The Current State of Oncolytic Herpes Simplex Virus for Glioblastoma Treatment

Chen

et al. 2022

J Immunother Cancer

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers worldwide. Despite the promising outcome of immune checkpoint inhibitors and agonist antibody therapies in different malignancies, PDAC exhibits high resistance due to its immunosuppressive tumor microenvironment (TME). Ameliorating the TME is thus a rational strategy for PDAC therapy. The intratumoral application of oncolytic herpes simplex virus-1 (oHSV) upregulates pro-inflammatory macrophages and lymphocytes in TME, and enhances the responsiveness of PDAC to immunotherapy. However, the antitumor activity of oHSV remains to be maximized. The aim of this study is to investigate the effect of the CD40L armed oHSV on the tumor immune microenvironment, and ultimately prolong the survival of the PDAC mouse model.MethodsThe membrane-bound form of murine CD40L was engineered into oHSV by CRISPR/Cas9-based gene editing. oHSV-CD40L induced cytopathic effect and immunogenic cell death were determined by microscopy and flow cytometry. The expression and function of oHSV-CD40L was assessed by reporter cell assay. The oHSV-CD40L was administrated intratumorally to the immune competent syngeneic PDAC mouse model, and the leukocytes in TME and tumor-draining lymph node were analyzed by multicolor flow cytometry. Intratumoral cytokines were determined by ELISA.ResultsIntratumoral application of oHSV-CD40L efficiently restrained the tumor growth and prolonged the survival of the PDAC mouse model. In TME, oHSV-CD40L-treated tumor accommodated more maturated dendritic cells (DCs), which in turn activated T helper 1 and cytotoxic CD8+ T cells in an interferon-γ-dependent and interleukin-12-dependent manner. In contrast, the regulatory T cells were significantly reduced in TME by oHSV-CD40L treatment. Repeated dosing and combinational therapy extended the lifespan of PDAC mice.ConclusionCD40L-armed oncolytic therapy endues TME with increased DCs maturation and DC-dependent activation of cytotoxic T cells, and significantly prolongs the survival of the model mice. This study may lead to the understanding and development of oHSV-CD40L as a therapy for PDAC in synergy with immune checkpoint blockade.

Section: Introductionmentioning

confidence: 99%

CD40L-armed oncolytic herpes simplex virus suppresses pancreatic ductal adenocarcinoma by facilitating the tumor microenvironment favorable to cytotoxic T cell response in the syngeneic mouse model

Chen

et al. 2022

J Immunother Cancer

“…Importantly, OVs replicate specifically in cancer cells, generate and release viral progeny that can infect neighboring malignant cells, amplifying the therapeutic effect. Furthermore, OVs can be genetically modified (armed) to deliver pro-drugs activating genes, anti-angiogenic or immune stimulating genes [ 5 , 6 ]. Finally, the virus itself acts as an immunological adjuvant triggering immune response [ 7 , 8 ], potentially favoring an agnostic vaccination against tumor associated antigens (TAA) released following the lysis of tumor cells [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Among all OVs, oncolytic HSVs (oHSVs) appear to be the most promising. HSV advantages encompass its high cytolytic effect, its large and stable genome that can be easily engineered, its ability to grow at high titres and the availability of specific anti-viral drugs to counter any possible adverse reactions [ 6 , 21 ]. In many instances, oHSV selectivity for cancer cells has been achieved generating attenuated viruses, carrying deletion of specific genes necessary for virus replication in non-dividing cells and dispensable for viral replication in proliferating tumor cells.…”

Section: Introductionmentioning

confidence: 99%

“…The attenuating modifications described above improve the safety of the treatment but, at the same time, reduce the viral replicative and lytic ability, thus limiting the therapeutic potential [ 6 , 25 ]. dlsptk , the first genetically engineered oHSV tested for glioblastoma treatment carried the deletion of the thymidine kinase gene, improved survival of treated mice and boosted research in the field of oncolytic virotherapy [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

“…Many more attenuated oHSV were developed [ 21 ]. Most of them were engineered with deletion in both copies of the γ 1 34.5 neurovirulence gene and possibly additional deletions [ 6 ]: oHSV G207, lacking the two copies of γ 1 34.5 and UL39 genes, showed an increased glioblastoma selectivity, and oHSV G47Δ, with an additional deletion in US12, had an increased viral replication in glioblastoma cells [ 27 , 28 ]. Other strategies to rescue viral replication in attenuated Δγ 1 34.5 oHSVs included the re-insertion of the γ 1 34.5 gene under the nestin promoter (oHSV rQNestin34.5v.2) to prevent replication in differentiated neural cells and limit it to glioblastoma cells [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Specificity, Safety, Efficacy of EGFRvIII-Retargeted Oncolytic HSV for Xenotransplanted Human Glioblastoma

Appolloni

Alessandrini

Menotti

et al. 2021

Viruses

Glioblastoma is a lethal primary brain tumor lacking effective therapy. The secluded onset site, combined with the infiltrative properties of this tumor, require novel targeted therapies. In this scenario, the use of oncolytic viruses retargeted to glioblastoma cells and able to spread across the tumor cells represent an intriguing treatment strategy. Here, we tested the specificity, safety and efficacy of R-613, the first oncolytic HSV fully retargeted to EGFRvIII, a variant of the epidermal growth factor receptor carrying a mutation typically found in glioblastoma. An early treatment with R-613 on orthotopically transplanted EGFRvIII-expressing human glioblastoma significantly increased the median survival time of mice. In this setting, the growth of human glioblastoma xenotransplants was monitored by a secreted luciferase reporter and showed that R-613 is able to substantially delay the development of the tumor masses. When administered as late treatment to a well-established glioblastomas, R-613 appeared to be less effective. Notably the uninfected tumor cells derived from the explanted tumor masses were still susceptible to R-613 infection ex vivo, thus suggesting that multiple treatments could enhance R-613 therapeutic efficacy, making R-613 a promising oncolytic HSV candidate for glioblastoma treatment.

The Journal of Gene Medicine

Augmentation of Solid Tumor Immunotherapy With IL‐12

Geils,

Kathrein

2024

Immunotherapy describes a class of therapies in which the immune system is manipulated for therapeutic benefit. These treatments include immune checkpoint inhibitors, adoptive cell therapy, and vaccines. For many hematological malignancies, immunotherapy has emerged as an essential treatment component. However, this success has yet to be replicated for solid tumors, which develop advanced physical and molecular mechanisms for suppressing and evading immune destruction. Nevertheless, cytokine immunotherapy presents a potential remedy to these barriers by delivering a proinflammatory immune signal to the tumor and thereby transforming it from immunologically “cold” to “hot.” Interleukin‐12 (IL‐12), one of the most potent proinflammatory cytokines, was initially investigated for this purpose. However, initial murine and human studies in which IL‐12 was administered systemically resulted in dangerous immunotoxicity associated with off‐target immune activation. As a result, recent studies have employed advanced cell and molecular engineering approaches to reduce IL‐12 toxicity while increasing or maintaining its efficacy such that its effective doses can be tolerated in humans. This review highlights such developments and identifies promising future directions.