Amplification of Virus-Induced Antimelanoma T-Cell Reactivity by High-Dose Interferon- a2b: Implications for Cancer Vaccines

Authors: Astsaturov I, et al.
Source:Clinical Cancer Research, 9, 2003, pg 4347

Background

• A number of tumor antigens have been identified in melanoma and other cancers. These have been used to make specific cancer vaccines
• Current cancer vaccines often activate T cells for only a short time without providing strong, long-lasting antitumor activity
• There are many hypotheses regarding the reason for this weak immunogenicity: T-cells are only weakly reactive to tumor antigens that are also self-antigens, T-cells exposed to tumor antigens during tumor progression may become anergic, mechanisms that prevent autoimmune diseases may also prevent antitumor responses, and tumor cells alone may not be able to sustain the vaccine-primed antitumor responses
• The authors recently completed a trial investigating the use of a tumor specific antigen for melanoma (viral gp100) as a vaccine in patients with metastatic or high-risk disease. They found that vaccine-induced anti-gp100 T-cell responses were often transient
• This paper reports on the administration of high dose interferon- a2b to determine if a recall anti-tumor T-cell response could be elicited

Materials and Methods

• The patient population consisted of seven patients with metastatic or high risk melanoma who had previously been administered the vaccine involving the ALVAC (2)-gp100M recombinant virus, a canarypox virus expressing the gp100 gene (the tumor specific antigen)
• Patients were administered high dose interferon- a consisting of 20 doses over four weeks. The interferon dose was reduced by 33% for grade 3 or 4 toxicity
• T-cell reactivity was measured by ELISPOT assays
• Toxicity was measured weekly
• Clinical response was investigated after the full course of interferon

Results

• The interferon- a2b was administered at various times after the vaccine (mean 7.2 months after +/-4.9 months)
• All patients developed flu-like symptoms typically associated with interferon administration as well as cytopenias and mild liver function test abnormalities that resolved when the interferon course was completed
• One patient also developed a clinical depression which also resolved after the interferon was stopped
• These toxicities caused dose reductions and dose delays in all patients
• By ELISPOT assay, gp100 specific T-cells were noted in four patients by the second week of interferon- a2b administration. These four patients also had definite but transient T-cell activation during the vaccine protocol. In the four patients who had no reaction during the protocol, there was no activation of T-cells with the interferon- a2b
• All patients had stable disease over the course of interferon administration. Two patients (of the four that had T-cell reactivation) had clinical evident regression of metastatic melanoma after interferon administration
• The differences in the quantities of gp100 specific T-cells did not seem to be sufficient to account for the clinical effects in these two patients. Therefore, the quality of these T-cells induced by interferon- a2b was investigated. It was found that the T-cells induced by vaccine were unable to kill cells carrying the gp100 antigen, while the T-cells recalled by interferon- a2b were potent killers of cells expressing gp100, at a rate of 80%

Authors' Conclusions

• High dose interferon- a2b alters both the quantity and quality of reactive T-cells that recognize tumor antigens
• How this was accomplished is not exactly clear. Hypotheses include increased antigen presentation by melanoma cells and professional antigen presenting cells, and the prevention of T-cell death by interferon- a2b, hence increasing their numbers
• As the two patients who had clinical responses and mounted recall T-cell reactivity had interferon- a2b administered fairly early after completing the original vaccine (1.5-8 months), it is logical that interferon should be administered soon after completing vaccination

Scientific Implications

This paper reports on the use of an immunogenic cytokine (interferon- a2b) to attempt to increase the efficacy of a tumor vaccine for melanoma. The results are interesting as the patients who originally responded to the vaccine also responded to the administration of interferon. These were not directly correlated, though the observations are fairly convincing. It is not known, however, if the secondary recall responses will be transient, as they were during the vaccination protocol. It is likely this will be the case, deterring its clinical usefulness. Also, interferon therapy is not pleasant, as patients are usually sick with flu-like symptoms during the entire treatment course. Inducing a more significant tumor response with the original vaccine would likely be more efficacious. However, the immunogenicity evident from the administration of interferon- a2b has definite implications for future study. Namely, the concurrent administration with vaccines themselves and investigations into the mechanism behind the increased quality of T-cells induced by interferon. As is usually the case, pioneering studies such as this create more questions than definite answers.