Mucin 1 (MUC1) is a large complex glycoprotein that is highly expressed in breast cancer, and as such could be a target for immunotherapy. In mice, human MUC1 is highly immunogenic, particularly when conjugated to mannan, where a high frequency of CD8

The mucin MUC1 is greatly increased in breast cancer and is a potential target for immunotherapy. In mice, MUCI conjugated to oxidized mannan (MUC1-mannan fusion protein [M-FP]) targets the mannose receptor and induces a high frequency of cytotoxic T lymphocytes and anti-tumor responses. On this basis, three phase I trials were performed in patients with adenocarcinoma to evaluate the toxicity and the immunologic responses to mannan MUCI. Forty-one patients with metastatic or locally advanced carcinoma of the breast (trial 1), colon (trial 2), and various adenocarcinomas (trial 3) received increasing doses of M-FP (1 to 300 microg). The immunizations were given at weekly intervals (weeks 1 to 3) and repeated in weeks 7 to 9. Cyclophosphamide (to increase cellular immunity) was given on weeks 1 and 4. M-FP was given intramuscularly in trial 1 and intraperitoneally in trial 2. No toxic effects occurred, and delayed-type hypersensitivity responses were present only as a microscopic lymphocytic infiltration. Overall, approximately 60% of the patients had high-titer MUC1 immunoglobulin G1 antibody responses, with the intraperitoneal route yielding approximately 10-fold higher responses. Cellular responses (proliferation, cytotoxic T cells, or CD8 T cells secreting tumor necrosis factor-alpha alphand interferon-gamma in response to MUC1 stimulation in vitro) were found in 28% of the patients, which was similar to that seen without cyclophosphamide. In most patients, disease progressed, but in five it remained stable. In addition, there were no objective responses. M-FP is not toxic and induces immune responses that were amplified by the intraperitoneal route of immunization. Cyclophosphamide was of no benefit.

Tumor immunotherapy is currently receiving close scrutiny. However, with the identification of tumor antigens and their production by recombinant means, the use of cytokines and knowledge of major histocompatibility complex (MHC) class I and class II presentation has provided ample reagents for use and clear indications of how they should be used. At this time, much attention is focused on using peptides to be presented by MHC class I molecules to both induce and be targets for CD8+ cytolytic T cells. Many peptides generated endogenously or given exogenously can enter the class I pathway, but a number of other methods of entering this pathway are also known and are discussed in detail herein. While the review concentrates on inducing cytotoxic T cells (CTLs), it is becoming increasingly apparent that other modes of immunotherapy would be desirable, such as class II presentation to induce increased helper activity (for CTL), but also activating macrophages to be effective against tumor cells.

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Summary In a prospective study to assess the accuracy of monoclonal immunoscintigraphy for the detection of axillary lymph node metastases in breast cancer, two murine monoclonal antibodies that react with human breast cancer (3E1.2 and RCC-1) were labelled with 13'iodine, and the radiolabelled antibody was injected subcutaneously into the interdigital spaces of both hands of 40 patients, 36 of whom had breast cancer and the remaining four of whom had fibroadenoma (the normal, contralateral axilla was used as a control). Of the patients with breast cancer, the findings from the scintigraphy images were correlated with histopathology or cytology of the axillary lymph nodes; images were regarded as positive and hence indicative of lymph node metastases if the amount of background-subtracted radioactive count in axilla on the side of breast cancer exceeded the contralateral normal side by a ratio ) 1.5:1.0 as assessed by computer analysis. Using this method, immunoscintigraphy had an overall sensitivity of 33% (23% with 1311-3E1.2 and 50% with 1311-RCC-1) for the detection of lymph node metastases and a specificity of 63% (67% with 1311-3E1.2 and 60% with 131I-RCC-1) with problems of non-specific uptake by presumably normal lymph nodes. The results of immunoscintigraphy obtained with 1311-RCC-1 (IgG) were superior to 1311-3E1.2 (IgM) although the accuracy of immunoscintigraphy using 131I-RCC-1 (56%) was not much better than preoperative clinical assessment (50%). However, there were cases when immunoscintigraphy using radiolabelled antibody (IgM or IgG) detected axillary lymph node metastases not suspected by clinical examination. Thus it appears that while immunoscintigraphy may be a useful adjunct to preoperative clinical assessment and is simple and safe, a major improvement in its accuracy is needed before it can replace axillary dissection and histological examination in the accurate staging of axilla in breast cancer.The detection of overt tumour deposits by means of gammacamera imaging and radiolabelled monoclonal antibodies to tumour-associated antigens (immunoscintigraphy) has met with encouraging results (Armitage et al., 1984;Epenetos, 1985;Leyden et al., 1986;Mach et al., 1981;Rainsbury, 1984;Smedley et al., 1983;William et al., 1984). However, most of these studies have been performed on patients with well documented and widespread disease; few being prospective studies of the value of monoclonal immunoscintigraphy in the initial staging of patients with malignant disease. Immunoscintigraphy is complicated in that imaging using intravenously administered radiolabelled antibodies has a considerable background radioactivity because of the uptake of radiolabelled material in the blood pool and extravascular spaces, and antibodies may be catabolised before reaching their target, resulting in only a very small tumour uptake. In addition, dehalogenation of radiolabelled antibody, poor penetration of the conjugate into tumour deposits and antibody binding to cross-reactive antigens present on normal cells are...