Showing papers by "Piero Dalerba published in 2002"

Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going?

Abstract: Many human tumor-associated antigens (TAAs) have recently been identified and molecularly characterized. When bound to major histocompatibility complex molecules, TAA peptides are recognized by T cells. Clinical studies have therefore been initiated to assess the therapeutic potential of active immunization or vaccination with TAA peptides in patients with metastatic cancer. So far, only a limited number of TAA peptides, mostly those recognized by CD8 + T cells in melanoma patients, have been clinically tested. In some clinical trials, partial or complete tumor regression was observed in approximately 10%–30% of patients. No serious side effects have been reported. The clinical responses, however, were often not associated with a detectable T-cellspecific antitumor immune response when patients’ T cells were evaluated in ex vivo assays. In this review, we analyze the available human TAA peptides, the potential immunogenicity (i.e., the ability to trigger a tumor-specific T-cell response) of TAA peptides in vitro and ex vivo, and the potential to construct slightly modified forms of TAA peptides that have increased T-cell stimulatory activity. We discuss the available data from clinical trials of TAA peptide-based vaccination (including those that used dendritic cells to present TAA peptides), identify possible reasons for the limited clinical efficacy of these vaccines, and suggest ways to improve the clinical outcome of TAA peptide-based vaccination for cancer patients. [J Natl Cancer Inst 2002;94:805–18] Tumor cells express antigens that can be recognized by the host’s immune system. These tumor-associated antigens (TAAs) can be injected into cancer patients in an attempt to induce a systemic immune response that may result in the destruction of the cancer growing in different body tissues. This procedure is defined as active immunotherapy or vaccination inasmuch as the host’s immune system is either activated de novo or restimulated to mount an effective, tumor-specific immune reaction that may ultimately lead to tumor regression. However, until now, the vaccination approach for cancer has been carried out in the presence of the disease (i.e., in immunocompromised subjects) and not, as it occurs in prophylactic vaccination against infectious diseases, in healthy individuals. Moreover, although in infectious disease vaccination, the antibody response is of major importance, in anticancer vaccination, the focus is on the induction of T-lymphocyte responses. In fact, a considerable body of data from animal models and with human cells in vitro indicates that T cells are the major factor for the immunologic control of

Immunity to cancer: attack and escape in T lymphocyte–tumor cell interaction

Abstract: Tumor cells may express antigens which are recognized in a form of HLA/peptide complexes by T cells. The frequency at which different antigens are seen by T cells of melanoma patients and healthy donors was evaluated by human leukocyte antigen (HLA)/peptide tetramer technology which stains T cells bearing the specific receptor for a given epitope. By this technique, it was found that the majority of metastatic melanoma patients can recognize differentiation antigens (particularly Melan-A/MART-1), whereas such a recognition is scanty in the early phase of the disease and in healthy subjects. Despite the presence of melanoma-specific T cells infiltrating tumor lesions, tumor rejection rarely occurs. Among the different mechanisms of such inefficient antitumor response, this review discusses the possible anti-T-cell counterattack mediated by FasL-positive tumor cells, and shows that FasL is located in the cytoplasm of melanoma cells and is transported in the tumor microenvironment through the release of melanosomes. Additionally, mechanisms of suboptimal T cell activation through tumor cell expression of peptide analogs with antagonist activity are described, together with the possibility of overcoming such anergy induction by the usage of optimized tumor epitopes. Down-modulation of HLA expression by target tumor cells and its multiple mechanisms is also considered. Finally, we discuss the role of inducible nitric oxide synthases in determining the inhibition of apoptosis in melanoma cells, which can make such tumor cells resistant to the T-cell attack.