title: Salmonella engineered to express CD20-targeting antibodies and a drug-converting enzyme can eradicate human lymphomas.
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.
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Italian Foundation for Cancer Research-Institute for Molecular Oncology, European Institute of Oncology Campus, Milan, Italy.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Massa
authors.forename: Aida
authors.initials: A
authors.lastname: Paniccia
authors.forename: Ana
authors.initials: A
authors.lastname: Monegal
authors.forename: Ario
authors.initials: A
authors.lastname: de Marco
authors.forename: Maria
authors.initials: M
authors.lastname: Rescigno
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000235:genetics / Q000627:therapeutic use; D018951:Antigens, CD20 / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D005818:Genetic Engineering; D006801:Humans; D008223:Lymphoma / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011355:Prodrugs / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D012074:Remission Induction / Q000379:methods; D012486:Salmonella typhimurium / Q000235:genetics / Q000378:metabolism*; D013937:Thymidine Kinase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D011355:Prodrugs; D011994:Recombinant Proteins; D013937:Thymidine Kinase