Phase-I Study of Synthetic Muc1 Peptides in Breast-Cancer

Xing, Puyuan; Michael, M; Apostolopoulos, Vasso; Prenzoska, Julie; Marshall, C.; Bishop, Jennifer; McKenzie, Ifc

doi:10.3892/ijo.6.6.1283

Cited by 31 publications

(44 citation statements)

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“…Phase I clinical trials demonstrating the safety of MUC1 peptide formulations for cancer patients have been reported (Xing et al, 1995;Gilewski et al, 1996;Goydos et al, 1996;Longenecker et al, 1996). In our phase I study using a MUC1 peptide KLH conjugate formulation, we have found induction of T 1 responses including class I restricted CTLs in cancer patients (Longenecker et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity and antitumor activity of a liposomal MUC1 peptide-based vaccine

Samuel

Budzyński²,

Reddish³

et al. 1998

Int. J. Cancer

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Section: Discussionmentioning

confidence: 99%

Immunogenicity and antitumor activity of a liposomal MUC1 peptide-based vaccine

Samuel

Budzyński²,

Reddish³

et al. 1998

Int. J. Cancer

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“…MUC1 is attracting increasing interest as a target for immunotherapy of adenocarcinomas; several phase I clinical trials, involving different vaccine substrates, adjuvants and carrier proteins have been carried out [28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

An Enzyme-Linked Immunosorbent Assay for the Measurement of Circulating Antibodies to Polymorphic Epithelial Mucin (MUC1)

S¹,

Mm²,

Kenemans³

et al. 1998

Tumor Biol

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Introduction: About one-third of breast and ovarian carcinoma patients have circulating antibodies reactive with polymorphic epithelial mucin (MUC1), either free or bound to immune complexes. While the presence of these immune complexes has prognostic significance in breast cancer patients, the significance of free MUC1 antibodies is less clear. The objective of this study was to develop a reliable assay for the accurate determination of circulating free antibodies to MUC1. Material and Methods: We developed an enzyme-linked immunosorbent assay (ELISA) (PEM.CIg) employing a 60 mer peptide (a triple tandem repeat sequence of the MUC1 peptide core) conjugated to bovine serum albumin and peroxidase-labeled antihuman immunoglobulin G or M antibodies. The assay was standardized and its analytical performance evaluated. A total of 492 serum samples were obtained from 40 healthy men, from 201 healthy women (including 55 women without a history of pregnancy and 45 pregnant women), and (before primary treatment) from 62 benign breast tumor patients and 190 breast cancer patients. MUC1 serum levels were determined with commercial CA 15-3 tests. Results: Circulating antibodies to MUC1 are present both in healthy subjects and in breast cancer patients. The within- and between-assay coefficients of variation were, respectively, 2 and 12% for the IgG determinations and 1.2 and 3% for the IgM determinations. Correlation coefficients for serially diluted serum samples ranged from 0.9998 to 0.9920 for IgG and from 0.9996 to 0.9818 for IgM determinations. The reactivity of serum samples was partially blocked by the addition of various MUC1 peptides and by MUC1 mucin. The inhibiting effect of modified 60 mer peptides suggests the presence of antibodies directed to more than one epitope. Conclusions: The PEM. CIg assay is a reliable ELISA for measuring free MUC1 antibodies in serum. We are in the process of relating the results obtained in the breast cancer group to disease outcome to evaluate its prognostic significance. In addition, the assay may become a useful tool for vaccine therapy monitoring.

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“…These changes in cancer generate a potential new target for immunotherapy that is apparently absent in normal mucin (7)(8)(9)(10). The APDTR sequence [from the variable number of tandem repeats (VNTR) region] is immunogenic in mice, leading to antibody formation, whether the antigen is administered as MUC1+ cancer cells, purified mucin (HMFG), or as peptides (11,12). Such studies of immunogenicity in mice would be of little relevance to humans were it not for the findings that tumorspecific CTL precursors (CTLp) exist in the lymph nodes of patients with cancer of breast, ovary, or pancreas, or in multiple myeloma patients (13)(14)(15)(16).…”

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confidence: 99%

Oxidative/reductive conjugation of mannan to antigen selects for T1 or T2 immune responses.

Apostolopoulos

Pietersz

Loveland

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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183

134

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The induction of CD8+ cytotoxic T lymphocytes (CTLs) is desirable for immunization against many diseases, and recombinant-synthetic peptide antigens are now favored agents to use. However, a major problem is how to induce CTLs, which requires a Ti-type response to such synthetic antigens. We (refs. 4 and 5; unpublished data). The unusual finding is that if the conjugation is done under oxidizing conditions, then cell-mediated immunity is selectively stimulated, compared with using reducing conditions for conjugation when antibody responses occur.A successful vaccine for cancer immunotherapy requires a suitable target antigen and production of cytotoxic T lymphocyte (CTL) responses (6). In adenocarcinomas, it appears that mucins, particularly MUC1, may provide a suitable target as there is a 10-fold increase in mucin expression on the cell surface, and altered glycosylation leads to exposure of normally hidden peptide sequences (e.g., APDTR). These changes in cancer generate a potential new target for immunotherapy that is apparently absent in normal mucin (7-10). The APDTR sequence [from the variable number of tandem repeats (VNTR) region] is immunogenic in mice, leading to antibody formation, whether the antigen is administered as MUC1+ cancer cells, purified mucin (HMFG), or as peptides (11,12). Such studies of immunogenicity in mice would be of little relevance to humans were it not for the findings that tumorspecific CTL precursors (CTLp) exist in the lymph nodes of patients with cancer of breast, ovary, or pancreas, or in multiple myeloma patients (13-16). The CTLp can be stimulated by antigen and interleukin 2 (IL-2) in vitro to become functional CD8+ CTLs, the target antigen being the APDTR sequence of MUC1 (13-16 MATERIALS AND METHODSChemical Studies. MUC1 FP containing 5 VNTR of human MUC1 and peptide (Cpl3-32) were produced as described (2). FP was conjugated to mannan in two ways. (i) Ox-M-FP: Mannan (Sigma), at 14 mg/ml in 0.1 M phosphate buffer (pH 6.0), was oxidized with sodium periodate (0.01 M) for 60 min at 40C. Ethanediol (10 ,ul) was added and incubated for a further 30 min at 4°C, and the mixture was passed through a Sephadex-G25 column equilibrated in bicarbonate buffer (pH 6.0-9.0). The oxidized mannan that eluted in the void volume (2 ml) was mixed with 900 gg of MUC1 FP, incubated overnight at room temperature, and used without further purification. (ii) Reduced (Red)-M-FP: The ox-M-FP mixture was treated with sodium borohydride (1 mg/ml) for 3 hr and used without further purification.Immunizations 10128The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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Phase-I Study of Synthetic Muc1 Peptides in Breast-Cancer

Cited by 31 publications

References 0 publications

Immunogenicity and antitumor activity of a liposomal MUC1 peptide-based vaccine

Immunogenicity and antitumor activity of a liposomal MUC1 peptide-based vaccine

An Enzyme-Linked Immunosorbent Assay for the Measurement of Circulating Antibodies to Polymorphic Epithelial Mucin (MUC1)

Oxidative/reductive conjugation of mannan to antigen selects for T1 or T2 immune responses.

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