Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non–small cell lung cancer patients with <scp>K</scp>RAS‐activated tumors

Villalona‐Calero, Miguel A.; Lam, Elaine T.; Otterson, Gregory A.; Zhao, Weiqiang; Timmons, Matthew; Subramaniam, Deepa; Hade, Erinn M.; Gill, George M.; Coffey, Matthew; Selvaggi, Giovanni; Bertino, Erin M.; Chao, Bo H.; Knopp, Michael V.

doi:10.1002/cncr.29856

Cited by 61 publications

(41 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Advances in virus engineering and understanding of tumor biology have enabled the development of multiple OVs exploiting different cellular mechanisms to drive tumor selectivity, oncolytic efficacy, and immunogenicity. Indeed, several other candidates are currently being evaluated in the clinic, including the reovirus, Reolysin [3] and coxsackievirus A21, CVA21 (Cavatak) [4], for which interim results suggest some antitumor efficacy with manageable safety profiles. The approval of TVEC in patients with metastatic melanoma and the recent demonstration that its use could potentiate current IO therapy provide a further rationale for development of other OV candidates [5].…”

Section: Introductionmentioning

confidence: 99%

Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro

Burke

Shergold

Elder

et al. 2020

Cancer Immunol Immunother

View full text Add to dashboard Cite

Oncolytic virus (OV) therapy is an emerging approach with the potential to redefine treatment options across a range of cancer indications and in patients who remain resistant to existing standards of care, including immuno-oncology (IO) drugs. MEDI5395, a recombinant Newcastle disease virus (NDV), engineered to express granulocyte-macrophage colonystimulating factor (GM-CSF), exhibits potent oncolytic activity. It was hypothesized that activation of immune cells by MEDI5395, coupled with its oncolytic activity, would enhance the priming of antitumor immunity. Using MEDI5395 and recombinant NDVs encoding fluorescent reporter genes, we demonstrated preferential virus uptake and non-productive infection in myeloid cells, including monocytes, macrophages, and dendritic cells (DCs). Infection resulted in immune-cell activation, with upregulation of cell surface activation markers (e.g., CD80, PD-L1, HLA-DR) and secretion of proinflammatory cytokines (IFN-α2a, IL-6, IL-8, TNF-α). Interestingly, in vitro M2-polarized macrophages were more permissive to virus infection than were M1-polarized macrophages. In a co-culture system, infected myeloid cells were effective virus vectors and mediated the transfer of infectious NDV particles to tumor cells, resulting in cell death. Furthermore, NDV-infected DCs stimulated greater proliferation of allogeneic T cells than uninfected DCs. Antigens released after NDV-induced tumor cell lysis were cross-presented by DCs and drove activation of tumor antigen-specific autologous T cells. MEDI5395 therefore exhibited potent immunostimulatory activity and an ability to enhance antigen-specific T-cell priming. This, coupled with its tumor-selective oncolytic capacity, underscores the promise of MEDI5395 as a multimodal therapeutic, with potential to both enhance current responding patient populations and elicit de novo responses in resistant patients.

show abstract

Section: Introductionmentioning

confidence: 99%

Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro

Burke

Shergold

Elder

et al. 2020

Cancer Immunol Immunother

View full text Add to dashboard Cite

show abstract

“…To establish infection, the virus must first attach to its target cell. This is mediated by the binding of the reovirus capsid protein, sigma1, to different cellular targets, such as the tight junction protein JAM-A and sialic acids, on the target cell surface (4)(5)(6)(7)(8)(9)(10)(11). Reovirus is an oncolytic virus that has been tested in experimental animal models and in human clinical trials for the treatment of head and neck cancers, melanoma, lung cancer, ovarian cancer, and colorectal cancer (1,7,8,12,13).…”

mentioning

confidence: 99%

NKp46 Recognizes the Sigma1 Protein of Reovirus: Implications for Reovirus-Based Cancer Therapy

Bar-On¹,

Charpak-Amikam²,

Glasner³

et al. 2017

J Virol

View full text Add to dashboard Cite

The recent approval of oncolytic virus for therapy of melanoma patients has increased the need for precise evaluation of the mechanisms by which oncolytic viruses affect tumor growth. Here we show that the human NK cell-activating receptor NKp46 and the orthologous mouse protein NCR1 recognize the reovirus sigma1 protein in a sialic-acid-dependent manner. We identify sites of NKp46/NCR1 binding to sigma1 and show that sigma1 binding by NKp46/NCR1 leads to NK cell activation Finally, we demonstrate that NCR1 activation is essential for reovirus-based therapy Collectively, we have identified sigma1 as a novel ligand for NKp46/NCR1 and demonstrated that NKp46/NCR1 is needed both for clearance of reovirus infection and for reovirus-based tumor therapy. Reovirus infects much of the population during childhood, causing mild disease, and hence is considered to be efficiently controlled by the immune system. Reovirus also specifically infects tumor cells, leading to tumor death, and is currently being tested in human clinical trials for cancer therapy. The mechanisms by which our immune system controls reovirus infection and tumor killing are not well understood. We report here that natural killer (NK) cells recognize a viral protein named sigma1 through the NK cell-activating receptor NKp46. Using several mouse tumor models, we demonstrate the importance of NK cells in protection from reovirus infection and in reovirus killing of tumors Collectively, we identify a new ligand for the NKp46 receptor and provide evidence for the importance of NKp46 in the control of reovirus infections and in reovirus-based cancer therapy.

show abstract

“…6,7 In October 2015, the US Food and Drug Administration (FDA) approved the first genetically modified herpes simplex virus 1 (talimogene laherparepvec [T-VEC]) for the treatment of melanoma. 8 During the past decades, several oncolytic viruses (both RNA and DNA viruses), including coxsackievirus A21, 9 reovirus, 10 vaccinia virus, 11 adenovirus, 12 measles virus, 13 Newcastle disease virus, 14 and vesicular stomatitis virus, 15 have been tested in clinical trials for the treatment of lung cancer. However, overall anti-cancer efficacy and specificity remain low and there is still no FDA-approved virotherapy for lung cancer.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA Modification of Coxsackievirus B3 Decreases Its Toxicity, while Retaining Oncolytic Potency against Lung Cancer

Liu

Xue

Deng

et al. 2020

Molecular Therapy - Oncolytics

View full text Add to dashboard Cite

We recently discovered that coxsackievirus B3 (CVB3) is a potent oncolytic virus against KRAS mutant lung adenocarcinoma. Nevertheless, the evident toxicity restricts the use of wild-type (WT)-CVB3 for cancer therapy. The current study aims to engineer the CVB3 to decrease its toxicity and to extend our previous research to determine its safety and efficacy in treating TP53/RB1 mutant small-cell lung cancer (SCLC). A microRNA-modified CVB3 (miR-CVB3) was generated via inserting multiple copies of tumor-suppressive miR-145/miR-143 target sequences into the viral genome. In vitro experiments revealed that miR-CVB3 retained the ability to infect and lyse KRAS mutant lung adenocarcinoma and TP53/RB1mutant SCLC cells, but with a markedly reduced cytotoxicity toward cardiomyocytes. In vivo study using a TP53/RB1mutant SCLC xenograft model demonstrated that a single dose of miR-CVB3 via systemic administration resulted in a significant tumor regression. Most strikingly, mice treated with miR-CVB3 exhibited greatly attenuated cardiotoxicities and decreased viral titers compared to WT-CVB3-treated mice. Collectively, we generated a recombinant CVB3 that is powerful in destroying both KRAS mutant lung adenocarcinoma and TP53/RB1-mutant SCLC, with a negligible toxicity toward normal tissues. Future investigation is needed to address the issue of genome instability of miR-CVB3, which was observed in~40% of mice after a prolonged treatment.

show abstract

Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non–small cell lung cancer patients with KRAS‐activated tumors

Cited by 61 publications

References 40 publications

Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro

Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro

NKp46 Recognizes the Sigma1 Protein of Reovirus: Implications for Reovirus-Based Cancer Therapy

MicroRNA Modification of Coxsackievirus B3 Decreases Its Toxicity, while Retaining Oncolytic Potency against Lung Cancer

Contact Info

Product

Resources

About