Oncolytic Viruses and Immune Checkpoint Inhibition: The Best of Both Worlds

Sivanandam, Venkatesh; LaRocca, Christopher J.; Chen, Nanhai G.; Fong, Yuman; Warner, Susanne G.

doi:10.1016/j.omto.2019.04.003

Cited by 117 publications

(121 citation statements)

References 120 publications

(145 reference statements)

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“…Clinical activity of CAVATAK was highly tumor-selective and demonstrated the ability to induce tumor inflammation and hemorrhage following either single or multiple administrations of CAVATAK in several patients, and led to a complete resolution of tumor in one patient. Whether used alone or in combination with mitomycin C, CAVATAK caused marked inflammatory changes within NMIBC tissue biopsies by upregulating interferoninducible genes including both Th1-associated chemokines and immune checkpoint inhibitory genes (PD-L1 and LAG3) supporting future combination studies with immune checkpoint inhibitors (40)(41)(42).…”

Section: The Urinary Microbiome: a Potential Emerging Factor In The Imentioning

confidence: 91%

Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response

2020

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It is now well-recognized that the tumor microenvironment (TME) is not only a key regulator of cancer progression but also plays a crucial role in cancer treatment responses. Recently, several high-profile publications have demonstrated the importance of particular immune parameters and cell types that dictate responsiveness to immunotherapies. With this increased understanding of TME-mediated therapy, approaches that increase therapeutic efficacy by remodeling the TME are actively being pursued. A classic example of this, in practice by urologists for over 40 years, is the manipulation of the bladder microenvironment for the treatment of non-muscle invasive bladder cancer (NMIBC) by instillation of intravesical bacillus Calmette-Guerin (BCG). The success of BCG treatment is thought to be due to its ability to induce a massive influx of Th1-polarized inflammatory cells, production of Th1 inflammatory cytokines and the generation of tumor-targeted Th1-mediated cytotoxic responses. Whilst BCG immunotherapy is currently the best treatment for NMIBC, ∼30% of patients show no response to this treatment. Here we present a review highlighting a variety of promising alternative immunotherapies being developed that remodel the bladder tumor microenvironment. These include (1) the use of oncolytic viruses which selectively replicate within cancer cells whilst also modifying the immunological components of the TME, (2) manipulation of the bladder microbiome to augment the response to BCG or other immunotherapies (3) utilizing Toll-like Receptor agonists as anti-tumor agents due to their potent stimulation of innate and adaptive immunity and (4) the growing recognition that immunotherapeutic strategies that will have the largest impact on patients may require multiple therapeutic approaches combined together. The accumulating knowledge on TME remodeling holds promise for providing an alternative therapy for patients with BCG-unresponsive NMIBC.

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Section: The Urinary Microbiome: a Potential Emerging Factor In The Imentioning

confidence: 91%

Modifying the Non-muscle Invasive Bladder Cancer Immune Microenvironment for Optimal Therapeutic Response

2020

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“…Very recently, a ERBB2-retargeted oHSV armed with IL-12 proved to be efficacious in subcutaneous and glioblastoma tumour models 27,28 . Accordingly, combination of OVs and immune checkpoint inhibitors have shown improved clinical activity 8,29,30 .In this paper, we describe the implementation and the characterization of a non-attenuated, virulent oHSV obtained by combining cancer selective replication by transcription control and receptor retargeting. The characterization of tumour associated promoters highlighted the suitability of the Survivin promoter for restriction of viral replication in tumour cell lines by conditional expression of the immediate-early ICP4 viral gene.…”

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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“…TSAs result from the accumulation of mutations within a tumor cell line (19,37). A special category of these antigens comprises neoantigens, which are present on MHC molecules (38,39) (Figure 1). Surprisingly, neoantigens are unique to the patient rather than to the tumor, and are often downregulated in tumors, suggesting that tumors evade immune destruction (40)(41)(42)(43)(44)(45).…”

Section: Tumor Immunosurveillance and Tumor Antigensmentioning

confidence: 99%

“…OVs can also induce viral infection cascades known to elicit a type 1 interferon response thereby stimulating cytokine release, cancer cell lysis, and apoptosis (97,98). The first OV approved by the FDA was Imlygic, a herpes simplex virus I tweaked to preferentially kill cancer cells, which was approved in 2015 for the treatment of advanced melanoma (39,99). TG4010, an attenuated poxvirus engineered to express MUC-1 and IL-2 prolonged the survival of patients with advanced NSCLC when administered with first-line chemotherapy and is now being tested in phase III clinical trials (43).…”

Section: Oncolytic Virusesmentioning

confidence: 99%