Antibody-dependent cell-mediated cytotoxicity can be induced by MUC1 peptide vaccination of breast cancer patients

Snijdewint, F.G.M.; Mensdorff‐Pouilly, Silvia von; Karuntu-Wanamarta, A. H.; Verstraeten, A.A.; Livingston, Philip O.; Hilgers, J.; Kenemans, P.

doi:10.1002/ijc.1286

Cited by 67 publications

(51 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The MUC1-KLH plus QS-21 conjugate vaccine fails to induce a consistent T-cell response against MUC1 despite the fact that it does induce consistent IgM and IgG antibodies against MUC1, which were able to mediate ADCC in a pattern consistent with a T-helper cell 1 response. 44 The strong proliferation and interferon gamma ELISPOT reactivity against KLH that we demonstrate here suggest that this Thelper 1-type antibody response is a consequence of the help provided by KLH.…”

mentioning

confidence: 82%

Reevaluation of the cellular immune response in breast cancer patients vaccinated with MUC1

Musselli

Ragupathi

Gilewski

et al. 2001

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Conjugation of antigens to a carrier protein like keyhole limpet hemocyanin (KLH) has proven effective in clinical trials for inducing antibodies against selected tumor antigens. The impact of this approach on T-cell immunity has not been previously tested. We utilized peripheral blood mononuclear cells (PBMC) obtained at leukapheresis from 6 breast cancer patients vaccinated 4 times each with a 106-amino acid-long MUC1 peptide conjugated with KLH plus immune adjuvant QS-21. Proliferation after 6 days of in vitro culture and an interferon gamma ELISPOT assay with and without 6 days of in vitro sensitization with the immunizing antigen were used. Parallel experiments employed the use of the cytokine IL2. Our results indicate that despite a high response to KLH in all patients with precursor frequencies as high as 1/120 peripheral blood lymphocytes and augmentation of proliferation in excess of 200-fold after vaccination, the T-cell response against MUC1 peptide was minimal and inconsistent. The strength and consistency of the vaccine-induced T-cell response against KLH in these patients excludes general immune incompetence and assay insensitivity or inconsistency as explanations for the weak and inconsistent response against MUC1. We conclude that for any report of augmented T-cell responses against MUC1 to be convincing, one or more postimmunization blood samples will be needed to demonstrate augmented MUC1-specific immunity consistently on multiple occasions. Assuming this criteria, convincing induction of T-cell immunity against MUC1 by vaccination has yet to be described.

show abstract

mentioning

confidence: 82%

Reevaluation of the cellular immune response in breast cancer patients vaccinated with MUC1

Musselli

Ragupathi

Gilewski

et al. 2001

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…HuHMFG1 has been demonstrated to be a potent mediator of ADCC by recruiting natural components of the body's immune system (Snijdewint et al, 2001) HuHMFG1 binds to the extracellular MUC1 peptide sequence, PDTR. These sequences are not exposed in normal cells because of full glycosylation, but aberrant glycosylation in cancer cells exposes the epitope to the antibody.…”

mentioning

confidence: 99%

Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer

Royer

Wu²,

Pegram

et al. 2010

Br J Cancer

View full text Add to dashboard Cite

BACKGROUND: HuHMFG1 (AS1402) is a humanised monoclonal antibody that has undergone a phase I trial in metastatic breast cancer. The aim of this study was to characterise the pharmacokinetics (PKs) of HuHMFG1 using a population PK model. METHOD: Data were derived from a phase I study of 26 patients receiving HuHMFG1 at doses ranging from 1 to 16 mg kg À1 . Data were analysed using NONMEM software and covariates were included. A limited sampling strategy (LSS) was developed using training and a validation data set. RESULTS: A linear two-compartment model was shown to be adequate to describe data. Covariate analysis indicated that weight was not related to clearance. An LSS was successfully developed on the basis of the model, in which one sample is collected immediately before the start of an infusion and the second is taken at the end of infusion. CONCLUSION: A two-compartment population PK model successfully describes HuHMFG1 behaviour. The model suggests using a fixed dose of HuHMFG1, which would simplify dosing. The model could be used to optimise dose level and dosing schedule if more data on the correlation between exposure and efficacy become available from future studies. The derived LSS could optimise further PK assessment of this antibody.

show abstract

“…15) HuHMFG-1 induced strong ADCC to breast cancer cells and is currently being used in clinical studies on breast carcinoma. 16,17) Herein, we investigated the effect of antibody immunotherapy of anti-MUC1 mAb to oral squamous cell carcinomas, and demonstrated that anti-MUC1 mAb C595 was able to kill OSCC cells mediated by CDC and ADCC, and these effects were strongly correlated with MUC1 expression.…”

Section: Discussionmentioning

confidence: 99%

Effect of the Antibody Immunotherapy by the Anti-MUC1 Monoclonal Antibody to the Oral Squamous Cell Carcinoma in Vitro

Shimizu

Imai

2008

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

squamous cell carcinomas (OSCCs) were estimated to be the eighth leading cause of cancer, accounting for 3% of malignancies in men.1) At present, surgery and radiation therapy, separately or in combination, are the main courses of treatment. In advanced stages of the disease, chemotherapy is added to surgery and/or radiation.1) However, preservation of organ structure and function and fewer therapeutic side effects in the oral area are important for the treatment of oral cancer, because some patients worry that they may become functionally and cosmetically unacceptable. In addition, OSCC is resistant to both radiation 2,3) and chemotherapy. 3,4) Thus, there are a number of problems associated with OSCC treatment. Recently, various basic and clinical observations suggest that the patient's immune system plays a role in the course of oral cell cancer. In vivo tumor regression by IL-12 and IL-2, inducing CD80 expression, 5) the presence of a CD8 ϩ T-cell-mediated immune response 6) and the number of dendritic cells infiltrating the tumor are highly significant prognostic parameters. 7) These results have lead to the hypothesis that activation of the patient's immune system will enhance anti-OSCC therapy.MUC1 (human mucin 1, epsialin) is an epithelial, cell-associated mucin normally expressed on the apical surface, but differences in MUC1 expression on cancer cells make MUC1 epitopes tumor-specific. On tumor cells, MUC1 is highly overexpressed and loses its polarized distribution on the cell surface. Tumor-associated MUC1 is also underglycosylated, resulting in the exposure of immunodominant peptide sequences that are normally concealed. MUC1 is expressed by most adenocarcinomas of the breast, lung, stomach, pancreas, colon, ovary, bladder and prostate. MUC1 is thus an important marker of malignancy and is a target for several immunotherapies currently under investigation (for reviews on MUC1 and cancer, see ref. 8). The level of MUC1 expression has been shown to correlate with the degree of breast tumor differentiation, estrogen receptor status, and clinical outcome of breast cancers, 9) plus both progression and metastases of epithelial ovarian cancers.10) Anti-MUC1 C595 monoclonal antibody (mAb) recognizes a tumor-associated core protein epitope and currently investigates under the clinical studies. In OSCCs, distinct membrane MUC1 mucin staining patterns were identified in 59.7% of OSCC patients.11) Furthermore, the malignant transformation of oral epithelium, tumor invasion, and tumor metastasis were associated with higher MUC1 mucin expression.11) Thus, MUC1 mucin expression may be a useful diagnostic marker for prediction of the invasive/metastatic potential of OSCC.Immunotherapy using mAbs holds great promise as an anti-cancer therapeutic strategy because of its ability to target cancer cells specifically while sparing the surrounding normal tissue. This is an important advantage over relatively non-specific chemo-and radio-therapeutic treatments. Eight anti-cancer mAbs have been approved by the Food and Dru...

show abstract

Antibody-dependent cell-mediated cytotoxicity can be induced by MUC1 peptide vaccination of breast cancer patients

Cited by 67 publications

References 47 publications

Reevaluation of the cellular immune response in breast cancer patients vaccinated with MUC1

Reevaluation of the cellular immune response in breast cancer patients vaccinated with MUC1

Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer

Effect of the Antibody Immunotherapy by the Anti-MUC1 Monoclonal Antibody to the Oral Squamous Cell Carcinoma in Vitro

Contact Info

Product

Resources

About