Effective anti-tumor responses induced by recombinant bacillus Calmette–Guérin vaccines based on different tandem repeats of MUC1 and GM-CSF

Abstract

In this study, we constructed several novel breast cancer vaccines, Bacillus Calmette-Guérin (BCG)-MUC1 variable-number tandem repeats (VNTR) 1/4/8-CSF, that consist of BCG and express 1, 4, and 8 of the tandem repeats of MUC1 and human granulocyte-macrophage colony-stimulating factor (GM-CSF). The ability of the three recombinant BCG vaccines to inhibit breast cancer growth was observed in human (hu)-peripheral blood lymphocyte (PBL)-severe combined immunodeficient (SCID) mice. Prophylactic protective responses were successfully induced and the tumor incidence in mice immunized with recombinant BCG (rBCG)-MVNTR4-CSF (37.5%) or rBCG-MVNTR8-CSF (25%) was significantly decreased compared with control (100%) at 42 days after tumor implantation (P<0.05 vs. control group). We also found that CD4-positive and CD8-positive lymphocytes were detected only in tumors grown in rBCG-MVNTR4/8-CSF-immunized animals, and strong IFN-gamma responses were induced by immunization with rBCG-MVNTR4-CSF and rBCG-MVNTR8-CSF vaccines. This study suggests a potential role of coexpressed GM-CSF and tandem repeats of MUC1 in eliciting tumor-specific immune response. Our results indicate that rBCG-MVNTR4-CSF and rBCG-MVNTR8-CSF immunization preventively inhibited breast cancer growth in hu-PBL-SCID mice and the both rBCG vaccines may be good candidates for breast cancer immunotherapy.

Th1 Cytokine-Secreting Recombinant Bacillus Calmette-Guérin: Prospective Use in Immunotherapy of Bladder Cancer

“…SCID mice reconstituted with human PBL followed by immunization with the rBCG strains developed MUC1-specific cellular immune respnses and enhanced protection against MUC1-positive human breast cancer xenografts compared to control mice reconstituted with human PBL and immunized with non-cytokine secreting BCG. Studies have also www.intechopen.com demonstrated that the antitumor effects of the rBCG strains were correlated with the number of MUC1 tandem repeats delivered by BCG ( a Yuan et al, 2009Yuan et al, , 2010. These results suggest that these MUC1 rBCG strains coexpressing Th1-stimulating cytokines are promising candidates as breast cancer vaccines and thus deserve further investigation.…”

“…Most of these cytokine-and chemokine-secreting rBCG strains showed their abilities to enhance BCG-induced cellular immune responses including Th1 cytokine production, cellular cytotoxicity, DC activation, and anti-BCG or anti-M.tb infection. Some of them even showed their antitumor effects in animal models of melanoma (Duda et al, 1995), breast cancer (Chung et al, 2003;a Yuan et al, 2009, Yuan et al, 2010, and bladder cancer (Arnold et al, 2004). Certain cytokine-secreting rBCG strains also induced humoral immune responses and Th2 cytokine production other than cellular immune responses in vitro and in vivo.…”

“…In addition, we further observed that mice primed with the rBCG-PSA strain and boosted with Ad-PSA, a replicationdefective adenoviral vector carrying the full-length PSA coding sequence (Elzey et al, 2001), developed enhanced PSA-specific CTL activity and IFN-γ expressing CD4 + and CD8 + T cells (our unpublished observations). Several studies including ours have also demonstrated that BCG could be engineered to express mucin-1 (MUC1), a candidade tumor-associated antigen for breast cancer and other epithelial adenocarcinomas, in a manner of multiple tandem repeats with coexpression of IL-2, GM-CSF or CD80 (He et al, 2002;Chung et al, 2003; Yuan et al, 2009Yuan et al, , 2010. Severe combined immunodeficient (SCID) mice reconstituted with human peripheral blood lymphocytes (PBL) followed by immunization with these MUC1 expressing rBCG strains developed specific protective immunity against MUC1-positive human breast cancer xenografts.…”

“…However, it was not until recently that the potential of rBCG for treating cancer has gained further appreciation. We and others have developed rBCG strains that deliver the breast cancer-associated antigen MUC1 in a form of multiple tandem repeats with coexpression of human IL-2 or human GM-CSF (He et al, 2002;Chung et al, 2003;a Yuan et al, 2009Yuan et al, , 2010. SCID mice reconstituted with human PBL followed by immunization with the rBCG strains developed MUC1-specific cellular immune respnses and enhanced protection against MUC1-positive human breast cancer xenografts compared to control mice reconstituted with human PBL and immunized with non-cytokine secreting BCG.…”

A novel recombinant &lt;italic&gt;Mycobacterium bovis&lt;/italic&gt; bacillus Calmette&minus;Guerin strain expressing human granulocyte macrophage colony-stimulating factor and &lt;italic&gt;Mycobacterium tuberculosis&lt;/italic&gt; early secretory antigenic target 6 complex augments Th1 immunity

“…Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a good adjuvant and immune regulatory molecule, which can be designed as vaccines for cancers and infectious diseases [26,27]. Recombinant GM-CSF stimulates up-regulation of major histocompatibility complex (MHC) class II and co-stimulatory molecules such as CD80 and CD86 on antigen presentation cells (APC) [26].…”