The future of interleukin-2: enhancing therapeutic anticancer vaccines.
OBJECTIVE
The purpose of our efforts is to trigger the immune destruction of established cancer. Interleukin (IL)-2 can mediate the regression of tumors in patients with melanoma and renal cell carcinoma. In animal models, the antitumor effects of IL-2 are mediated by T lymphocytes. Stimulation with specific antigen can enhance the ability of T cells to respond to IL-2 by triggering the rapid upregulation of the high-affinity IL-2 receptor. We are seeking to design recombinant and synthetic vaccines capable of preferentially priming T cells with specificity for tumor cells.


METHODS
The antitumor activity of experimental vaccines is being studied preclinically using recently developed murine models that employ the mouse homologues of human tumor-associated antigens. Once the most effective experimental vaccines are optimized in experimental animals, clinical trials can be conducted. Vaccines are being evaluated for their ability to mediate the regression of established tumors, and a variety of immunologic correlates are being measured.


RESULTS
In animal models, vaccines based on molecularly defined tumor-associated antigens expressed in viral vectors or delivered as "naked" DNA stimulate the expansion of CD4+ and CD8+ tumor-specific T lymphocytes. Coadministration of IL-2 with these vaccines dramatically enhances their ability to mediate the regression of established cancer. In the clinic, treatment of melanoma patients with peptide vaccine and IL-2 resulted in objective responses in approximately 40% of patients, a response rate more than twice that typically achieved with IL-2 alone. Paradoxically, tumor-specific CD8+ T-cell levels were not increased in these patients.


CONCLUSIONS
The addition of recombinant and synthetic cancer vaccines to a regimen of IL-2 can result in improved antitumor responses in both animal models and melanoma patients. Vaccine-primed, tumor-specific T cells may preferentially proliferate upon administration of IL-2. The apparent lack of increase in CD8+ T-cell numbers in this setting suggests that the vaccine-primed T cells functionally disappear after a transient period of activation. Preventing the disappearance of activated T cells upon IL-2 administration-for example, by blocking proapoptotic signals-may enhance the therapeutic effectiveness of anticancer vaccines.
Overwijk
W W
WW
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1502, USA.
Theoret
M R
MR
Restifo
N P
NP
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000627:therapeutic use*; D008213:Lymphocyte Activation; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*
D019496:Cancer Vaccines; D007376:Interleukin-2