Salmonella engineered to express CD20-targeting antibodies and a drug-converting enzyme can eradicate human lymphomas
Salmonella engineered to express CD20-targeting antibodies and a drug-converting enzyme can eradicate human lymphomas
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DOI：
10.1182/blood-2012-12-474098
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发表时间：
2013-08-01
期刊：
影响因子：
20.3
通讯作者：
Rescigno, Maria
中科院分区：
文献类型：
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作者：
Massa, Paul E.;Paniccia, Aida;Rescigno, Maria
逃避免疫检测有利于肿瘤的存活和进展，而规避这一点的新方法对于对抗癌症至关重要。无毒的嗜肿瘤细菌，如鼠伤寒沙门氏菌，可以通过将其转化为炎症部位来揭开肿瘤;然而，沙门氏菌的非特异性侵袭性导致脱靶效应，稀释其治疗效果，并使其在人类患者中的使用具有固有的风险。在这里，我们证明，沙门氏菌肿瘤特异性可以显着提高通过表面表达的单域抗体针对肿瘤相关抗原（CD 20）。抗体依赖性细菌靶向在体外和体内指定CD 20+淋巴瘤细胞的感染，同时显著减少非特异性细胞侵袭。事实上，以CD 20为靶点的沙门氏菌的侵袭性较低，即使在通常作为生理储存库的器官中也是如此。此外，肿瘤特异性沙门氏菌工程携带单纯疱疹病毒胸苷激酶前体药物转化酶有效地治疗人类淋巴瘤异种移植物时，共同管理肿瘤内或静脉注射更昔洛韦在缺乏功能性适应性免疫系统的小鼠。因此，肿瘤靶向沙门氏菌可以证明即使在那些免疫系统衰弱的患者中也是有效的，这通常是晚期癌症的情况。总之，抗体展示沙门氏菌载体可以介导肿瘤特异性应答和排斥，几乎没有可检测的不良反应，同时特异性地递送细胞毒性有效载荷。
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 co-administered 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.