Neoadjuvant Use of Oncolytic Herpes Virus G47Δ Enhances the Antitumor Efficacy of Radiofrequency Ablation

Abstract

G47Δ is a triple-mutated oncolytic herpes simplex virus type 1 designed to induce antitumor immune responses efficiently. We examine the usefulness of G47Δ as a neoadjuvant therapy for radiofrequency ablation (RFA), a standard local treatment for certain cancers such as liver cancer, but remote recurrences within the same organ often occur. In A/J mice harboring bilateral subcutaneous Neuro2a tumors, the left tumors were treated with G47Δ intratumoral injections followed by RFA. Whereas the RFA-treated tumors were all eradicated, the growth of the right tumors was evaluated and tumor-infiltrating lymphocytes were analyzed. The G47Δ+RFA treatment caused smaller volumes of right tumors, accompanied by increased CD8 + /CD45 + T cells, compared with G47Δ monotherapy. After depletion of CD8 + T cells, the enhanced efficacy on the contralateral tumors was completely abolished. Neoadjuvant G47Δ led to rejection of rechallenged tumors, which was caused by efficient induction of specific antitumor immune responses shown by enzyme-linked immunospot (ELISPOT) assays. Treatment of tumor-harboring animals with an anti-programmed cell death 1 ligand 1 (PD-L1) antibody led to even greater efficacy on contralateral tumors. Our study indicates that the neoadjuvant use of G47Δ effectively enhances the efficacy of RFA via CD8 + T cell-dependent immunity that is further augmented by an immune checkpoint inhibitor.

Immunotherapeutic Efficacy of Retargeted oHSVs Designed for Propagation in an Ad Hoc Cell Line

“…(see Figure 6 , panel A). It can be seen that, when combined with anti-PD-1 in a simultaneous regimen [ 62 , 63 , 64 , 65 ], R-335 displayed a tendency to increase efficacy ( Figure 6 B–E). Thus, in mice treated with R-335 alone, CR and PR occurred in 31 and 25% of mice, respectively, in agreement with data shown in Figure 4 .…”

“…injections of anti-PD-1, at 2–3 days intervals. The administration schedule of oHSV and anti-PD-1 treatments was according to [ 62 , 63 , 64 , 65 ]. At d 44, the mice which survived the primary tumor received a contralateral challenge LLC-1-HER2 tumor.…”

Advances in Lipid-Based Nanoparticles for Cancer Chemoimmunotherapy

“…GBM has an average overall survival of 15 to 21 months after first diagnosis and a 5-year survival rate of less than 5%, which is the lowest among other central nervous system (CNS) tumors and second lowest out of all other types of cancer [ 78 , 79 , 80 ]. These numbers have slightly improved as existing therapies such as surgical removal, chemotherapy, and radiotherapy are used in conjunction with new therapeutic advances such as the use of oncolytic viruses, dendritic cell vaccines, tumor-treating fields, and immunotherapy [ 81 , 82 , 83 , 84 , 85 ]. However, these treatment options have failed to effectively treat GBM patients as they often result in eventual relapse or death.…”

Human Herpesvirus and the Immune Checkpoint PD-1/PD-L1 Pathway: Disorders and Strategies for Survival

“…In addition, HSV has been used as an oncolytic virus, and use of PD-1/PD-L1 pathway inhibitors in combination with oncolytic HSV was shown to result in increased antitumor immunity [21][22][23].…”