European Institute of Oncology, Department of Experimental Oncology, Italian Foundation for Cancer Research-Institute for Molecular Oncology, European Institute of Oncology Campus, Milan, Italy.
Blood. 2013 Aug 1;122(5):705-14. doi: 10.1182/blood-2012-12-474098. Epub 2013 Jun 4.
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.
逃避免疫检测有利于肿瘤的存活和进展，因此，需要新的方法来规避这一问题，以对抗癌症。非毒性、肿瘤趋向性细菌，如鼠伤寒沙门氏菌，可以通过将肿瘤转化为炎症部位来揭示肿瘤；然而，沙门氏菌的非特异性侵袭性导致了脱靶效应，削弱了其治疗效果，使其在人类患者中的应用本身存在风险。在这里，我们证明通过表面表达针对肿瘤相关抗原（CD20）的单域抗体，可以显著提高沙门氏菌的肿瘤特异性。抗体依赖性细菌靶向特异性感染体外和体内的 CD20+淋巴瘤细胞，同时显著减少非特异性细胞侵袭。事实上，即使在通常作为生理储库的器官中，靶向 CD20 的沙门氏菌的侵袭性也较低。此外，当携带单纯疱疹病毒胸苷激酶前药转化酶的工程化肿瘤特异性沙门氏菌与无功能性适应性免疫系统的小鼠中的更昔洛韦联合瘤内或静脉内给药时，可有效治疗人淋巴瘤异种移植物。因此，即使在免疫系统受损的患者中，靶向肿瘤的沙门氏菌也可能有效，而免疫系统受损通常是晚期癌症的情况。总之，展示抗体的沙门氏菌载体可以介导肿瘤特异性反应和排斥反应，而几乎没有可检测到的不良反应，同时特异性地递送细胞毒性有效载荷。
