Escape from immune detection favors both tumor survival and progression, and new approaches to circumvent this are essential to combat cancers. Nonvirulent, tumor-tropic bacteria, such as Salmonella typhimurium, can unmask a tumor by transforming it into a site of inflammation; however, the nonspecific invasiveness of Salmonella leads to off-target effects diluting its therapeutic efficacy and making its use in human patients inherently risky. Here, we demonstrate that Salmonella tumor specificity can be significantly improved via a surface-expressed single-domain antibody directed to a tumor-associated antigen (CD20). Antibody-dependent bacterial targeting specifies the infection of CD20+ lymphoma cells in vitro and in vivo, while significantly diminishing nonspecific cell invasion. Indeed, CD20-targeted Salmonella was less generally invasive, even in organs that normally serve as physiological reservoirs. Furthermore, tumor-specific Salmonella engineered to carry the herpes simplex virus thymidine kinase prodrug-converting enzyme effectively treats human lymphoma xenografts when coadministered intratumorally or intravenously with ganciclovir in mice lacking a functional adaptive immune system. Therefore, tumor-targeted Salmonella could prove effective even in those patients displaying a debilitated immune system, which is often the case with late-stage cancers. Altogether, antibody-displaying Salmonella vectors can mediate a tumor-specific response and rejection with few detectable adverse effects while specifically delivering cytotoxic payloads.

Salmonella engineered to express CD20-targeting antibodies and a drug-converting enzyme can eradicate human lymphomas

M. Rescigno
2013

Abstract

Escape from immune detection favors both tumor survival and progression, and new approaches to circumvent this are essential to combat cancers. Nonvirulent, tumor-tropic bacteria, such as Salmonella typhimurium, can unmask a tumor by transforming it into a site of inflammation; however, the nonspecific invasiveness of Salmonella leads to off-target effects diluting its therapeutic efficacy and making its use in human patients inherently risky. Here, we demonstrate that Salmonella tumor specificity can be significantly improved via a surface-expressed single-domain antibody directed to a tumor-associated antigen (CD20). Antibody-dependent bacterial targeting specifies the infection of CD20+ lymphoma cells in vitro and in vivo, while significantly diminishing nonspecific cell invasion. Indeed, CD20-targeted Salmonella was less generally invasive, even in organs that normally serve as physiological reservoirs. Furthermore, tumor-specific Salmonella engineered to carry the herpes simplex virus thymidine kinase prodrug-converting enzyme effectively treats human lymphoma xenografts when coadministered intratumorally or intravenously with ganciclovir in mice lacking a functional adaptive immune system. Therefore, tumor-targeted Salmonella could prove effective even in those patients displaying a debilitated immune system, which is often the case with late-stage cancers. Altogether, antibody-displaying Salmonella vectors can mediate a tumor-specific response and rejection with few detectable adverse effects while specifically delivering cytotoxic payloads.
Animals; Antibodies; Monoclonal; Antigens; CD20; Cell Line; Tumor; Female; Gene Expression; Genetic Engineering; Humans; Lymphoma; Mice; Inbred C57BL; Inbred NOD; SCID; Prodrugs; Recombinant Proteins; Remission Induction; Salmonella typhimurium; Thymidine Kinase; Xenograft Model Antitumor Assays; Hematology; Biochemistry; Cell Biology; Immunology
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11699/1119
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