Recent advances in tumour antigen‐specific therapy: In vivo veritas

Abstract

Modern cancer therapies should strive not only to eliminate malignant tissues but also to preserve healthy tissues and the patient's quality of life. Antigen-specific immunotherapy approaches are promising for either aspect since they are designed to only act against tissues expressing 1 or more specified tumour antigens. In order to develop successful vaccine and adoptive transfer protocols, longitudinal monitoring of cancer patients taking part in clinical trials is mandatory. Here, in vivo expansion of antigenspecific cells, as well as their ex vivo functional status represent important parameters to be analysed. To obtain results that most closely reflect the cells' in vivo status, functional assays must be carried out with as little in vitro culturing as possible. The present minireview discusses recent advances in these domains. Key words: cancer vaccines; T cell monitoring; tetramers; immunotherapy Tumour antigensRapid advances in the identification of MHC class I-restricted tumour antigens (TA) and their antigenic peptides 1 took place at the end of the 20th century, engendering antigen (Ag)-specific immunotherapy approaches to cancer treatment. [2][3][4] In contrast, progress in the molecular identification of MHC class II restricted peptides of TA has been much slower. Although tumour-specific CD8 ϩ T-cell responses have been documented upon vaccination with MHC class I-restricted peptides, it could be shown in murine tumour models that the generation of potent and long-lasting anti-tumour immunity is improved when both MHC class I-and class II-restricted T-cell epitopes are included in tumour vaccines. [5][6][7] These observations fostered the search for TA-derived peptides that are presented by class II molecules in cancer patients and lead to the isolation of diverse CD4 ϩ T-cell clones specific for given TA, though the precise epitopes have not yet been identified in all cases. 8,9 The high number of human MHC class II alleles severely limits the applicability of many of the antigenic peptides identified thus far. An exception is the HLA-DP4 molecule. Indeed, 2 highly prevalent alleles encode its ␤ chain and their combined frequency reaches approximately 60% of the population world-wide. Two HLA-DP4-restricted tumour associated antigenic peptides have been identified thus far. 10,11 Moreover, detailed analysis of HLA-DP4 peptide binding may facilitate future searches of novel tumour antigenic peptides restricted by this frequently occurring class II MHC allele. 12 Another favourable trait is the "degenerate" DR binding of certain antigenic peptides, i.e., various TA-derived antigenic peptides have been reported to bind to diverse HLA-DR molecules. 13,14 The identification of TA-derived epitopes presented by MHC class II molecules is complicated by the lack of effective screening methods. Recently, by combination of a computer-based algorithm for MHC-binding with T-cell functional analyses, a class II-restricted epitope of carcinoembryonic Ag (CEA, aa 116 -140) was identified that is naturally proce...

Suppression of T cell responses in the tumor microenvironment

“…0.001-0.0001% of CD8 + T cells (but in some protocols for some types of cancers can be considerably more abundant [29]). Following vaccination, in spite of increased numbers of T cells in PBL that express effector phase functions in vitro (cytolysis and IFNg secretion), the number of antigen-specific cells within the tumor typically remains low, and tumor growth is progressive [30,31]. The inability to increase the presence of tumor-reactive T cells in the tumor tissue following successful vaccination implicates a particular impediment to immunotherapeutic control of tumor growth (a 'vascular checkpoint', that will be discussed below) and illustrates the notion that defective antitumor immune responses are primarily localized to the tumor microenvironment.…”

Raf kinases: Oncogenesis and drug discovery

“…172,173 As already mentioned above, a couple of early preclinical studies have evaluated the usefulness of B-RAF as target for immunotherapy. In melanoma patients harboring the V600E B-RAF mutation, a 29-mer B-RAF peptide incorporating the V600E mutation was used for in vitro stimulation of lymphocytes, generating MHC class II-restricted CD4 1 T cells specific for this peptide as well as for melanoma cells expressing V600E B-RAF.…”

Tumor Progression Can Occur despite the Induction of Very High Levels of Self/Tumor Antigen-Specific CD8+ T Cells in Patients with Melanoma

“…These efforts have resulted in generally low rates of immunization as assessed using a variety of techniques (3,4) and objective clinical responses to vaccines used alone are rare and sporadic (reviewed in Refs. [5][6][7]. Immunizations with peptide in saline without adjuvant, used alone or in combination with vaccines encoded by an avian poxvirus, have confirmed the poor T cell responses-even among vaccinated patients showing a detectable CTL response, many have tumor-specific T cell responses ranging between 0.0001 and 0.001% of CD8 ϩ T cells.…”