The inability of previously tested antigens (including CEA, KRAS, MUC1 and gastrin) to induce immune-specific responses underscores the challenge to identify more relevant immunogenic targets. Indeed, these antigens were chosen only because they were overexpressed or had altered expression in pancreatic tumours, and not because they had been shown to be immunogenic. Therefore, there might be additional as-yet-unidentified antigens that might be more immunogenic for inducing effective immunity against pancreatic cancers. How will such new candidate pancreatic cancer antigens be discovered? Two methods are routinely used in an attempt to identify new targets. The first method, serological analysis of recombinant tumour cDNA expression libraries (SEREX), uses serum to screen phage-display libraries prepared from tumour cells to identify candidate antigen targets that have elicited both humoral and cell-mediated immune responses in cancer patients. This method has identified coactosin-like protein (an actin-filament-binding protein that interacts directly with 5-liopoxygenase and has an important role in cellular leukotriene synthesis) as a potential pancreatic cancer target antigen. This protein seems to be recognized by antibody and T-cell responses in patients with pancreatic cancer155.
The second method uses tumour-specific T cells that have been isolated from patients with pancreatic cancer to screen cDNA libraries prepared from autologous tumour cells. This method requires the isolation and culture of tumour-specific T cells, along with tumour cells, from patients with pancreatic cancer and is a technically challenging approach. This approach has been most successful in identifying melanoma-associated antigens156.
A relatively newer, more promising method of tumour-antigen identification is the use of the patient's lymphocytes to evaluate proteins that are found to be differentially expressed by pancreatic cancer157-158 approach has several advantages. First, it allows for a rapid screen of a large number of candidate antigens but requires the isolation from patients of only a few lymphocytes, which are limited in availability. Second, this approach is not dependent on the availability of autologous tumour cells, which are difficult to isolate in large enough numbers for generating cDNA libraries. Third, this approach can be used to identify tumour antigens that are expressed by any HLA type, allowing for the generalization of this approach to most patients. Finally, this approach has the potential to rapidly identify 'immune relevant' antigens, as it uses immunized lymphocytes from patients vaccinated with a whole-tumour-cell vaccine approach who ideally have demonstrated clinical evidence of immune activation following vaccination. So this method provides the best insurance that the antigens identified are ones that the patient's immune system is reacting to after immunization.
As additional 'immune relevant' pancreatic tumour antigens are identified, the next significant challenge lies in developing strategies to improve the in vivo delivery of these antigens to APCs and thereby allow effective antigen processing and presentation, and subsequent activation of a potent antitumour immune response. DCs are now accepted as the most efficient APCs in B- and T-cell activation. Several clinical trials have tested ex vivo expanded and primed DCs as a vaccine approach. However, these studies have revealed the difficulty in reliably producing phenotypically mature DCs for clinical testing, as only mature DCs are capable of efficiently presenting antigens to T cells. If an antigen is not presented in the proper context by mature DCs, immune downregulation or tolerance can occur. It has been shown in animal models that immature DCs induce T-cell tolerance. As an alternative to DC-based delivery, recombinant viral- and bacterial-vector delivery systems are currently under development or are already undergoing clinical testing. The use of modified viral particles or targeted bacteria to deliver tumour antigens to the immune system is based on the innate ability of the agent to efficiently infect APCs in vivo. Early approaches have included viruses such as vaccinia 159,160 er, the use of immunogenic vectors in cancer patients who have been previously exposed to a similar vector often induces vigorous immune responses against the vector before effective priming against the tumour antigen can occur. As such, other viral particles and bacterial delivery systems are currently nearing or are already undergoing clinical development for the treatment of pancreatic cancer.
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