State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China.
Cancer Center, Department of Pathology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
J Immunother Cancer. 2024 Mar 7;12(3):e008431. doi: 10.1136/jitc-2023-008431.
The redundant extracellular matrix (ECM) within tumor microenvironment (TME) such as hyaluronic acid (HA) often impairs intratumoral dissemination of antitumor drugs. Oncolytic viruses (OVs) are being studied extensively for cancer therapy either alone or in conjunction with chemotherapy and immunotherapy. Here, we designed a novel recombinant vaccinia virus encoding a soluble version of hyaluronidase Hyal1 (OVV-Hyal1) to degrade the HA and investigated its antitumor effects in combination with chemo drugs, polypeptide, immune cells, and antibodies.
We constructed a recombinant oncolytic vaccinia virus encoding the hyaluronidase, and investigated its function in remodeling the ECM of the TME, the antitumor efficacy both in vitro and in several murine solid tumors either alone, or in combination with chemo drugs including doxorubicin and gemcitabine, with polypeptide liraglutide, with immune therapeutics such as PD-L1/PD-1 blockade, CD47 antibody, and with CAR-T cells.
Compared with control OVV, intratumoral injection of OVV-Hyal1 showed superior antitumor efficacies in a series of mouse subcutaneous tumor models. Moreover, HA degradation by OVV-Hyal1 resulted in increased intratumoral dissemination of chemo drugs, infiltration of T cells, NK cells, macrophages, and activation of CD8 T cells. When OVV-Hyal1 was combined with some antitumor therapeutics, for example, doxorubicin, gemcitabine, liraglutide, anti-PD-1, anti-CD47 blockade, or CAR-T cells, more profound therapeutic outcomes were obtained.
OVV-Hyal1 effectively degrades HA to reshape the TME, therefore overcoming some major hurdles in current cancer therapy, such as limited OVs spread, unfavored dissemination of chemo drugs, polypeptides, antibodies, and insufficient infiltration of effector immune cells. OVV-Hyal1 holds the promise to improve the antitumor outcomes of current cancer therapeutics.
肿瘤微环境（TME）中多余的细胞外基质（ECM），如透明质酸（HA），常常会阻碍抗肿瘤药物在肿瘤内的扩散。溶瘤病毒（OVs）正被广泛研究用于癌症治疗，无论是单独使用还是与化疗和免疫疗法联合使用。在这里，我们设计了一种新型重组痘苗病毒，编码透明质酸酶 Hyal1 的可溶性版本（OVV-Hyal1），以降解 HA，并研究其与化疗药物、多肽、免疫细胞和抗体联合使用的抗肿瘤效果。
我们构建了一种编码透明质酸酶的重组溶瘤痘苗病毒，并研究了其在重塑 TME 的 ECM 中的功能，以及单独或与化疗药物（包括多柔比星和吉西他滨）、多肽利拉鲁肽、免疫治疗药物（如 PD-L1/PD-1 阻断、CD47 抗体）和 CAR-T 细胞联合使用时，在体外和几种小鼠实体瘤中的抗肿瘤疗效。
与对照 OVV 相比，OVV-Hyal1 瘤内注射在一系列小鼠皮下肿瘤模型中显示出更好的抗肿瘤疗效。此外，OVV-Hyal1 降解 HA 导致化疗药物在肿瘤内的扩散增加、T 细胞、NK 细胞、巨噬细胞的浸润和 CD8 T 细胞的激活。当 OVV-Hyal1 与一些抗肿瘤治疗药物联合使用时，例如多柔比星、吉西他滨、利拉鲁肽、抗 PD-1、抗 CD47 阻断或 CAR-T 细胞，会获得更深刻的治疗效果。
OVV-Hyal1 能有效降解 HA，重塑 TME，从而克服当前癌症治疗中的一些主要障碍，如 OVs 传播受限、化疗药物、多肽、抗体的扩散不理想以及效应免疫细胞的浸润不足。OVV-Hyal1 有望提高当前癌症治疗的抗肿瘤效果。
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