溶瘤腺病毒
病毒学
病毒载体
病毒
HSL和HSV色彩空间
单纯疱疹病毒
体内
医学
遗传增强
嵌合抗原受体
癌症
载体(分子生物学)
作者
Divya Ravirala,Brandon Mistretta,Preethi H. Gunaratne,Guangsheng Pei,Zhongming Zhao,Xiaoliu Zhang
标识
DOI:10.1136/jitc-2021-002454
摘要
Background Although oncolytic virotherapy has shown substantial promises as a new treatment modality for many malignancies, further improvement on its therapeutic efficacy will likely bring more clinical benefits. One plausible way of enhancing the therapeutic effect of virotherapy is to enable it with the ability to concurrently engage the infiltrating immune cells to provide additional antitumor mechanisms. Here, we report the construction and evaluation of two novel chimeric molecules (bispecific chimeric engager proteins, BiCEP and trispecific chimeric engager protein, TriCEP) that can engage both natural killer (NK) and T cells with tumor cells for enhanced antitumor activities. Methods BiCEP was constructed by linking orthopoxvirus major histocompatibility complex class I-like protein, which can selectively bind to NKG2D with a high affinity to a mutant form of epidermal growth factor (EGF) that can strongly bind to EGF receptor. TriCEP is similarly constructed except that it also contains a modified form of interleukin-2 that can only function as a tethered form. As NKG2D is expressed on both NK and CD8+ T cells, both of which can thus be engaged by BiCEP and TriCEP. Results Both BiCEP and TriCEP showed the ability to engage NK and T cells to kill tumor cells in vitro. Coadministration of BiCEP and TriCEP with an oncolytic herpes simplex virus enhanced the overall antitumor effect. Furthermore, single-cell RNA sequencing analysis revealed that TriCEP not only engaged NK and T cells to kill tumor cells, it also promotes the infiltration and activation of these important immune cells. Conclusions These novel chimeric molecules exploit the ability of the oncolytic virotherapy in altering the tumor microenvironment with increased infiltration of important immune cells such as NK and T cells for cancer immunotherapy. The ability of BiCEP and TriCEP to engage both NK and T cells makes them an ideal choice for arming an oncolytic virotherapy.
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