Modulation of the Intratumoral Immune Landscape by Oncolytic Herpes Simplex Virus Virotherapy

Yin, Jie; Markert, James M.; Leavenworth, Jianmei W.

doi:10.3389/fonc.2017.00136

Cited by 48 publications

(51 citation statements)

References 69 publications

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“…Pathologic type I IFN production is well described in chronic viral infections and induces a dysfunctional immune state where T cells become exhausted by the chronic inflammatory state, thus unable to clear the virus (45). Paradoxically, chronic expression of an antitumor cytokine (type I IFN) creates both an inflamed, yet immunosuppressive, environment that prevents an effective antitumor immune response after oHSV treatment (46). Chronic inflammation promotes tumor initiation, progression, and metastasis by providing a tumor-supporting microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy Using Ruxolitinib and Oncolytic HSV Renders Resistant MPNSTs Susceptible to Virotherapy

Ghonime

Cassady

2018

Cancer Immunology Research

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Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas resistant to most cancer treatments. Surgical resection remains the primary treatment, but this is often incomplete, ultimately resulting in high mortality and morbidity rates. There has been a resurgence of interest in oncolytic virotherapy because of encouraging preclinical and clinical trial results. Oncolytic herpes simplex virus (oHSV) selectively replicates in cancer cells, lysing the cell and inducing antitumor immunity. We previously showed that basal interferon (IFN) signaling increases interferon-stimulated gene (ISG) expression, restricting viral replication in almost 50% of MPNSTs. The FDA-approved drug ruxolitinib (RUX) temporarily resets this constitutively active STAT signaling and renders the tumor cells susceptible to oHSV infection in cell culture. In the studies described here, we translated our in vitro

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Section: Discussionmentioning

confidence: 99%

Combination Therapy Using Ruxolitinib and Oncolytic HSV Renders Resistant MPNSTs Susceptible to Virotherapy

Ghonime

Cassady

2018

Cancer Immunology Research

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“…Host immunity is important to the outcome of certain OV, as has been shown for HSV 18 . Additionally, T and NK cells have been identified as major components of host immunity after vaccinia infection and contribute to OV-mediated anti-tumor effects 19 .…”

Section: Discussionmentioning

confidence: 95%

Effective Combination Immunotherapy using Oncolytic Viruses to Deliver CAR Targets to Solid Tumors

Park

Fong

Chen

et al. 2019

Preprint

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Chimeric antigen receptor (CAR)-engineered T cell therapy for solid tumors is limited by the lack of tumor-restricted and homogeneous expression of tumor antigens1,2. Therefore, we engineered an oncolytic virus to express a non-signaling, truncated CD19 (CD19t) protein for tumor-selective delivery, enabling targeting by CD19-specific CAR T cells. Infecting tumor cells with a chimeric oncolytic vaccinia virus coding for CD19t (OV19t) produced de novo CD19 surface-antigen expression prior to virus-mediated tumor lysis. Co-cultured CD19-CAR T cells secreted cytokines and elicited potent cytolytic activity against infected tumors. Using multiple mouse tumor models, intratumoral delivery of OV19t induced tumor expression of CD19t and improved tumor control following CD19-CAR T cell administration. CAR T cell–mediated tumor killing also promoted release of virus from dying tumor cells, which propogated tumor expression of CD19t. These data demonstrate a novel immunotherapy approach utilizing oncolytic viruses to promote de novo CAR T cell targeting of solid tumors.One Sentence SummaryWe describe a novel and effective combination immunotherapy utilizing oncolytic viruses to deliver de novo cell surface expression of CD19 antigen promoting CD19-CAR T cell anti-tumor responses against solid tumors.

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“…Therefore, in addition to direct tumor lysis, the importance of the immune response on the efficacy of OV therapy has been widely demonstrated [11][12][13][14]. 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].…”

Section: Oncolytic Virotherapymentioning

confidence: 99%

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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Modulation of the Intratumoral Immune Landscape by Oncolytic Herpes Simplex Virus Virotherapy

Cited by 48 publications

References 69 publications

Combination Therapy Using Ruxolitinib and Oncolytic HSV Renders Resistant MPNSTs Susceptible to Virotherapy

Combination Therapy Using Ruxolitinib and Oncolytic HSV Renders Resistant MPNSTs Susceptible to Virotherapy

Effective Combination Immunotherapy using Oncolytic Viruses to Deliver CAR Targets to Solid Tumors

Oncolytic Viruses: Priming Time for Cancer Immunotherapy

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