A new oncolyticVacciniavirusaugments antitumor immune responses to prevent tumor recurrence and metastasis after surgery

Abstract

BackgroundLocal recurrence and remote metastasis are major challenges to overcome in order to improve the survival of patients with cancer after surgery. Oncolytic viruses are a particularly attractive option for prevention of postsurgical disease as they offer a non-toxic treatment option that can directly target residual tumor deposits and beneficially modulate the systemic immune environment that is suppressed post surgery and allows residual disease escape from control. Here, we report that a novelVaccinia virus(VV), VVΔTKΔN1L (with deletion of both thymidine kinase (TK) and N1L genes) armed with interleukin 12 (IL-12), can prolong postoperative survival when used as a neoadjuvant treatment in different murine and hamster surgical models of cancer.MethodsA tumor-targeted replicating VV with deletion of TK gene and N1L gene (VVΔTKΔN1L) was created. This virus was armed rationally with IL-12. The effect of VVΔTKΔN1L and VVΔTKΔN1L-IL12 on modulation of the tumor microenvironment and induction of tumor-specific immunity as well the feasibility and safety as a neoadjuvant agent for preventing recurrence and metastasis after surgery were assessed in several clinically relevant models.ResultsVVΔTKΔN1L can significantly prolong postoperative survival when used as a neoadjuvant treatment in three different surgery-induced metastatic models of cancer. Efficacy was critically dependent on elevation of circulating natural killer cells that was achieved by virus-induced cytokine production from cells infected with N1L-deleted, but not N1L-intact VV. This effect was further enhanced by arming VVΔTKΔN1L with IL-12, a potent antitumor cytokine. Five daily treatments with VVΔTKΔN1L-IL12 before surgery dramatically improved postsurgical survival. VVΔTKΔN1L armed with human IL-12 completely prevented tumor recurrence in surgical models of head and neck cancer in Syrian hamsters.ConclusionsThese data provide a proof of concept for translation of the regime into clinical trials. VVΔTKΔN1L-IL12 is a promising agent for use as an adjuvant to surgical treatment of solid tumors.

A systemically deliverable Vaccinia virus with increased capacity for intertumoral and intratumoral spread effectively treats pancreatic cancer

“…We have previousl demonstrated that a TK-deleted, N1L-deleted VV has potent efficacy and tumor selectivity in vivo 13 14 ( online supplemental figure S1 ). To maximize the oncolytic potential of VV, we enhanced the capacity for systemic spread by increasing EEV production.…”

“…NK cells play a critical role in the elimination of MHCI-deficient tumors that may otherwise evade immune surveillance. We previously demonstrated that modulation of the VV backbone by deletion of the N1L gene could enhance systemic NK cell responses and prevent postsurgical tumor recurrence in murine models of pancreatic, lung and breast cancer 13 and IL-21 is able to increase these responses further. Interestingly, Seo et al recently reported a critical role for IL-21 in the reversal of NK cell exhaustion, common to MHCI-deficient tumors, 46 thus further phenotypic examination of the NK populations induced by VVL-21 is warranted in future experiments, although based on our results, this can reasonably be expected to extend to our model.…”

“…VVΔTKΔN1L was described previously 25 26 and tumor specificity ensured by rational deletion of TK and N1L genes. 13 14 16 VVΔTKΔN1L-IL21 (containing the murine or human IL-21 cytokine) construction was described previously. 27 For in vitro and mouse studies, VVL-21 armed with murine IL-21 was used.…”

Latest evidence on immunotherapy for cholangiocarcinoma (Review)

“…In addition, the use of an OV in combination with inhibition of transforming growth factor-β signaling is thought to increase the efficacy of immunotherapy ( 42 ). According to a recent study, a novel Vaccinia virus known as VVΔTKΔN1L , with thymidine kinase and N1L gene deletions and armed with interleukin 12, successfully prevented the recurrence of tumors in surgical models of head and neck cancer in Syrian hamsters ( 46 ). This study laid an important experimental foundation for the development of new drugs in the treatment of solid tumors.…”

A novel vaccinia virus enhances anti-tumor efficacy and promotes a long-term anti-tumor response in a murine model of colorectal cancer

“… 20 , 21 We have recently reported that an additional deletion of the VV 13.8-kDa N1L protein, a neurovirulence factor, 22 can further increase the safety profile of the virus (named VVLΔTKΔN1L) and enhance anti-tumor immune responses, particularly adaptive CD8 + T cell and innate natural killer (NK) cell responses, consequent to viral infection, resulting in superior anti-tumor efficacy of VVLΔTKΔN1L compared to VVLΔTK in a number of in vivo murine and hamster models of cancer. 23 …”