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Review

Antigenic targets for renal cell carcinoma immunotherapy

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Pages 1791-1801 | Published online: 23 Feb 2005

Bibliography

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  • •This work details a clinical trial of a chimeric fusion protein comprising G250 and GM-CSF in RCC patients, in which T cell responses were induced againstG250/carbonic anhydrase IX antigen. Studies have shown that the G250 antigen contains a number of defined T cell epitopes. Vaccination with G250/GM-CSF fusion protein not only elicited a CTL response, but also primed T helper cell responses in vaccinated patients.
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  • •The HER-2/neu proto-oncogene is overexpressed by many different carcinomas and is shown in this study to contain a number of CTL epitopes. Importantly, primed CTLs specific for these epitopes were detected in freshly isolated TILs from three RCC patients. More recent studies by the same group have demonstrated the importance of subdominant or cryptic CTL epitopes as vaccine candidates for both HER-2/neu and hTERT.
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  • •In a vaccine setting, the use of tumour-derived antigens is often not possible, due to the restricted amount of tumour tissue. The above studies [14,15] circumvent this obstacle by demonstrating that virtually unlimited amounts of mRNA can be amplified by PCR techniques for use in vaccines.
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  • •This study suggests that immature DCs may not be optimal, but rather induce tolerance in a vaccination setting. This work highlighted the need for a better understanding of DC biology.
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  • •Marten et al. show that it is not necessary to culture DCs from patients, but rather that allogeneic DCs from healthy donors can be used with similar efficacy. Allogeneic DCs not only provide the necessary antigen-presenting and costirnulatory environment, but their HLA-mismatch also stimulates immune responses.
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  • •This study shows that fusions formed between autologous DCs and patients' tumour cells can be used to induce antiturnour immune and clinical responses in RCC.
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  • •These manuscripts [30-32] describe how tumour-derived HSPs act as chaperones for antigenic peptides. Furthermore, preparations of tumour-derived HSPs can be used to effectively elicit immune responses specific for the original tumour without autoirnmune complications.
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  • •Until recently, much attention has been attributed to vaccines that activate CTL responses against tumour cells. However, only recently have the importance of Cal' T helper cell responses, in particular antigen-specific Cal' responses, been appreciated. Vaccines that activate bothCD8' andT cell responses totumour antigen are more effective becauseT cells not only enhance a CTLresponse, but also assist in establishing long-term T cell memory.
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  • •This study demonstrated that a chimeric hTERT/LAMP-1 protein presented by DCs enhanced antigen-specific Cal' T cell responses in vitro.
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  • •See [38].
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  • •This clinical study is important, as it shows that vaccination with tumour RNA-transfected DCs elicits both immune and clinical responses in patients with metastatic RCC. An important aspect of this study and that of Heiser [37] is that the T cell responses stimulated by the DC-RNA vaccine were polydonal and directed against several different RCC antigens.
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  • •The authors demonstrate that hTERT can be processed for class I presentation. Furthermore, they show that CTL responses can be generated to hTERT and that these can recognise and lyse tumour cells. Universal tumour antigens are often important to maintain the survival of tumour cells and are broadly applicable to many different types of cancer, thus making them ideal targets for vaccine development.
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  • •Carbonic anhydrase IX/G250 has recently been identified and has been used as a target for monoclonal antibody therapyand as a T cell antigen. The relative paucity of other RCC-specific antigens has, until recently, hampered the development of other RCC-specific defined vaccines.
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  • •These manuscripts [55,56] demonstrate important deficiencies in the antigen-processing machinery (APM) of tumour cells. Tumour cells can avoid presenting key target peptides by downregulating the expression of specific APM components (e.g., TAP molecules), or escape immune attack by downregulating expression of specific HLA alleles.
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  • •See [58].
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  • •These manuscripts [57,58] demonstrate that it is possible to simultaneously elicitmultiple CTL responses by combining several peptide vaccines either alone or when pulsed onto DCs. This work addresses one of the major short-comings of vaccination with single tumour peptides - the evolution of antigen-loss variants.
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  • •This clinical study is important because it is the first of its kind to apply hTERT mRNA-transduced mature DCs in cancer patients. The vaccine not only induced concomitant Cal' and CD8+ T cell responses, but was also found to alter surrogate clinical indicators byprolonging the PSA-doubling time for a subgroup of patients.
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  • •See [67].
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  • •The above manuscripts [66,67]demonstrate the induction of antiturnour immune responses to the non-mutated universal antigen survivin. Survivin is an inhibitor of apoptosis and is abundantly expressed by a wide range of malignancies. In addition to being an RCC antigen, survivin is considered a potentially potent CTL target, as downregulation or antigen-loss as a mechanism ofimmune escape would hinder tumour growth and progression.
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  • •This work demonstrates the potential for combining vaccination against tumour and stromal antigens.
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  • •See [77].
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  • •See [77].
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  • •These references [75-77] show that tolerance against vascular endothelium canbe broken by a range of different vaccination strategies, and that the ensuing T cell responses inhibit tumour growth by preventing angiogenesis. Thus far, it was unknown that CTL precursors specific for endothelial-specific targets existed or if they could be activated by vaccination.
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