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Immunization of High-Risk Breast Cancer Patients with Clustered Stn-KLH Conjugate Plus the Immunologic Adjuvant QS-21 Teresa A

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Immunization of High-Risk Breast Cancer Patients with Clustered Stn-KLH Conjugate Plus the Immunologic Adjuvant QS-21 Teresa A Cancer Therapy: Clinical Immunization of High-Risk Breast Cancer Patients with Clustered sTn-KLH Conjugate plus the Immunologic Adjuvant QS-21 Teresa A. Gilewski,1Govind Ragupathi,1Maura Dickler,1Shemeeakah Powell,1Sonal Bhuta,1 Kathy Panageas,1R. Rao Koganty,2 Jeannette Chin-Eng,1Clifford Hudis,1Larry Norton,1 Alan N. Houghton,1and Philip O. Livingston1 Abstract Purpose: To determine the clinical toxicities and antibody response against sTnand tumor cells expressing sTnfollowing immunization of high-risk breast cancer patients with clustered sTn-KLH [sTn(c)-KLH] conjugate plus QS-21. Experimental Design:Twenty-seven patients with no evidence of disease and with a history of either stage IV no evidence of disease, rising tumor markers, stage II (z4 positive axillary nodes), or stage III disease received a total of five injections each during weeks 1, 2, 3, 7, and 19. Immuni- zations consisted of sTn(c)-KLH conjugate containing 30, 10, 3, or 1 Ag sTn(c) plus 100 Ag QS-21. Induction of IgM and IgG antibodies against synthetic sTn(c) and natural sTn on ovine submaxillary mucin were measured before and after therapy. Fluorescence-activated cell sorting analyses assessed reactivity of antibodies to LSC and MCF-7 tumor cells. Results: The most common toxicities were transient local skin reactions at the injection site and mild flu-like symptoms. All patients developed significant IgM and IgG antibody titers against sTn(c). Antibody titers against ovine submaxillary mucin were usually of lower titers. IgM reactiv- ity with LSC tumor cells was observed in 21patients and with MCF-7 cells in 13 patients. There was minimal IgG reactivity with LSC cells. Conclusion: Immunization with sTn(c)-KLH conjugate plus QS-21is well tolerated and immuno- genic in high-risk breast cancer patients. Future trials will incorporate sTn(c) as a component of a multiple antigen vaccine. Several structurally similar blood group–related carbohydrate provides a natural source of sTn (13, 14). An association may antigens, including Thomsen-Freidenreich (TF), Tn, and sialyl exist between greater sTn expression on tumors and a poorer Tn (sTn), attached to protein backbones of glycoproteins, are prognosis in breast cancer (15, 16); sTn may also be predictive promising targets for vaccine therapy due to their widespread of response to adjuvant chemotherapy in node-positive breast presence on the cell surface of human tumors (1, 2). In cancer (17). particular, the disaccharide sTn [NeuAca(2!6)GalNAca-0-Ser/ Expression of sTn on normal cells is limited and primarily Thr], O-linked to serine and threonine residues on mucins, is restricted to luminal surfaces (18). In tumors, this pattern is recognized by monoclonal antibodies (i.e., B72.3; refs. 3, 4) often disrupted. Abnormal glycosylation of tumor cell mucins and expressed on tumors of breast, gastric, colon, pancreas, results in shorter and fewer carbohydrate chains, allowing for prostate, lung, endometrial, and ovarian origin (5–11). In this greater exposure of antigens such as sTn; this may contribute study, the evaluation of sTn as an antigenic target in breast to increased expression of sTn on tumors in comparison with cancer patients is explored. normal cells (19–22). However, the role of sTn has not yet There is limited expression of sTn on normal human cells been clearly defined (23–27). (5, 8, 11, 12), although ovine submaxillary mucin (OSM) Development of a sTn-based vaccine requires consideration of several variables. First, the source of sTn can be natural (from OSM or human cells) or synthetic and influence the reactivity of various monoclonal antibodies (14). Second, sTn is not Authors’ Affiliations: 1Departments of Medicine and Biostatistics, Memorial Sloan-Kettering Cancer Center, NewYork, NewYork and 2Biomira, Inc., Edmonton, highly immunogenic because it is a carbohydrate as well as a Alberta, Canada ‘‘self-antigen’’. One approach to increase immunogenicity is Received 9/28/06; revised 2/21/07; accepted 2/27/07. conjugation of an antigen to keyhole limpet hemocyanin Grant support: National Cancer Institute grant R01CA 61422. (KLH), an immunogenic protein carrier (20, 28), and the The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance addition of immunologic adjuvants such as QS-21 (2, 29). with 18 U.S.C. Section 1734 solely to indicate this fact. Third, the conformation of sTn found on naturally occurring Note: Presented in part at theAmerican Society of Clinical Oncology Meeting,1997. mucins may be different from that of synthetic sTn. For Requests for reprints: Teresa Gilewski, Memorial Sloan-Kettering Cancer Center, example, the monoclonal antibody B72.3, preferentially 1275 York Avenue, New York, NY 10021. Phone: 212-639-8319; Fax: 646-888- reactive with tumor cells over normal cells and OSM, has been 4555; E-mail: [email protected]. F 2007 American Association for Cancer Research. shown to react primarily with clusters of sTn (5, 30, 31). A doi :10.1158/1078-0432.CCR-0 6-2189 clustered formation of Tn antigens may have more relevant www.aacrjournals.org 2977 Clin Cancer Res 2007;13(10) May 15, 2007 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2007 American Association for Cancer Research. Cancer Therapy: Clinical antigenicity than single Tn antigens (32), and this may be true disease within 24 months of completing adjuvant therapy. A minimum for sTn as well. of 4 weeks must have elapsed since surgery, chemotherapy, or radiation Immunization of mice with either synthetic single sTn-KLH therapy and 6 weeks since immunotherapy. Exclusion criteria included or clustered sTn-KLH [sTn(c)-KLH] conjugates plus QS-21 pregnancy, seafood allergy, known autoimmune or immunodeficiency induced IgM and IgG antibodies reactive with OSM and the disorder, significant heart disease, other active cancers (excluding skin carcinomas), and Karnofsky performance status V 80. The following respective synthetic antigens as well as IgG antibodies reactive were required: lymphocyte count z 0.5 Â 106/mL, WBC count z 3,000 with sTn-positive tumor cells in both groups of mice (30). per AL, serum creatinine/aspartate aminotransferase/alkaline phospha- Inhibition assays revealed that the post-immunization sera tase V 1.5Â upper limit of normal, and g-glutamyltranspeptidase V 2Â were primarily inhibited by the particular construct in the upper limit of normal. All patients signed an informed consent, vaccine. The similar reactivity of both sets of sera with OSM approved by the Institutional Review Board and the Food and Drug and sTn-positive tumor cells implies that the sera were reactive Administration. Tumor sTn expression was not evaluated in this study. with either the clustered or the unclustered configuration. Immunization schedule and on-study evaluation. Each patient However, monoclonal antibodies, such as B72.3, that have the received a total of five s.c. injections (during weeks 1, 2, 3, 7, and 19), greatest specificity for tumor cells over normal cells react usually into the upper arm or thigh and rarely in the buttocks. Four primarily with sTn clusters, suggesting that this is the most groups of patients received sTn(c)-KLH conjugate containing either A A relevant target for vaccine construction. 30, 10, 3, or 1 g sTn(c) plus 100 g QS-21 in each dose. History and physical exams and carcinoembryonic antigen and CA15-3 levels were The immunogenicity of sTn-KLH and sTn(c)-KLH vaccines done during weeks 1, 7, and 19. Complete blood count and chemistry in mice has been assessed using two different conjuga- profiles were drawn before injection and then during weeks 3, 7, and 19. tion methods: by direct reductive amination or with a Blood for immune response was drawn during weeks 1, 2, 3, 5, 7, 9, 4-(4-N-maleimidomethyl) cyclohexane-1-carboxyl hydrazide 13, 19, and 21 and then every 3 months if feasible. Computerized heterobifunctional linker (33). The 4-(4-N-maleimidomethyl) tomography scans and bone scans were obtained before study and then cyclohexane-1-carboxyl hydrazide linker was found to be the during weeks 21 to 24. preferred method of conjugation for sTn(c) as it resulted in a sTn(c)-KLH + QS-21 preparation. The synthetic sTn(c) was prepared more efficient yield and higher antibody titers against sTn(c). at Biomira, Inc. and then transported to Memorial Sloan-Kettering Other studies have shown inhibition of tumor growth in mice Cancer Center. The cluster was prepared by the attachment of a following immunization with constructs containing desialy- synthetic sTn disaccharide to a serine. With Fmoc technology, three serine-sTn constructs were attached followed by conjugation of the lated OSM (primarily Tn antigen; ref. 34) or synthetic TF (35). last serine with a crotyl linker arm. The cluster was then conjugated to The earliest clinical trials of sTn constructs evaluated patients KLH by a 4-(4-N-maleimidomethyl) cyclohexane-1-carboxyl hydrazide with colorectal carcinoma following immunization with linker for patient injections and to human serum albumin (HSA) for partially desialylated OSM plus either bacillus Calmette-Guerin use in skin tests and in vitro analyses (41). The sTn cluster/KLH molar or DETOX (36) and sTn-KLH plus either DETOX or QS-21 (37). ratio was 409:1. Each vial contained either 30, 10, 3, or 1 Ag sTn(c)-KLH The vaccines were well tolerated, and IgG and/or IgM anti- plus 100 Ag QS-21 (Antigenics, Inc.) in PBS. Samples underwent testing bodies reactive with the respective antigens were induced. for toxicity and immunogenicity in mice as well as for sterility and Antibodies induced against sTn by the OSM constructs were of endotoxin. relatively low titers, whereas those induced by the sTn-KLH Skin tests. General immune competence was evaluated by topical constructs were of greater titers.
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