accrual as of 4/13/2004).
Based on knowledge gained over the last decade, I believe it warrants us/you to revisit this combinatorial approach.
Base on Dr. Wolchok’s research, the dose of the anti-CTLA-4 was to low to shift from tolerance to activation. Also, the addition of the HD IL-2 was added at the time to proliferate the CD4+ T-cells which may have caused a five fold expansion of the Tregs. There is now new data that suggests that IL-2 addition should be added after the contraction of the CD4+ T-cells. Et al Wherry.
By adding the The HD IL-2 after the expansion of the T-cells, IL-2 therapy was highly beneficial during the death phase, resulting in increased proliferation and survival of tumor-specific T cells. IL-2 treatment also increased proliferation of resting memory T cells.
If you add the combination of IL-2 and TGF- beta (tumor secreted) at the beginning of the treatment, it induces naive or total CD4+CD25– cells to develop strong suppressive effects both in vitro and in vivo according to Horwitz et al 2001. The T-Cell differentiation is pushed towards developing Treg suppressive immune cells.
So increasing the dose of Anti-CTLA-4 Blockade and delaying the addition of the HD IL-2 can have a dramatic effect on the overall response of the immune system. Here is a graphic representation of the protocol.
I know you will get a synergistic response with this protocol because it happen to Dr. Vivian Bucay and myself.
Please, if you get a chance, consider this new protocol and revisit the combinatorial
therapy of Anti-CTLA-4 Blockade and HD IL-2.
Thanks for you time
Melanoma and The Magic Bullet (Monoclonal Antibodies)
The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2
Eureka!!!!!! A possible cure for Melanoma, the Deadly Skin Cancer