Critical Interactions between Immunogenic Cancer Cell Death, Oncolytic Viruses, and the Immune System Define the Rational Design of Combination Immunotherapies

Vloten, Jacob P. van; Workenhe, Samuel T.; Wootton, Sarah K.; Mossman, Karen; Bridle, Byram W.

doi:10.4049/jimmunol.1701021

Cited by 80 publications

(60 citation statements)

References 129 publications

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“…For example, they trigger immunogenic cell death in tumor beds, which can promote the maturation and function of dendritic cells (DCs). 9 Stimulated DCs produce large amounts of type I interferons (IFNs) and pro-inflammatory chemokines and cytokines, which further induce widespread pro-inflammatory effects, leading to the recruitment of T cells and the regulation of immune responses. 10 This process facilitates the destruction of the physical barrier that inhibits T cell infiltration.…”

Section: Introductionmentioning

confidence: 99%

oHSV2 Can Target Murine Colon Carcinoma by Altering the Immune Status of the Tumor Microenvironment and Inducing Antitumor Immunity

Zhang

Liang

et al. 2020

Molecular Therapy - Oncolytics

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Oncolytic viruses are promising immunoreagents. Numerous studies have shown that oncolytic virotherapy is effective for many tumors. Herein, we investigated the therapeutic effect of oHSV2, an oncolytic type 2 herpes simplex virus, on mouse colon carcinoma. The in vivo antitumor efficacy of oHSV2 was observed in both unilateral and bilateral colon cancer models. oHSV2 effectively eliminated tumors and prolonged the survival of mice without side effects. Additionally, treatment with oHSV2 effectively prevented the growth of rechallenged tumors and distant implanted tumors. The specific killing ability of splenic immune cells to tumor cells was enhanced. oHSV2 treatment effectively reduced the content of inhibitory immune cells (regulatory T cells [Tregs] and myeloid-derived suppressor cells [MDSCs]) and increased the content of positive immune cells (natural killer [NK], CD8 + T, and dendritic cells [DCs]) in the spleen. Moreover, treatment with oHSV2 remodeled the tumor immune microenvironment. In summary, treatment with oHSV2 can effectively eliminate primary tumors, generate tumor-specific immunity, and elicit immune memory to inhibit tumor recurrence and metastasis. Furthermore, this virotherapy can reshape the immune status of the spleen and tumor microenvironment in mice, which can further improve the therapeutic antitumor effect.

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Section: Introductionmentioning

confidence: 99%

oHSV2 Can Target Murine Colon Carcinoma by Altering the Immune Status of the Tumor Microenvironment and Inducing Antitumor Immunity

Zhang

Liang

et al. 2020

Molecular Therapy - Oncolytics

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“…Besides reducing the tumour bulk, OVs also act as immunotherapeutic agents. This feature is principally due to the immunogenic cell death (ICD) mechanisms induced by OVs, including immunogenic apoptosis, necrosis, necroptosis, pyroptosis, and autophagic cell death [3][4][5] . Viral infection also induces the release of stimulating cytokines, such as IL-1, IL-6, IL-12, IL-18, IFN-γ.…”

mentioning

confidence: 99%

Replicative conditioning of Herpes simplex type 1 virus by Survivin promoter, combined to ERBB2 retargeting, improves tumour cell-restricted oncolysis

Sasso

Froechlich

Cotugno

et al. 2020

Sci Rep

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Oncolytic virotherapy is emerging as a promising therapeutic option for solid tumours. Several oncolytic vectors in clinical testing are based on attenuated viruses; thus, efforts are being taken to develop a new repertoire of oncolytic viruses, based on virulent viral genomes. This possibility, however, raises concerns dealing with the safety features of the virulent phenotypes. We generated a double regulated Herpes simplex type-1 virus (HSV-1), in which tumour cell restricted replicative potential was combined to selective entry via ERBB2 receptor retargeting. The transcriptional control of the viral alpha4 gene encoding for the infected cell protein-4 (ICP4) by the cellular Survivin/BIRC5 promoter conferred a tumour cell-restricted replicative potential to a virulent HSV-1 genome. The combination of the additional ERBB2 retargeting further improved the selectivity for tumour cells, conferring to the double regulated virus a very limited ability to infect and propagate in non-cancerous cells. Accordingly, a suitable replicative and cytotoxic potential was maintained in tumour cell lines, allowing the double regulated virus to synergize in vivo with immune checkpoint (anti-PD-1) blockade in immunocompetent mice. Thus, restricting the replicative spectrum and tropism of virulent HSV-1 genomes by combination of conditional replication and retargeting provides an improved safety, does not alter the oncolytic strength, and is exploitable for its therapeutic potential with immune checkpoint blockade in cancer.Oncolytic viruses (OVs) represent a class of natural or engineered viral species, possessing the ability to infect cancer cells, while sparing healthy tissues 1 . This selectivity is usually conferred by attenuating mutations, resulting in preferential replication of viral genomes in tumour cells 2 . Besides reducing the tumour bulk, OVs also act as immunotherapeutic agents. This feature is principally due to the immunogenic cell death (ICD) mechanisms induced by OVs, including immunogenic apoptosis, necrosis, necroptosis, pyroptosis, and autophagic cell death [3][4][5] . Viral infection also induces the release of stimulating cytokines, such as IL-1, IL-6, IL-12, IL-18, IFN-γ. Along with these molecules, lysed cancer cells release tumour-associated antigens and cancer-related proteins. These mechanisms allow the immunosuppressed tumour microenvironment (TME) to turn into an immunocompetent habitat. This effect is potentiated in OVs, in which immunostimulatory cytokines or chemokines are encoded by engineered viral genomes, and can synergize with immune checkpoint blockade 6-8 . This may translate into a therapeutic opportunity to potentiate the effects of immune checkpoint blockade in patients refractory to immunotherapy 9,10 . Talimogene laherparepvec (T-VEC), a Herpes simplex-based OV (oHSV), was approved by FDA in 2015 for treatment of recurrent melanoma after initial surgery 11,12 . It holds a ICP34.5-deleted genome, resulting in attenuated neurovirulence, and diminished infection of normal cells. Transgen...

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“…Currently, most of the efforts to 'arm' OV consist of adding genes that have the ability to boost the activation of immune responses within the tumor microenvironment, such as cytokines or costimulatory molecules [15]. Following the approval of T-VEC, a large number of oncolytic virotherapy trials, using myriad viral platforms, have been initiated either as monotherapies or as combination therapies with other modalities, such as chemotherapy, radiotherapy and, in particular, immunotherapies [16,17].…”

Section: Oncolytic Virotherapymentioning

confidence: 99%

“…Therefore, activated innate immune cells, including neutrophils, granulocytes, natural killer (NK) cells, and antigen-presenting cells (APCs), will be the first to arrive and respond at the site(s) of infection. To consolidate pathogen control, an antiviral adaptive immune response produced by B and T cells is subsequently established [17,18]. Tumor cells and their microenvironment have evolved many mechanisms to suppress the generation of any local or systemic antitumoral immune effectors [19,20].…”

Section: Oncolytic Viruses (Ovs) and Activation Of Immune Responsesmentioning

confidence: 99%

“…These cells can destroy viralinfected tumor cells, release cytokines that can reduce tumor growth, and pick up viral and tumor antigens from dying tumor cells for presentation to, and activation of, T cells. However, at the same time, myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) may also be recruited into the tumor microenvironment, serving to inhibit immune responses [17,21]. OVs that can tilt the balance towards the generation of proinflammatory responses that cannot be counteracted by host/tumor immunosuppression would be appealing for further development.…”

Section: Oncolytic Viruses (Ovs) and Activation Of Immune Responsesmentioning

confidence: 99%

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Oncolytic Viruses: Priming Time for Cancer Immunotherapy

Russell¹,

et al. 2019

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New immuno-oncology therapies are improving cancer treatments beyond the former standard of care, as evidenced by the recent and continuing clinical approvals for immunotherapies in a broad range of indications. However, a majority of patients (particularly those with immunologically cold tumors) still do not benefit, highlighting the need for rational combination approaches. Oncolytic viruses (OV) both directly kill tumor cells and inflame the tumor microenvironment. While OV spread can be limited by the generation of antiviral immune responses, the initial local tumor cell killing can reverse the immunosuppressive tumor microenvironment, resulting in more effective release of tumor-associated antigens (TAAs), cross-presentation, and antitumoral effector T cell recruitment. Moreover, many OVs can be engineered to express immunomodulatory genes. Rational combination approaches to cancer immunotherapy include the use of OVs in combination with immune checkpoint inhibitors (ICIs) or adoptive T cell therapy (ACT) to promote sustained antitumoral immune responses. OV combinations have additive or synergistic efficacy in preclinical tumor models with ICIs or ACT. Several preclinical studies have confirmed systemic reactivation and proliferation of adoptively transferred antitumoral T cells in conjunction with oncolytic OVs (expressing cytokines or TAAs) resulting from the specific tumor cell killing and immunostimulation of the tumor microenvironment which leads to increased tumor trafficking, activity, and survival. Recent clinical trials combining OVs with ICIs have shown additive effects in melanoma. Additional clinical data in an expanded range of patient indications are eagerly awaited. The relative timings of OV and ICI combination remains under-studied and is an area for continued exploration. Studies systematically exploring the effects of systemic ICIs prior to, concomitantly with, or following OV therapy will aid in the future design of clinical trials to enhance efficacy and increase patient response rates. Key Points Oncolytic viruses induce immunogenic tumor cell death, which makes them ideal partners for combination with immunotherapies such as immune checkpoint inhibitors and adoptive T cell therapies. Effective combination therapies will depend on careful scheduling of the component parts.

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Critical Interactions between Immunogenic Cancer Cell Death, Oncolytic Viruses, and the Immune System Define the Rational Design of Combination Immunotherapies

Cited by 80 publications

References 129 publications

oHSV2 Can Target Murine Colon Carcinoma by Altering the Immune Status of the Tumor Microenvironment and Inducing Antitumor Immunity

oHSV2 Can Target Murine Colon Carcinoma by Altering the Immune Status of the Tumor Microenvironment and Inducing Antitumor Immunity

Replicative conditioning of Herpes simplex type 1 virus by Survivin promoter, combined to ERBB2 retargeting, improves tumour cell-restricted oncolysis

Oncolytic Viruses: Priming Time for Cancer Immunotherapy

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