While vaccines alone may not be sufficient to combat melanoma, researchers like Dr. Kaufman are tirelessly devising strategies of combinations with cytokines and vaccines that are showing synergistic effects.
"The work in the past has shown that we can clearly induce immune responses of melanoma patients, but it may not be robust enough to mediate tumor regression," Dr. Kaufman says, at the American Academy of Dermatology's Academy '05 here.
"The results of our recent study highlight the fact that what's occurring in the local tumor micro-environment is very important in determining the outcome of the battle between the immune system and the tumor."
Metastatic melanoma may have prevailed over previous vaccine strategies, yet Dr. Kaufman and colleagues from Columbia University are proving that there is a method to empower T-cells and their stimulatory molecules, while ultimately invading the tumor. One costimulatory molecule is proving its command against melanoma is B7.1.
"We injected a live vaccinia virus (into the tumors) that was engineered to express B7.1," he explains. "The natural B7.1 is found on antigen presenting cells in the body and activates T-cells through the costimulatory molecule pathway - this is a complex system that includes both activating and inhibitory pathways that ultimately regulate how T-cells are going to respond," Dr. Kaufman says.
In the study presenting data from the B7.1 vaccine (published July 1, Journal of Clinical Investigation) the vaccinia virus was injected into 12 human subjects. It was the first clinical trial to directly inject the virus in humans. Of those 12, six had stabilization or partial responses for a prolonged period of time; a third of the patients showed regression of distant disease in sites that were not injected.
"Interestingly, three of the patients also developed autoimmune vitiligo, which we think is a correlative of a strong anti-melanoma response," Dr. Kaufman says. "One patient went on to have a complete response and has not had a disease recurrence in five years."
The encouraging results prove the vaccine to be safe and feasible to use for local delivery into established subcutaneous melanoma lesions. Most importantly, the approach may be useful for altering the tumor environment in order to induce anti-tumor immunity, and it may provide a foundation for other vaccine strategies.
The evidence that materialized from B7.1 instigated follow-up work by Dr. Kaufman and his colleagues that is based on the same concept of targeting the local tumor microenvironment, but with B7.1 replaced by two additional costimulatory molecules referred to as the TRICOM vector. In their findings, yet to be published, the TRICOM vector produced similar results.
"Depending on how you look at these results, TRICOM vector wasn't better than the B7.1 (vaccine), but it was as good as the B7.1," Dr. Kaufman says. "We're just starting to learn how to manipulate not only B7.1, but there are an additional 50 to 70 molecules like it that all have a complex interplay to mediate immune responses."
Just as B7.1 and its related molecules began showing their competence in animal subjects beginning in 1997, so is the case with newer cytokines that are displaying compelling evidence of anti-melanoma activity in non-humans.
"The three most interesting (cytokines) being studied are members of the interleukin (IL)-2 and 12 family, including IL-15, IL-21 and IL-23, with these showing significant antimelanoma properties in mice," Dr. Kaufman tells Dermatology Times. "IL-18 should be mentioned because it is being tested in patients and has passed phase 1 studies, and is now being studied in the phase 2 study for melanoma."