Mucins In Diagnosis And Therapy

Vaccination Is Not Immunization Vaccine Risks Exposed

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Several TAAs have been shown to have many properties consistent with their association with mucins. Tumor-associated epitopes on mucins (Figure 12.2) have been implicated in the pathogenesis of many cancers including pancreatic cancer. Several clinically useful antibodies that recognize epitopes on mucins were initially generated against tumors of secretory epithelial cell origin from the pancreas, breast, colon, and lung, and include (but are not limited to) DUPAN2, HMFG2, SM-3, and CA 199. Some of the antibodies recognize epitopes that are aberrantly expressed on tumor mucin but not on corresponding normal cell populations (SM-3), whereas others recognize epitopes expressed on mucin from both normal and malignant cells from a given organ site (DUPAN2 and CA 199). These and other mucin-reactive antibodies generally show distinct patterns of tissue reactivity by immunohistochemical analysis.

There are no tumor-specific markers for pancreatic cancer; markers such as serum CA 19-9, DUPAN-2, and CA125 that are being used as potential targets have low specificity.123-126 For over two decades, the structure of these antigens (CA 19-9, DUPAN2, or CA 125) has been heavily investigated for the development of serum-based immunoassays to detect early cancers. These antigens contain oligosaccharide structures that are being recognized by monoclonal antibodies. Further, these saccharide epitopes are present on the O-glycosidic chains harbored by the apomucin backbones. For example, MUC1 carries CA19-994,127,128 and DUPAN-275,127 epitopes, and MUC16 carries the CA 125 epitope.129

At this time, CA19-9 remains the only Food and Drug Administration (FDA)-approved marker to monitor pancreatic cancer. The CA 19-9 recognizes a mucin-type glycoprotein sialosyl Lewis A/B antigen.130 Because 5% of the general population are Lewis A/B negative, the maximum sensitivity of this marker is 95%.131,132 Patients (65%) with pancreatic cancer will have CA 19-9 levels greater than 120 U/L, whereas only 2% of the cases of pancreatitis will have levels this high. The specificity for pancreatic cancer increases with high levels of CA 19-9; however, most of these cancers will be unresectable.

A unique TAA is TAG-72, a pan-adenocarcinoma antigen that is expressed by majority of human adenocarcinoma of pancreas, colon, ovary, prostate, lung, and esophagus and is absent in most normal tissues. TAG-72 has been identified by its immunoreactivity with the monoclonal antibody (MAb) B72.3, a murine MAb, which was developed by the immunization of mice with a membrane-enriched fraction of human met-astatic breast carcinoma tissue. The epitope recognized by MAb B72.3 is sialyl-Tn, a unique disaccharide present in multiple copies on the tumor-associated mucin TAG-72.

A retrospective analysis of 25 primary adenocarcinomas of the pancreas, 16 metastatic pancreatic tumors, 8 cases of chronic pancreatitis, and 3 adult normal pancreas for the expression of TAG-72 antigen using MAb B72.3 was performed.133 Out of 25 malignant primary tumors, 21 (83%) were reactive, and all 16 metastatic sites expressed the B72.3 antigen. In contrast, all cases of pancreatitis and normal pancreas were either weakly reactive or nonreactive. Interestingly, 10 malignant and 2 benign pancreatic fine-needle aspirates showed results similar to those seen with fixed tissues. Another study examined the incidence and expression of TAG-72 along with other tumor-associated antigens CA19.9, DU-PAN2, and CA125 in serum and tissues of patients with pancreatic cancer.134 Eighty-three percent of tumor tissues demonstrated the expression of 3 or more antigens. The least commonly detected antigen was CA125. Expression of TAG-72 was rare in the normal pancreas but was commonly expressed in ductal cells of chronic pancreatitis. Serologic coexpression of elevated antigen levels was less common because 30% of the patients showed increased levels of 3 or more antigens.

Nevertheless, the unique epitopes provided by these antigens are being used as potential targets for active and passive immunotherapy of cancer. Radioimmunoconjugates against TAG-72 of B72.3 and CC49 monoclonal antibodies have been tested in clinical trials for colorectal, pancreatic, and other cancers. Results so far in Phase I and Phase II trials (systemic administration) of these agents have not produced cures for several reasons.135 A new generation of genetically engineered immunoconjugates, with desired pharmacokinetics and biodistribution properties, has been developed to address these issues and are in the process of being evaluated in preclinical and clinical trials.136

The immune system has the potential to recognize such TAA structures as foreign and to mount specific immune responses against them, so as to reject tumor cells. This provides the basis for the development of active specific immunotherapeutic agents (tumor vaccines). The first mucin cDNA to be cloned, MUC1, is highly overexpressed and differentially glycosylated by pancreatic adenocarcinomas and is a cell surface-associated mucin with a structure that is remarkably similar to some of the selectins and selectin ligands. There have been studies that evaluated the effect of immunizations with MUC1 on immunity to tumors in animal models. Vaccine strategies against MUC1 include DNA, peptide, glycopeptide, fusion proteins, and recombinant vaccines delivered by adenovirus, vaccinia virus, and other viral vectors, administered directly or in vivo to manipulated cells.

In one study, the vaccinia vector expressing MUC1 (epithelial tumor antigen) provided protection in a murine model against tumors expressing ETA; however, the specificity of the protective response for MUC1 was not demonstrated unequivocally.137 In another study, major histocompatibility complex (MHC)-restricted MUC1-specific CTLs were produced in C57BL/6 mice immunized with a MUC1-mannan fusion protein.138 CTLs that specifically recognize carbohydrate structures on specific peptides in association with MHC Class I molecules have been described.139

Human T-lymphocytes that recognize epitopes on the MUC1 core protein have been produced by in vitro stimulation with MUC1 from patients with breast, pancreatic, and ovarian carcinomas.140,141 These in vitro stimulated T-lymphocytes are unusual in that they show some cytotoxic activity against human tumor cells but they are not MHC-restricted in their specificity. The fact that they are derived from patients with progressive disease suggests that some mechanism prevents these cells from eradicating tumors in situ. There is an anecdotal report, however, of a case in which a long-term breast cancer survivor has relatively high levels of CTL precursors with MHC restricted specificity for MUC1 and a clinical history that is consistent with the development of anti-MUC1 responses in situ. A Phase I trial was conducted by Finn and collaborators142 in which 3 doses of 100 mg of 105 amino acid peptide corresponding to 5 tandem repeat units of MUC1 mixed with BCG were administered over a 9-week period. Persistent recall DTH (delayed type hypersensitivity) responses were noted in over half of the immunized patients. No significant side effects were observed, and no objective responses were reported from this trial. Most of the studies on MUC1 utilized exclusively the tandem repeat moiety of the protein. Because this portion of the molecule is secreted and found on the extracellular domain of tumor cells, it may not be the best target for immunization procedures that will produce conventional cellular immune responses (i.e., to peptides associated with MHC molecules). Recent studies are investigating the use of other domains of MUC1 such as the signal sequence or cytoplasmic tail.

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