Pilot Phase III Immunotherapy Study in Early-Stage Breast Cancer Patients Using Oxidized Mannan-MUC1 [ISRCTN71711835]

Vasso Apostolopoulos; Geoffrey A Pietersz; Anastasios Tsibanis; Annivas Tsikkinis; Heleni Drakaki; Bruce E Loveland; Sara J Piddlesden; Magdalena Plebanski; Dodie S Pouniotis; Michael N Alexis; Ian F McKenzie; Stamatis Vassilaros

Disclosures

Breast Cancer Res. 2006;8(3) 

In This Article

Abstract and Introduction

Introduction: Mucin 1 (MUC1) is a high molecular weight glycoprotein overexpressed on adenocarcinoma cells and is a target for immunotherapy protocols. To date, clinical trials against MUC1 have included advanced cancer patients. Herein, we report a trial using early stage breast cancer patients and injection of oxidized mannan-MUC1.
Method: In a randomized, double-blind study, 31 patients with stage II breast cancer and with no evidence of disease received subcutaneous injections of either placebo or oxidized mannan-MUC1, to immunize against MUC1 and prevent cancer reoccurrence/metastases. Twenty-eight patients received the full course of injections of either oxidized mannan-MUC1 or placebo. Survival and immunological assays were assessed.
Results: After more than 5.5 years had elapsed since the last patient began treatment (8.5 years from the start of treatment of the first patient), the recurrence rate in patients receiving the placebo was 27% (4/15; the expected rate of recurrence in stage II breast cancer); those receiving immunotherapy had no recurrences (0/16), and this finding was statistically significant (P = 0.0292). Of the patients receiving oxidized mannan-MUC1, nine out of 13 had measurable antibodies to MUC1 and four out of 10 had MUC1-specific T cell responses; none of the placebo-treated patients exhibited an immune response to MUC1.
Conclusion: The results suggest that, in early breast cancer, MUC1 immunotherapy is beneficial, and that a larger phase III study should be undertaken.

Outcomes of breast cancer treatment have improved, mostly as a result of earlier diagnosis. Although newer modes of therapy are being applied, traditional therapy involving surgery, radiotherapy and chemotherapy, followed by long-term antioestrogen therapy continues to be used. Immunotherapy could be a useful adjunct to conventional therapy, particularly in an adjuvant setting and (as shown here) in patients with early disease and no metastasis. New therapeutic procedures in breast cancer are usually tried in patients with advanced disease, who may be appropriate candidates for cytotoxic drugs. However, such patients may be unable to respond appropriately to immunotherapy, given that an intact and competent immune system is required to induce a therapeutic immune response.

Treatment of cancer with immunotherapy has been the goal of many researchers since the advent of effective immunization against infectious diseases. Previously, tumour antigens were not easily identified, but currently identified antigens include glycoproteins and glycolipids (for example, gangliosides), developmental and over-expressed antigens (for example, CEA (carcinoembryonic antigen), gp75, MAGE, tyrosinase, melan-A, mucin [MUC]1), and mutated oncogenes (for example, p53, HER-2/neu, ras).[1] Our laboratory has focused on MUC1 as a target for tumour immunotherapy. Mucins (such as MUC1) are high-molecular-weight glycoproteins that are secreted by many epithelial cells such as breast, ovary, colon and pancreatic carcinomas. MUC1 is of interest and a potential target for tumour immunotherapy for the following reasons: there is an up to 100-fold increase in the amount of mucin present on cancer cells compared with normal cells; MUC1 has a ubiquitous rather than focal cellular distribution; and MUC1 has altered glycosylation, revealing peptide epitopes not easily identified in normal mucins.

Cloning of the cDNA for MUC1 and definition of the structure revealed that the molecule is transmembranous, with a relatively large extracellular domain and a cytoplasmic tail. It was discovered that most of the immunogenicity (in terms of antibody production) resided in a repeated (variable number of tandem repeats [VNTR]) 20-amino-acid peptide (PDTRPAPGSTAPPAHGVTSA) domain in the extracellular portion of the molecule.[2,3,4] Such studies of immunogenicity in mice would not be relevant to humans other than the findings that, in humans, MUC1 can stimulate T cells in breast, pancreatic and ovarian cancers.[5,6,7] Restricted cytotoxic T lymphocytes in humans with breast cancer and in pregnancy, as well as in mice, have also been detected.[8,9,10] In addition, T cell immunity and B cell immune responses to selected epitopes of MUC1 from ovarian, breast, pancreatic and colon cancer patients have been demonstrated,[11,12,13] as have circulating immune complexes to MUC1 in the serum of breast and ovarian carcinoma patients.[14] In mice, we demonstrated that a 20-mer MUC1 VNTR (made as a fusion protein comprising five VNTR repeats), when coupled to oxidized mannan (that is, oxidized mannan-MUC1 fusion protein [M-FP]), generates H2 restricted cytotoxic T lymphocytes, which protect mice against challenge with MUC1+ mouse tumours.[9,15,16,17,18,19,20,21,22]

Over the past 12 years, we have injected many patients with different MUC1 formulations in an effort to induce protective and therapeutic immunity, aiming to reproduce the same effect as seen in mice.[1,9,16,17,18,19,20,23,24,25,26,27,28,29,30,31,32,33,34,35] In more than 250 patients with advanced cancer, moderate cellular immune responses and substantial antibody responses were noted.[36,37,38,39] However, clinical responses were not apparent in these patients, possibly because of the advanced and immunocompromised state of their disease. Therefore, in the present study we aimed to evaluate the effect of M-FP in patients with early disease. Specifically, these patients had stage II disease with fewer than four lymph nodes involved, all of which had been removed, and had no evidence of disease and were entirely healthy at the start of the trial. Although a small number of patients were recruited into this randomized, double-blind pilot study, the early results reported here are promising and justify the performance of a larger study.

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