Cancer vaccines based on human tumor associated antigens (TAA) have been tested in patients with advanced or recurrent cancer, in combination with or following standard therapy. Their immunogenicity and therapeutic efficacy has been difficult to properly evaluate in that setting characterized by multiple highly suppressive effects of the tumor and the standard therapy on the patient’s immune system. In animal models of human cancer, vaccines administered in the prophylactic setting are most immunogenic and effectively prevent cancer development and progression. We report results of a clinical study that show that in patients without cancer but with a history of premalignant lesions (advanced colonic adenomas, precursors to colon cancer), a vaccine based on the TAA MUC1 was highly immunogenic in 17/39 (43.6%) of vaccinated individuals, eliciting high levels of anti-MUC1 IgG and long-lasting immune memory. Lack of response in 22/39 individuals was correlated with high levels of circulating myeloid derived suppressor cells pre-vaccination. Vaccine-elicited MUC1-specific immune response and immune memory were not associated with any toxicity. Our study shows that vaccines based on human tumor associated antigens are immunogenic and safe and capable of eliciting long term memory that is important for cancer prevention. We also show that in the premalignant setting, immunosuppressive environment (e.g. high levels of MDSC) might already exist in some individuals, suggesting an even earlier premalignant stage or preselection of non-immunosuppressed patients for prophylactic vaccination.

Many cancers, including ovarian, overexpress epithelial mucin (MUC1) and promote anti-MUC1 antibodies that may correlate with more favorable prognosis. By extension, risk for ovarian cancer might be reduced by preexisting MUC1-specific immunity. We measured anti-MUC1 antibodies in 705 control women, identified events predicting antibodies, and estimated ovarian cancer risk by comparing profiles of events generating antibodies in controls with those in 668 ovarian cancer cases. Factors predicting antibodies included oral contraceptive use, breast mastitis, bone fracture or osteoporosis, pelvic surgeries, nonuse of talc in genital hygiene, and to a lesser extent intrauterine device use and current smoking. There was a significant increase in the likelihood of having anti-MUC1 antibodies from 24.2% in women with 0 or 1 condition, to 51.4% in those with five or more conditions. By the same index of events, the risk for ovarian cancer was inversely associated with number of conditions predisposing to anti-MUC1 antibodies. Compared with having experienced 0 or 1 event, the adjusted risk for ovarian cancer decreased progressively with relative risks (

MUC1 is a glycoprotein overexpressed in tumors as a hypoglycosylated form. A vaccine composed of a 100-amino acid peptide corresponding to five 20-amino acid long repeats, and SB-AS2 adjuvant, was tested in a phase I study for safety, toxicity, and ability to elicit or boost MUC1-specific immune responses. Patients with resected or locally advanced pancreatic cancer without prior chemotherapy or radiotherapy were eligible. Escalating doses of the peptide (100, 300, 1,000, and 3,000 mug) were admixed with SB-AS2 and administered intramuscularly every 3 weeks for three doses, in cohorts of four patients. Sixteen patients were enrolled. Common adverse effects were grade 1 flu-like symptoms, tenderness, and erythema at the injection site. Delayed-type hypersensitivity (DTH) sites showed few or no T cells prevaccination (Pre V), but increased T-cell infiltration postvaccination (Post V). There was an increase in the percentage of CD8(+) T cells in the peripheral blood Post V. An increase in total MUC1-specific antibody was seen in some patients, and several patients developed IgG antibody. Two of 15 resected pancreatic cancer patients are alive and disease free at follow-up of 32 and 61 months. MUC1 100mer peptide with SB-AS2 adjuvant is a safe vaccine that induces low but detectable mucin-specific humoral and T-cell responses in some patients. No difference was seen between different peptide doses. Further evaluation is warranted to examine the effect on disease-free survival and overall survival, especially in early disease and in the absence of immunosuppressive standard therapy.

Purpose: Cyclin B1 -derived peptides were shown by us to be targets of tumor-specific CD8 + T cells in patients with breast and head and neck cancer. We obtained further evidence of cyclin B1 immunogenicity and its potential to serve as a tumor-specific antigen by analyzing its ability to elicit T cell -dependent humoral immune responses in vivo in patients with different types of tumors.Experimental Design: Recombinant cyclin B1 protein from two different sources was purified and used as antigen in ELISA assays to test sera from patients with breast, pancreatic, colon, and lung cancer for the presence of anticyclin B1 antibody. We also analyzed patients with benign lung disease, premalignant disease, and a known history of heavy smoking.Results and Conclusions: Cyclin B1 elicits helper T cell -dependent antibody responses in vivo. Tumors with higher level of cyclin B1 expression elicit higher anti-cyclin B1 antibody levels. Antibodies in patients with breast and colon cancer are primarily of the IgG isotype whereas patients with pancreatic and lung cancer have in addition anti-cyclin B1 IgA. Cyclin B1 -specific IgG was also detected in long-term smokers and in patients with preneoplastic lung disease. Immune responses to aberrantly expressed cyclin B1 in tumors and premalignant lesions should be further explored as diagnostic and prognostic markers, in addition to their immunotherapeutic potential.

Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that accumulate in circulation of cancer patients and at tumor sites where they suppress anti-tumor immunity. We previously reported that in a colon cancer prevention trial of a MUC1 vaccine tested in individuals at increased risk for colon cancer, those who did not mount immune response to the vaccine had higher pre-vaccination levels of circulating MDSC compared to those who did. We also reported that individuals with pancreatic premalignancy, Intraductal Papillary Mucinous Neoplasm (IPMN), had increased circulating levels of MDSC that inversely correlated with spontaneous antibody responses against the pancreatic tumor associated antigen MUC1, abnormally expressed on IPMN. Accumulation of MDSC in cancer and their immunosuppressive role had been well established but their presence in premalignancy was unexpected. In this study we compared MDSC in premalignancy with those in cancer with the hypothesis that there might be differences in the composition of various MDSC subpopulations and their immunosuppressive functions due to different lengths of exposure to disease and/or different tissue microenvironments. In cohorts of patients with premalignant polyps, colon cancer, premalignant IPMN, and pancreatic cancer, we confirmed higher levels of MDSC in premalignancy compared to healthy controls, higher levels of MDSC in cancer compared to premalignancy, but no difference in their subpopulation composition or immunosuppressive capacity. We show that levels of MDSC in premalignancy correlate negatively in vivo with spontaneous MUC1-specific antibody responses and in vitro with polyclonal T cell proliferation and IFN-γ secretion.

Background: Risk for ovarian cancer correlates directly with ''ovulatory years or cycles'' estimated from time not pregnant, breast-feeding, or using oral contraceptives. Recently, we reported that several factors known to reduce ovarian cancer risk may operate by inducing antibodies against mucin 1 (MUC1), a glycoprotein overexpressed in ovarian cancer. Conversely, other events might increase risk by interfering with the development of protective immunity. In this study, we examined whether the total number of ovulatory cycles decreases the likelihood of anti-MUC1 antibodies and provides an immune basis for the association between ''incessant ovulation'' and ovarian cancer risk.Methods: From 1998 to 2003, we enrolled 668 epithelial ovarian cancer cases and 721 controls residing in eastern Massachusetts or New Hampshire, collected information on menstrual and reproductive events, and obtained blood

Background: The surface epithelial glycoprotein MUC1 becomes overexpressed and hypoglycosylated in adenocarcinomas; similar changes occur during nonmalignant inflammatory events. Antibodies developed against tumor-like MUC1 in response to such events could be one way through which ovarian cancer risk factors operate.Methods: We evaluated the association between anti-MUC1 antibodies and risk of ovarian cancer in a prospective nested case-control study in the Nurses' Health Studies. We used an ELISA to measure plasma anti-MUC1 antibodies in 117 ovarian cancer cases collected at least 3 years before diagnosis and 339 matched controls.Results: In controls, younger women (P-trend = 0.03), those with a tubal ligation (P = 0.03), and those with fewer ovulatory cycles (P-trend = 0.04) had higher antibody levels. In cases, women with late-stage disease (P = 0.04) and those whose specimen was >11 years remote from diagnosis (P = 0.01) had higher antibody levels. Overall, increasing anti-MUC1 antibody levels were associated with a nonsignificant trend for lower risk for ovarian cancer, but there was highly significant heterogeneity by age (P-heterogeneity = 0.005). In women <64 years, the antibody level in quartiles 2 to 4 versus quartile 1 were associated with reduced risk (relative risk = 0.53; 95% confidence interval, 0.31-0.93; P-trend = 0.03), whereas in women ≥64 years, the corresponding relative risk was 2.11 (95% confidence interval, 0.73-6.04); P-trend = 0.05).Conclusion: Anti-MUC1 antibodies evaluated several years before diagnosis may be associated with lower risk of subsequent ovarian cancer in women <64 years old at assessment.Impact: Key elements of an "immune model" to explain ovarian cancer risk factors are confirmed and should be evaluated in larger prospective studies. Cancer Epidemiol Biomarkers Prev; 19(6); 1595-601. ©2010 AACR.

Background Epidemiologic studies found childhood mumps might protect against ovarian cancer. To explain this association, we investigated whether mumps might engender immunity to ovarian cancer through antibodies against the cancer-associated antigen MUC1 abnormally expressed in the inflamed parotid gland. Methods Through various health agencies, we obtained sera from 161 cases with mumps parotitis. Sera were obtained from 194 healthy controls. We used an ELISA to measure anti-MUC1 antibodies and electro-chemiluminescence assays to measure MUC1 and CA 125. Log-transformed measurements were analyzed by t-tests, generalized linear models, and Pearson or Spearman correlations. We also conducted a meta-analysis of all published studies regarding mumps and ovarian cancer. Results Adjusting for assay batch, age, and sex, the level of anti-MUC1 antibodies was significantly higher in mumps cases compared to controls (p = 0.002). Free circulating levels of CA 125, but not MUC1, were also higher in cases (p = 0.02). From the meta-analysis, the pooled odds ratio estimate (and 95% CI) for the mumps and ovarian cancer association was 0.81 (0.68–0.96) (p = 0.01). Conclusion Mumps parotitis may lead to expression and immune recognition of a tumor-associated form of MUC1 and create effective immune surveillance of ovarian cancer cells that express this form of MUC1.