Oncolytic viruses: overcoming translational challenges

Liu

Sig Transduct Target Ther

et al. 2020

The use of oncolytic viruses has emerged as a promising therapeutic approach due to the features of these viruses, which selectively replicate and destroy tumor cells while sparing normal cells. Although numerous oncolytic viruses have been developed for testing in solid tumors, only a few have been reported to target acute myeloid leukemia (AML) and overall patient survival has remained low. We previously developed the oncolytic adenovirus rAd5pz-zTRAIL-RFP-SΔ24E1a (A4), which carries the viral capsid protein IX linked to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and results in increased infection of cancer cells and improved tumor targeting. To further improve the therapeutic potential of A4 by enhancing the engagement of virus and leukemia cells, we generated a new version of A4, zA4, by coating A4 with additional soluble TRAIL that is fused with a leucine zipper-like dimerization domain (zipper). ZA4 resulted in enhanced infectivity and significant inhibition of the proliferation of AML cells from cell lines and primary patient samples that expressed moderate levels of TRAIL-related receptors. ZA4 also elicited enhanced anti-AML activity in vivo compared with A4 and an unmodified oncolytic adenoviral vector. In addition, we found that the ginsenoside Rh2 upregulated the expression of TRAIL receptors and consequently enhanced the antitumor activity of zA4. Our results indicate that the oncolytic virus zA4 might be a promising new agent for treating hematopoietic malignancies such as AML.

Section: Discussionmentioning

confidence: 99%

Enhancing the antitumor activity of an engineered TRAIL-coated oncolytic adenovirus for treating acute myeloid leukemia

Liu

Sig Transduct Target Ther

et al. 2020

“…OVs can be delivered locally (mainly intratumorally) or systemically (mainly intravenously). Local intratumoral injection is the most common route of administration; intratumoral delivery maximizes the concentration of OVs at target tumor lesions while minimizing systemic toxicity [ 27 , 82 , 83 ]. However, this method cannot be applied to inaccessible or multifocal tumors.…”

Section: Current Limitations Of Ovs For Cancer Treatmentmentioning

confidence: 99%

“…Furthermore, viable tumor cells at the OV injection site are essential for viral transfection and immune cell recruitment. In addition, treatment efficacy can vary depending on the skill level of the operator [ 83 ]. On the other hand, theoretically, systemic administration is an ideal delivery route because it is minimally invasive and highly repeatable, covering both primary and metastatic tumors.…”

Section: Current Limitations Of Ovs For Cancer Treatmentmentioning

confidence: 99%

“…The intratumoral distribution of OV within the TME is also a critical factor that determines its anti-tumor efficacy. Besides the aforementioned virus size and envelope type, a dense ECM within tumors serves as a physical barrier to intratumoral OV infiltration and diffusion [ 27 , 28 , 83 ]. To overcome this barrier, new OVs with specific enzymes capable of ECM degradation have been generated and have shown significant anti-tumor effects in preclinical studies [ 87 , 88 ].…”

Section: Current Limitations Of Ovs For Cancer Treatmentmentioning

confidence: 99%

“…In addition to pre-existing neutralizing antibodies, anti-viral immunity can also be mediated by the complement system, anti-viral cytokines, and non-specific uptake by off-target organs [ 82 ]. Therefore, to tackle anti-viral immunity, multiple strategies, including genetic manipulation of OV, cytokines, immunomodulators, nanoparticles, and the depletion of neutralizing antibodies, have been explored [ 82 , 83 , 90 ]. On the other hand, there are several conflicting reports suggesting anti-viral immunity could sometimes be beneficial for anti-tumor immunity because anti-viral immunity can recruit anti-tumor immune cells into the TME and reverse the immunosuppressive TME [ 5 , 27 ].…”

Section: Current Limitations Of Ovs For Cancer Treatmentmentioning

confidence: 99%

See 2 more Smart Citations

Combination Immunotherapy Using Oncolytic Virus for the Treatment of Advanced Solid Tumors

Chon

Kim

2020

IJMS

Oncolytic virus (OV) is a new therapeutic strategy for cancer treatment. OVs can selectively infect and destroy cancer cells, and therefore act as an in situ cancer vaccine by releasing tumor-specific antigens. Moreover, they can remodel the tumor microenvironment toward a T cell-inflamed phenotype by stimulating widespread host immune responses against the tumor. Recent evidence suggests several possible applications of OVs against cancer, especially in combination with immune checkpoint inhibitors. In this review, we describe the molecular mechanisms of oncolytic virotherapy and OV-induced immune responses, provide a brief summary of recent preclinical and clinical updates on this rapidly evolving field, and discuss a combinational strategy that is able to overcome the limitations of OV-based monotherapy.

Tumors driven by RAS signaling harbor a natural vulnerability to oncolytic virus M1

et al. 2020

Oncolytic viruses are potent anticancer agents that replicate within and kill cancer cells rather than normal cells, and their selectivity is largely determined by oncogenic mutations. M1, a novel oncolytic virus strain, has been shown to target cancer cells, but the relationship between its cancer selectivity and oncogenic signaling pathways is poorly understood. Here, we report that RAS mutation promotes the replication and oncolytic effect of M1 in cancer, and we further provide evidence that the inhibition of the RAS/RAF/MEK signaling axis suppresses M1 infection and the subsequent cytopathic effects. Transcriptome analysis revealed that the inhibition of RAS signaling upregulates the type I interferon antiviral response, and further RNA interference screen identified CDKN1A as a key downstream factor that inhibits viral infection. Gain-and loss-of-function experiments confirmed that CDKN1A inhibited the replication and oncolytic effect of M1 virus. Subsequent TCGA data mining and tissue microarray (TMA) analysis revealed that CDKN1A is commonly deficient in human cancers, suggesting extensive clinical application prospects for M1. Our report indicates that virotherapy is feasible for treating undruggable RASdriven cancers and provides reliable biomarkers for personalized cancer therapy.