The Cancer Vaccine Collaborative (CVC) has pioneered vaccine approaches against Cancer Testis (CT) antigens. These molecules are characterized by expression in a wide variety of cancer types and very limited expression in non-malignant tissues. NY-ESO-1, which has been the focus of particular interest, is highly immunogenic and frequently induces spontaneous immunity, particularly in patients with advanced metastatic disease. It is not clear whether these immune responses modify the natural history of the cancer.
Vaccine trials with NY-ESO-1 have been undertaken using peptides, proteins and genetic vaccines. These trials have been undertaken in patients with fully resected cancer as well as those with advanced metastatic disease. Key observations include: (i) a broad integrated CD4, CD8 T cell and antibody response is induced in the majority of patients vaccinated with full length NY-ESO-1 and an appropriate adjuvant, (ii) the depth and breath of this response is complex and can involve many epitopes in an individual vaccine recipient, (iii) despite only being early phase trials, some strong indications of clinical activity have emerged, particularly in patients with minimal residual disease. We are currently performing a randomized international trial with NY-ESO-1 in such patients with resected melanoma under the aegis of the CVC in Australia and UK. If improved clinical outcomes are observed, this trial will establish the clinical value of targeting such molecules.
In contrast vaccination of patients with advanced metastatic melanoma resulted in attenuated immune responses and this difference appears to be due to tumor-related factors. A variety of regulatory mechanisms appear to be in play. Using immunohistochemistry and fl ow cytometric analysis of melanoma tissue, we detected expression of the transcription factor FoxP3 in the melanoma cells themselves as well as in regulatory T lymphocytes (Treg). Expression of FoxP3 may endow tumor cells with Treg-like activity, as demonstrated by contact-dependent suppression of T cell proliferation and contribute to tumor immune suppression. Although patients with advanced cancer may have NY-ESO-1 specific immune response, the quality of these responses may be critical for determining clinical outcomes and there is emerging evidence that antigen specific Treg may recognize peptides derived from CT antigens, including NY-ESO-1. Additionally, analysis of NY-ESO-1-specific T cells in patients with advanced ovarian cancer before and after depletion of Tregs revealed that Tregs masked spontaneous and vaccine induced effector T cells. The Treg suppressed effectors were generally of higher avidity than vaccine induced effector cells. Together, the CVC trials suggest that vaccine efficacy might be enhanced by targeting regulatory mechanisms via depletion of CD25+FOXP3+ Tregs and treatment with antibody against CTLA4.
This abstract was published in Cancer Immunity, a Cancer Research Institute journal that ceased publication in 2013 and is now provided online in association with Cancer Immunology Research.
- Copyright © 2008 by Jonathan Cebon