Other Dr Jekyll and Mr Hyde Like Tumor Antigens 551 Dr Jekyll CEA

The carcinoembryonic antigen (CEA), a heterogeneous cell surface and secreted glycoprotein (~50% glycosylation), member of the immunoglobulin supergene family, performs a function as an intercellular adhesion molecule. During malignant transformation its expression is largely upregulated, accompanied by changes in its glycosylation.

Because CEA is recognized as a self-antigen, individuals are immunologically tolerant to CEA. Although, immune responses to CEA have been observed in healthy and cancer bearing individuals, these are weak and have to be boosted to become protective against or to reject CEA positive tumors. Serum titers for CEA are used for diagnosis of a variety of tumors, especially of the colon, pancreas, breast and lung.

Using human CEA-transgenic mouse models immune tolerance has been successfully overcome by certain vaccination strategies that generate CEA-specific, MHC-restricted CTLs, T cell proliferation, CD4+ T cell responses and anti-CEA antibody generation, which resulted in tumor rejection in these mice [77-81]. Very recently it was shown that genetically modified DCs that express CEA and Th1-type cytokines IL-12 and GM-CSF, can overcome peripheral immune tolerance to CEA and induce strong cellular antitumor activity in transgenic mice without creating autoimmunity [82, 83]. Similar results were achieved with a vaccine based on anti-Id antibody pulsed DCs, which induced both humoral and cellular (CTLs, helper and memory T cells) immune responses in the vaccinated CEA-transgenic mice and provided protective antitumor immunity. The anti-Id antibody was raised against anti-CEA antibody and mimics a single protective epitope of human CEA. This might be of advantage in comparison to CEA protein or gene based vaccines, that contain multiple different CEA epitopes, some of which are protective but others could initiate immunosuppressive or autoimmune responses [81]. In general, humoral responses against CEA have been seen in response to vaccination with recombinant CEA protein and CEA anti-idiotype antibodies, whereas T cell responses have been preferentially generated by dendritic cells loaded with immunogenic epitopes of CEA [84].

In a recently performed clinical study, generation of CEA-specific T cell responses was seen in patients with advanced CEA-expressing tumors who received recombinant vaccinia and subsequently avipox vectors encoding CEA and costimu-latory molecules (e.g. B7.1). Additional supplementation with GM-CSF and low-dose IL-2 increased the number of CEA-specific T cell precursors. Some patients also developed anti-CEA antibodies [85]. In another vaccination study, several patients with advanced colorectal cancer developed responses to CEA after intra-dermally and intravenously administered vaccination with CEA-loaded matured monocyte-derived DCs [86]. CEA-specific CD8+ T cells were detected in post-treatment delayed type hypersensitivity biopsies and in one resected abdominal draining lymph node of one patient. These T cells produced large amounts of IFN-gamma and IL-2, but no IL-4 or IL-10 in response to CEA-peptide loaded target cells. Majority of the patients showed preexisting immunity against CEA (induration of the vaccination site), although this immunity did not yield outgrowth of T cells from the injection site. A larger clinical study was performed with recombinant CEA and with or without low-dose GM-CSF given with each immunization [87]. All patients generated CEA-specific T cells and anti-CEA antibodies of IgG isotype. The immune responses persisted for more than 2 years and correlated with increased survival. Of the patients that received only recombinant CEA vaccine and no GM-CSF, only about 70% developed humoral and cellular immune responses against CEA. In 2004 a clinical study was conducted on chemotherapy resistant colorectal cancer patients using synthetic CEA peptides that bind to either MHC

class I HLA-A 0201 or HLA-A2402 [88]. Peptide-pulsed dendritic cells were injected into the inguinal lymph node. About 70% of the patients showed significant increase in IFN-gamma producing CEA-specific CTLs. However, most patients still progressed and only two showed disease stabilization for 12 weeks. Similarly challenging combination therapy, chemotherapy with concurrent immunotherapy, against CEA was performed in patients with metastatic colorectal cancer [89]. The target antigen was the immunodominant epitope CAP-1, HLA-A2-restricted nonamer peptide. Approximately 47% of the patients showed significant increases in CAP-1-specific CTLs. Multiple adjuvants (CpG, GM-CSF or DCs) were tested in this trial without any major differences observed between them. The overall clinical response in this study was 35%.

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