Immunization of chimpanzees with tumor antigen MUC1 mucin tandem repeat peptide elicits both helper and cytotoxic T-cell responses.
CTLs and antibody responses to the tumor-associated antigen MUC1 mucin can be detected in patients with adenocarcinomas of the breast, pancreas, colon, and ovary. However, neither response is generally effective at controlling disease. Methods to augment immunity to MUC1 are being designed, with the expectation that this will lead to an antitumor response. The key to eliciting potent immunity to tumor MUC1 may be in generating MUC1-specific T-helper cell responses, which, to date, have not been reported in cancer patients. We have recently demonstrated that a synthetic vaccine representing five copies of the MUC1 tandem repeat peptide can be used to prime MUC1-specific human CD4+ T cells in vitro. Here, we extend these studies to test the immunogenicity and safety of the tandem repeat peptide in the chimpanzee, which has the identical MUC1 tandem repeat sequence to the human. To promote induction of Th1-type responses, we used the novel adjuvant LeIF, a Leishmania-derived protein that is known to stimulate human peripheral blood mononuclear cells (PBMCs) and antigen-presenting cells, to produce a Th1-type cytokine profile. We found that MUC1 tandem repeat peptide administered with LeIF elicited positive, albeit transient, proliferative T-cell responses to MUC1 in the PBMCs from four of four chimpanzees. Immunization induced MUC1-specific IFN-gamma but not interleukin 4 expression in CD4+ T cells from PBMCs and draining lymph nodes. MUC1-specific CTLs were also generated that did not induce detectable autoimmune dysfunction during the 1 year of observation. We conclude that the MUC1 tandem repeat peptide can be used to elicit both T-helper and cytotoxic cell responses to MUC1 in the primate and holds promise as a safe and effective cancer vaccine.
Barratt-Boyes
S M
SM
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pennsylvania 15261, USA. smbb+@pitt.edu
Vlad
A
A
Finn
O J
OJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D018396:Mucin-1 / Q000276:immunology*; D002679:Pan troglodytes; D010455:Peptides / Q000276:immunology; D020449:Repetitive Sequences, Amino Acid; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D018396:Mucin-1; D010455:Peptides; D007371:Interferon-gamma