Development and preclinical evaluation of a Bacillus Calmette-Guérin-MUC1-based novel breast cancer vaccine.
Due to the high incidence of breast cancer and associated mortality rate,the development of an effective vaccine may be beneficial for the prevention or adjuvant treatment of this malignancy. We have constructed a novel breast cancer vaccine, Bacillus Calmette-Guérin (BCG)-hIL2MUC1, that consists of BCG and expresses a truncated form of MUC1 and human interleukin (IL)-2. In vitro analysis of the BCG-hIL2MUC1 construct confirmed coexpression of MUC1 and human IL-2. The ability of BCG-hIL2MUC1 to inhibit breast cancer growth was evaluated in hu-PBL-SCID mice (severe combined immunodeficient mice reconstituted with 50 x 10(6) human peripheral blood lymphocytes) that received three biweekly injections of BCG-hIL2MUC1 (0.5 colony-forming unit). Control animals received PBS, MUC1 peptide (100 microg), or empty vector BCG-261 (0.5 colony-forming unit) vaccination. After immunization, hu-PBL-SCID mice (n = 8 in each group) were xenografted with 4 x 10(6) ZR75-1 human breast cancer cells. Whereas mice receiving the control vaccines developed a tumor, only 87% of BCG-hIL2MUC1-immunized animals developed a palpable tumor with a slower rate of tumor growth (P < 0.001). Histological analysis of the primary tumors in BCG-hIL2MUC1-immunized animals revealed areas of reduced MUC1 expression. CD8-positive human lymphocytes were detected only in tumors grown in BCG-hIL2MUC1-immunized animals. These results imply a critical role of coexpressed IL-2 and MUC1 in eliciting tumor-specific immune response. To our knowledge, this is the first report of BCG engineered to express a tumor-associated antigen. Our results suggest that BCG-hIL2MUC1 immunization inhibited breast cancer growth in hu-PBL-SCID mice. Therefore, BCG-hIL2MUC1 may be a promising candidate as a breast cancer vaccine.
Chung
Maureen A
MA
Department of Surgery, Women and Infants Hospital, Brown University, Providence, Rhode Island 02905, USA.
Luo
Yi
Y
O'Donnell
Michael
M
Rodriguez
Claire
C
Heber
Walter
W
Sharma
Surendra
S
Chang
Helena R
HR
D000595:Amino Acid Sequence; D000818:Animals; D001500:BCG Vaccine / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000235:genetics / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D001500:BCG Vaccine; D019496:Cancer Vaccines; D007376:Interleukin-2; D018396:Mucin-1; D014613:Vaccines, Attenuated