Efficacy Of Oncolytic Viruses Research Articles

Efficacy of oncolytic virus combined with HAIC of mFOLFOX for IMCC: A single-center, single-arm, prospective study.

e16265 Background: Hepatic arterial infusion chemotherapy (HAIC) is a well-established treatment for liver cancer. Our previous studies have demonstrated the effectiveness of HAIC with modified FOLFOX (mFOLFOX) for intrahepatic cholangiocarcinoma. However, intrahepatic mass-forming cholangiocarcinoma (IMCC) patients often lose the therapeutic opportunity due to obstructive jaundice caused by huge tumor compression. On the other hand, recombinant human adenovirus type 5 Injection (H101), an oncolytic virus (OVs), has direct anticancer effects and enhances cell-mediated immune responses. Therefor, this clinical study was designed to improve the prognosis of IMCC by the combination of OVs injection and HAIC. Methods: In this study, patients with unresectable IMCC and confirmed by biopsy were enrolled. H101 was used by ultrasound-guided injections 1-3 days before HAIC (a dosage of ≤10 cm, 1.0×1012 vp; ≥10 cm, 1.5×1012 vp). Then, patients were treated with HAIC, which is a night-administration regimen of 50 mg oxaliplatin plus 1.5g 5-fluorouracil and leucovorin, continuous infusion for 2-3 days. Patients received 4-6 cycles of treatment. The primary outcome was progression-free survival (PFS), the secondary outcomes were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and quality of life (QOL). Efficacy assessments were conducted every four weeks following mRECIST v1.1 criteria. Quality of life was assessed by the WHOQOL-BREF scale. Results: From April 1, 2022 to February 1, 2024, 11 patients were enrolled. The median age was 57 years (range 36-73) and the mean tumor diameter was 8.6cm (range 4.3-11.7cm). The primary endpoint was met with a mPFS of 9.6 months. The mOS was 13.2 months. ORR was 36.3% (4/11), and DCR was 90.9% (10/11). CA-199 decreased from 2036.47 to 560.55 U/ml (P < 0.01). The CD8+ T cells increased significantly (306.94 VS. 448.7 cell/ul, P < 0.05), but the CD4+ T cells were with a steady tendency (425.41 VS. 583.50 cell/ul, P = 0.32). In addition, all patients were placed 1-3 biliary drains before enrollment. After OVs plus HAIC treatment, 7 patients had removed or closed their biliary tract drainage tubes, and the QOL score increased from 71.23 to 77.18. Significantly, during the puncture operation, the tumor texture became softer during the multi-cycle OVs plus HAIC treatment. It explains why the tumor pressure on the biliary tract was quickly relieved and the biliary drainage tube was removed in most enrolled IMCC patients. Conclusions: The combination of OVs injection and HAIC with mFOLFOX showed promising anti-tumor and immune-activation efficacy in IMCC. Meanwhile, this strategy has an effect on relieving the pain and malnutrition of long-term biliary drainage and improving the quality of life of patients. Even more, the OVs plus HAIC regimen may be more effective, if combined with the immune checkpoint inhibitors in the future. Clinical trial information: NCT05124002 .

The combination therapy of oncolytic virotherapy.

Introduction: Compared to other cancer immunotherapies, oncolytic viruses possess several advantages, including high killing efficiency, excellent targeting capabilities, minimal adverse reactions, and multiple pathways for tumor destruction. However, the efficacy of oncolytic viruses as a monotherapy often falls short of expectations. Consequently, combining oncolytic viruses with traditional treatments to achieve synergistic effects has emerged as a promising direction for the development of oncolytic virus therapies. Methods: This article provides a comprehensive review of the current progress in preclinical and clinical trials exploring the combination therapies involving oncolytic viruses. Results: Specifically, we discuss the combination of oncolytic viruses with immune checkpoint inhibitors, chemotherapy, targeted therapy, and cellular therapy. Discussion: The aim of this review is to offer valuable insights and references for the further advancement of these combination strategies in clinical applications. Further research is necessary to refine the design of combination therapies and explore novel strategies to maximize the therapeutic benefits offered by oncolytic viruses.

Fast Track Adaptation of Oncolytic Coxsackie B3 Virus to Resistant Colorectal Cancer Cells - a Method to Personalize Virotherapy

BackgroundThe efficacy of oncolytic viruses (OV) in cancer treatment depends on their ability to successfully infect and destroy tumor cells. However, patients’ tumors vary, and in the case of individual insensitivity to an OV, therapeutic efficacy is limited. Here, we present a protocol for rapid generation of tumor cell-specific adapted oncolytic coxsackievirus B3 (CVB3) with enhanced oncolytic potential and a satisfactory safety profile. This is achieved by combining directed viral evolution (DVE) with genetic modification of the viral genome and the use of a microRNA-dependent regulatory tool.MethodsThe oncolytic CVB3 variant PD-H was adapted to the refractory colorectal carcinoma cell line Colo320 through serial passaging. XTT assays and virus plaque assays were used to determine virus cytotoxicity and virus replication in vitro. Recombinant PD-H variants were generated through virus mutagenesis. Apoptosis was detected by Western blots, Caspase 3/7 assays, and DAPI staining. The therapeutic efficacy and safety of the adapted recombinant OV PD-SK-375TS were assessed in vivo using a subcutaneous Colo320 xenograft mouse model.ResultsPD-H was adapted to the colorectal cancer cell line Colo320 within 10 passages. Sequencing of passage 10 virus P-10 revealed a heterogenous virus population with five nucleotide mutations resulting in amino acid substitutions. The genotypically homogeneous OV PD-SK was generated by inserting the five detected mutations of P-10 into the genome of PD-H. PD-SK showed significantly stronger replication and cytotoxicity than PD-H in Colo320 cells, but not in other colorectal carcinoma cell lines. Increase of apoptosis induction was detected as key mechanisms of Colo320 cell-specific adaptation of PD-SK. For in vivo safety PD-SK was engineered with target sites of the miR-375 (miR-375TS) to exclude virus replication in normal tissues. PD-SK-375TS, unlike the PD-H-375TS not adapted homolog suppressed the growth of subcutaneous Colo320 tumors in nude mice without causing any side effects.ConclusionTaken together, here we present an optimized protocol for the rapid generation of tumor cell-specific adapted oncolytic CVB3 based on the oncolytic CVB3 strain PD-H. The protocol is promising for the generation of personalized OV for tumor therapy and has the potential to be applied to other OV.

The heterogeneous sensitivity of pediatric brain tumors to different oncolytic viruses is predicted by unique gene expression profiles

Despite decades of research, the prognosis of high-grade pediatric brain tumors (PBTs) remains dismal, however, recent cases of favorable clinical responses were documented in clinical trials using oncolytic viruses (OVs). In the current study, we employed four different species of OVs: adenovirus Delta24-RGD, herpes simplex virus rQNestin34.5v1, reovirus R124 and the non-virulent Newcastle Disease Virus rNDV-F0-GFP against three entities of PBTs (high-grade gliomas, atypical teratoid/rhabdoid tumors and ependymomas) to determine their in vitro efficacy. These four OVs were screened on 14 patient-derived PBT cell cultures and the degree of oncolysis was assessed using an ATP-based assay. Subsequently, the observed viral efficacies were correlated to whole transcriptome data and Gene Ontology analysis was performed. Although no significant tumor type-specific OV efficacy was observed, the analysis revealed the intrinsic biological processes that associated with OV efficacy. The predictive power of the identified expression profiles was further validated in vitro by screening additional PBTs. In summary, our results demonstrate OV susceptibility of multiple patient-derived PBT entities and the ability to predict in vitro responses to OVs using unique expression profiles. Such profiles may hold promise for future OV preselection with effective oncolytic potency in a specific tumor, therewith potentially improving OV responses.

Combination Immunotherapy of Oncolytic Flu-Vectored Virus and Programmed Cell Death 1 Blockade Enhances Antitumor Activity in Hepatocellular Carcinoma.

Oncolytic viruses (OVs) are appealing anti-tumor agents. But it is limited in its effectiveness. In this study, we used combination therapy with immune checkpoint inhibitor to enhance the antitumor efficacy of OVs. Using reverse genetics technology, we rescued an oncolytic influenza virus with the name delNS1-GM-CSF from the virus. After identifying the hemagglutination and 50% tissue culture infectivedose (TCID50) of delNS1-GM-CSF, it was purified, and the viral morphology was observed under electron microscopy. Reverse transcription quantitative-polymerase chain reaction (RT-qPCR) was used to identify the level of GM-CSF expression in delNS1-GM-CSF, and the GM-CSF expression level was determined after infection with delNS1-GM-CSF by enzyme linked immunosorbent assay (ELISA). To study the tumor-killing effect of delNS1-GM-CSF, we utilized the hepatocellular carcinoma (HCC) tumor-bearing mouse model. To examine signaling pathways, we performed transcriptome sequencing on mouse tumor tissue and applied western blotting to confirm the results. Changes in T-cell infiltration in HCC tumors following treatment were analyzed using flow cytometry and immunohistochemistry. DelNS1-GM-CSF can target and kill HCCs without damaging normal hepatocytes. DelNS1-GM-CSF combined with programmed cell death 1 blockade therapy enhanced anti-tumor effects and significantly improved mouse survival. Further, we found that combination therapy had an antitumor impact via the janus kinase-signal transducer and activator of transcription (JAK2-STAT3) pathway as well as activated CD4+ and CD8+T cells. Interestingly, combined therapy also showed promising efficacy in distant tumors. DelNS1-GM-CSF is well targeted. Mechanistic investigation revealed that it functions through the JAK2-STAT3 pathway. Combination immunotherapies expected to be a novel strategy for HCC immunotherapy.

An Engineered Influenza a Virus Expressing the Co-Stimulator OX40L as an Oncolytic Agent Against Hepatocellular Carcinoma.

Oncolytic virus (OV) therapy has emerged as a promising novel form of immunotherapy. Moreover, an increasing number of studies have shown that the therapeutic efficacy of OV can be further improved by arming OVs with immune-stimulating molecules. In this study, we used reverse genetics to produce a novel influenza A virus, termed IAV-OX40L, which contained the immune-stimulating molecule OX40L gene in the influenza virus nonstructural (NS1) protein gene. The oncolytic effect of IAV-OX40L was explored on hepatocellular carcinoma (HCC)HCC cells in vitro and in vivo. Hemagglutination titers of the IAV-OX40L virus were stably 27-28 in specific-pathogen-free chicken embryos. The morphology and size distribution of IAV-OX40L are similar to those of the wild-type influenza. Expression of OX40L protein was confirmed by Western blot and immunofluorescence. MTS assays showed that the cytotoxicity of IAV-OX40L was higher in HCC cells (HepG2 and Huh7) than in normal liver cells (MIHA) in a time- and dose-dependent manner in vitro. We found that intratumoral injection of IAV-OX40L reduced tumor growth and increased the survival rate of mice compared with PR8-treated controls in vivo. In addition, the pathological results showed that IAV-OX40L selectively destroyed tumor tissues without harming liver and lung tissues. CD4+ and CD8+ T cells of the IAV-OX40L group were significantly increased in the splenic lymphocytes of mice. Further validation confirmed that IAV-OX40L enhanced the immune response mainly by activating Th1-dominant immune cells, releasing interferon-γ and interleukin-2. Taken together, our findings demonstrate the novel chimeric influenza OV could provide a potential therapeutic strategy for combating HCC and improve the effectiveness of virotherapy for cancer therapy.

Photodynamic augmentation of oncolytic virus therapy for central nervous system malignancies

Oncolytic viruses (OVs) have emerged as a clinical therapeutic modality potentially effective for cancers that evade conventional therapies, including central nervous system malignancies. Rationally designed combinatorial strategies can augment the efficacy of OVs by boosting tumor-selective cytotoxicity and modulating the tumor microenvironment (TME). Photodynamic therapy (PDT) of cancer not only mediates direct neoplastic cell death but also primes the TME to sensitize the tumor to secondary therapies, allowing for the combination of two potentially synergistic therapies with broader targets. Here, we created G47Δ-KR, clinical oncolytic herpes simplex virus G47Δ that expresses photosensitizer protein KillerRed (KR). Optical properties and cytotoxic effects of G47Δ-KR infection followed by amber LED illumination (peak wavelength: 585–595 nm) were examined in human glioblastoma (GBM) and malignant meningioma (MM) models in vitro. G47Δ-KR infection of tumor cells mediated KR expression that was activated by LED and produced reactive oxygen species, leading to cell death that was more robust than G47Δ-KR without light. In vivo, we tested photodynamic-oncolytic virus (PD-OV) therapy employing intratumoral injection of G47Δ-KR followed by laser light tumor irradiation (wavelength: 585 nm) in GBM and MM xenografts. PD-OV therapy was feasible in these models and resulted in potent anti-tumor effects that were superior to G47Δ-KR alone (without laser light) or laser light alone. RNA sequencing analysis of post-treatment tumor samples revealed PD-OV therapy-induced increases in TME infiltration of variable immune cell types. This study thus demonstrated the proof-of-concept that G47Δ-KR enables PD-OV therapy for neuro-oncological malignancies and warrants further research to advance potential clinical translation.

Developing Oncolytic Viruses for the Treatment of Cervical Cancer.

Cervical cancer represents one of the most important malignancies among women worldwide. Current therapeutic approaches for cervical cancer are reported not only to be inadequate for metastatic cervical cancer, but are also considered as cytotoxic for several patients leading to serious side effects, which can have negative implications on the quality of life of women. Therefore, there is an urgent need for the development of innovative and effective treatment options. Oncolytic viruses can eventually become effective biological agents, since they preferentially infect and kill cancer cells, while leaving the normal tissue unaffected. Moreover, they are also able to leverage the host immune system response to limit tumor growth. This review aims to systematically describe and discuss the different types of oncolytic viruses generated for targeting cervical cancer cells, as well as the outcome of the combination of virotherapy with conventional therapies. Although many preclinical studies have evaluated the therapeutic efficacy of oncolytic viruses in cervical cancer, the number of clinical trials so far is limited, while their oncolytic properties are currently being tested in clinical trials for the treatment of other malignancies.

Inhibition of Tumor Metastasis by Liquid-Nitrogen-Shocked Tumor Cells with Oncolytic Viruses Infection.

Despite the superior tumor lytic efficacy of oncolytic viruses (OVs), their systemic delivery still faces the challenges of limited circulating periods, poor tumor tropism, and spontaneous antiviral immune responses. Herein, a virus-concealed tumor-targeting strategy enabling OVs' delivery toward lung metastasis via systemic administration is described. The OVs can actively infect, be internalized, and cloak into tumor cells. Then the tumor cells are subsequently treated with liquid-nitrogen-shocking to eliminate the pathogenicity. Such a Trojan Horse-like vehicle avoids virus neutralization and clearance in the bloodstream and facilitates tumor-targeted delivery for more than 110-fold virus enrichment in the tumor metastasis. In addition, this strategy can serve as a tumor vaccine and initiate endogenous adaptive antitumor effects through increasing the memory T cells and modulating the tumor immune microenvironment, including reducing the M2 macrophage, downregulating Treg cells, and priming T cells.

Abstract 1845: Mammalian orthoreoviruses R124 and jin-3 demonstrate oncolytic and immune-stimulatory effects in human preclinical bladder cancer models

Abstract Immunotherapy, including the use of immune checkpoint inhibitors, has emerged as an attractive strategy for treatment of various cancers. Unfortunately, less than half of the bladder cancer patients demonstrate clinical benefit from immune checkpoint inhibitors. Novel therapeutic approaches such as oncolytic virotherapy may unleash the full potential of immunotherapy. Oncolytic viruses display tumor-lysing properties, while leaving normal cells unharmed. Besides the direct oncolytic effects, oncolytic viruses are capable of inducing systemic anti-tumor immune responses, thereby representing a promising anti-cancer therapy. In our multi-center oncolytic viro-immunotherapy (OVIT) consortium we evaluate and compare the oncolytic and immunomodulatory properties of several oncolytic viruses (reoviruses, novel non-human primate Adenoviruses, Newcastle disease virus), develop tools to predict oncolytic virus efficacy and design strategies to personalize oncolytic virus therapy. In this study we evaluated and compared the direct oncolytic and indirect immunostimulatory effects of wildtype reovirus R124 and mutant reovirus jin-3 in human bladder cancer. Mutant reovirus jin-3 harbors mutations in the spike protein Sigma-1 and can infect cells independently of junction adhesion molecule A (JAM-A) expression on the tumor cell surface. For this, we exploited multiple preclinical bladder cancer models, including patient-derived tumor models (e.g. 3D cultures) and ex-vivo cultured tumor tissue slices. Both R124 and jin-3 reoviruses could infect, replicate and induce cell death in a panel of 2D and 3D cultured bladder cancer cells lines with a basal, luminal or mixed phenotype. Furthermore, the viruses were capable of infecting the tumor cells and induced cell death in ex-vivo cultured tumor tissue slices. Reovirus mutant jin-3, and to a lesser extent R124, strongly induced immunogenic cell death markers (HMGB1, cell surface expression of calreticulin, HSP90), interferon-stimulated genes, and inflammatory cytokines (IFNβ, CXCL10, TNFα) in human bladder cancer cells. Co-culture of reovirus-infected murine bladder cancer cells MB-49 with murine splenocytes resulted in increased activation markers of dendritic cells and NK cells. In conclusion, reoviruses display oncolytic properties in multiple preclinical models of human bladder cancer. Mutant reovirus jin-3 displays more potent immunomodulatory responses in preclinical bladder cancer models compared with wildtype reovirus R124. Therefore, jin-3 represents an attractive candidate for clinical translation. Citation Format: Arjanneke F. Van De Merbel, Maaike H. van der Mark, Thijs J. Janssen, Lobke C. Hensen, Diana J. van den Wollenberg, Rob C. Hoeben, Rob F. Bevers, Rob C. Pelger, Gabri van der Pluijm, Geertje van der Horst. Mammalian orthoreoviruses R124 and jin-3 demonstrate oncolytic and immune-stimulatory effects in human preclinical bladder cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1845.

Establishing a New Platform to Investigate the Efficacy of Oncolytic Virotherapy in a Human Ex Vivo Peritoneal Carcinomatosis Model.

Oncolytic virotherapy constitutes a promising treatment option for many solid cancers, including peritoneal carcinomatosis (PC), which still represents a terminal stage of many types of tumors. To date, the in vitro efficacy of oncolytic viruses is mostly tested in 2D-cultured tumor cell lines due to the lack of realistic 3D in vitro tumor models. We have investigated the feasibility of virotherapy as a treatment option for PC in a human ex vivo peritoneum co-culture model. Human HT-29 cancer cells stably expressing marker genes GFP and firefly luciferase (GFP/luc) were cultured on human peritoneum and infected with two prototypic oncolytic viruses (GLV-0b347 and MeV-DsRed). Both viral constructs were able to infect HT-29 cells in patient-derived peritoneum with high tumor specificity. Over time, both GFP signal and luciferase activity decreased substantially, thereby indicating successful virus-induced oncolysis. Furthermore, immunohistochemistry stainings showed specific virotherapeutic infections of HT-29 cells and effective tumor cell lysis in infected co-cultures. Thus, the PC model established here provides a clinically relevant screening platform to evaluate the therapeutic efficacy of virotherapeutic compounds and also to investigate, in an autologous setting, the immunostimulatory potential of oncolytic viruses for PC in a unique human model system superior to standard 2D in vitro models.

Immunostimulatory Profile of Cancer Cell Death by the AdV-Lumc007-Derived Oncolytic Virus 'GoraVir' in Cultured Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy which shows unparalleled therapeutic resistance. Oncolytic viruses have emerged as a new treatment approach and convey their antitumor activity through lysis of cancer cells. The therapeutic efficacy of oncolytic viruses is largely dependent on the induction of immunogenic cell death (ICD) and the subsequent antitumor immune responses. However, the concurrent generation of antiviral immune responses may also limit the a virus' therapeutic window. GoraVir is a new oncolytic adenovirus derived from the Human Adenovirus B (HAdV-B) isolate AdV-lumc007 which was isolated from a gorilla and has demonstrated excellent lytic activity in both in vitro and in vivo models of PDAC. In this study, we characterized the immunostimulatory profile of cancer cell death induced by GoraVir and the concerted cellular antiviral responses in three conventional pancreatic cancer cell lines. While GoraVir was shown to induce late apoptotic/necrotic cell death at earlier time points post infection than the human adenovirus type 5 (HAdV-C5), similar levels of ICD markers were expressed. Moreover, GoraVir was shown to induce ICD not dependent on STING expression and regardless of subsequent antiviral responses. Together, these data demonstrate that GoraVir is an excellent candidate for use in oncolytic virotherapy.

Oncolytic Virotherapy.

Oncolytic virotherapy opens up avenues for cancer treatment by selectively targeting the cancer cells and destructs them either through direct lysis or by inducing an immune response in the tumor microenvironment. This platform technology utilizes a diverse range naturally existing or genetically modified oncolytic viruses for their immunotherapeutic potential. Due to the limitations associated with the conventional cancer therapies, immunotherapies using oncolytic viruses (OVs) have generated a great deal of interest in the modern era. Currently, several oncolytic viruses have entered clinical trials and have proven successful for a number of different cancers as monotherapies as well as in combination with the standard treatment methods like chemotherapy, radiotherapy, or immunotherapy. Efficacy of OVs can be further enhanced by utilizing several approaches. Efforts of the scientific community for getting better knowledge of individual patient tumor immune responses will enable medical community to treat cancer patients more precisely. In this regard, OV seems to be a part of multimodality cancer treatment option in the near future. In this chapter, the fundamental characteristics and mechanism of actions of oncolytic viruses are initially described and then overview of the important clinical trials of various oncolytic viruses for a number of cancers is presented.

Recent oncolytic virotherapy clinical trials outline a roadmap for the treatment of high-grade glioma.

Adult and pediatric high-grade gliomas (HGGs) are aggressive cancers of the central nervous system that confer dismal clinical prognoses. Standard radiation and chemotherapy have demonstrated only limited efficacy in HGGs, motivating the accelerated investigation of novel modalities such as oncolytic virus (OV) therapies. OV centered therapies work through a mixed mechanism centered on oncolysis and the stimulation of an antitumor immune response. Three recent clinical trials utilizing herpes simplex virus-1 and adenovirus-based oncolytic virotherapy demonstrated not only the safety and efficacy of OVs but also novel dosing strategies that augment OV response potential. Considering these recent trials, herein we present a roadmap for future clinical trials of oncolytic immunovirotherapy in both adult and pediatric HGG, as well as persistent roadblocks related to the assessment of OV efficacy within and between trials.

Application of Bioinformatics Tools for the Prediction of Helper MicroRNAs for Improvement of Oncolytic Virus Efficacy

Purpose. Oncolytic Reoviruses, as a self-limiting virus, can be used in cancer treatment, because they have the ability to replicate in tumor cells selectively and destroy them. Studies show that some immune response proteins may interfere with the virus life cycle. So, the main aim of this bioinformatic study is to check which microRNA is able to target some reovirus inhibitory proteins. Experimental Design. By use of online bioinformatics software, the microRNAs that could target inhibitory genes were selected. Then, other features like content ++ score and cell type were checked and finally the eligible microRNAs were determined. Results. After choosing 15 inhibitory proteins, analysis was performed and finally 37 microRNAs which could target inhibitory proteins in colorectal cell lines were selected. In the end, by investigation of web-based tools, just two microRNAs were finalized. Conclusions and Clinical Relevance. This bioinformatic study shows that microRNA-140 and microRNA-92a have the potential to target some inhibitory proteins which interfere with oncolytic Reovirus replication and it may help in the optimal use of this virus as a cancer treatment. Because selective reproduction of Reovirus in tumor cells, as a nonchemical therapy, can be a good way to overcome this disease with broad advantages.

Oncolytic Viruses and Cancer Immunotherapy.

Oncolytic viruses (OVs) exert their antitumor effect through selective killing of cancer cells and induction of host anti-tumor immunity. This review aims to summarize the recent and current trials with OVs for the treatment of lung cancer. Several OVs have been developed for the treatment of lung cancer including adenovirus, coxsackievirus B3, reovirus, and vaccinia virus and trials have demonstrated a safe toxicity profile. Early-phase trials in lung cancer with OVs have reported antiviral immune responses and evidence of clinical benefit. However, clinical efficacy of OVs in lung cancer either as monotherapy or in combination with chemotherapy has not been confirmed in larger phase II or III trials. Development of OVs in lung cancer has been limited by difficulty in administering OVs in the tumor directly as well as achieving adequate viral load at all tumor sites with systemically administered OVs. Developing novel combinations with OVs, especially checkpoint inhibitors and other immunotherapeutics, may be a strategy to address the limited success seen thus far. Integrating appropriate biomarker studies and meaningful endpoints in future clinical trials will be imperative. Using novel viral delivery systems in addition to increasing tumor specificity through improved genetic modifications in the OVs are other strategies to improve efficacy.

Progress of oncolytic virotherapy for neuroblastoma.

As a neuroendocrine tumor derived from the neural crest, neuroblastoma (NB) is the most common extracranial solid tumor in children. The prognosis in patients with low- and intermediate-risk NB is favorable while that in high-risk patients is often detrimental. However, the management of the considerably large proportion of high-risk patients remains challenging in clinical practice. Among various new approaches, oncolytic virus (OV) therapy offers great advantages in tumor treatment, especially for high-risk NB. Genetic modified OVs can target NB specifically without affecting normal tissue and avoid the widespread drug resistance issue in anticancer monotherapy. Meanwhile, its safety profile provides great potential in combination therapy with chemo-, radio-, and immunotherapy. The therapeutic efficacy of OV for NB is impressive from bench to bedside. The effectiveness and safety of OVs have been demonstrated and reported in studies on children with NB. Furthermore, clinical trials on some OVs (Celyvir, Pexa-Vec (JX-594) and Seneca Valley Virus (NTX-010)) have reported great results. This review summarizes the latest evidence in the therapeutic application of OVs in NB, including those generated in cell lines, animal models and clinical trials.

EXTH-54. CO-CULTURE OF PATIENT-DERIVED GLIOBLASTOMA CELL LINES WITH AUTOLOGOUS PBMCS FOR THE INVESTIGATION OF ONCOLYTIC VIRUS RESPONSE

Abstract BACKGROUND The dismal prognosis of glioblastoma (GBM) patients, with a median survival of less than 15 months despite maximal therapy urgently warrants new therapeutic approaches. Clinical trials employing oncolytic viruses (OVs) have shown encouraging results, however, in each OV clinical trial only a small subset of patients responded to treatment. As inter-tumoral heterogeneity has been the key challenge in treating GBM, we hypothesized that development of an in vitro co-culture model for assessment of viral replication and subsequent immune response might ultimately predict in vivo OV efficacy for individual GBM patients. METHODS 20 patient-derived GBM cell cultures were tested with dose-ranges of two clinically relevant OVs (DNX2401 and rQnestin34.5 V1) to determine the EC50 values (half-maximal effective concentration). To discriminate between responders and non-responders six of these cultures were infected using MOI 10 for DNX2401 and 0.25 for rQnestin34.5V1, and co-cultured with autologous PBMCs. OV-induced changes in gene and protein expression of immune associated genes were assessed using targeted gene expression (NanoString Technology) and ELISA. RESULTS DNX2401 EC50 values ranged from 0.35 to > 600 and from 0.04 to 1.77 for rQnestin34.5V1. Induction of pro-inflammatory cytokines and chemokines differed per virus and per patient. Enhanced OV infection or oncolysis efficiency did not lead to increased levels of IFNγ production. Importantly, longer exposure to dexamethasone prior to PBMC isolation correlated with suppressed IFNγ production. CONCLUSION We established an autologous GBM cells/PBMCs co-culture model which reflects inter-tumoral heterogeneity in terms of cytokine induction and virus-specific changes in gene and protein expression upon OV infection. Immune activation is not directly related to degree of infection or oncolysis and can be hampered by prolonged prior dexamethasone use. These first results support our hypothesis that improved prediction of response rates in oncolytic virotherapy for GBM may require a personalized approach with an in vitro test system.

Therapeutic Implementation of Oncolytic Viruses for Cancer Immunotherapy: Review of Challenges and Current Clinical Trials.

The development of cancer therapeutics has evolved from general targets with radiation and chemotherapy and shifted toward treatments with a more specific mechanism of action such as small molecule kinase inhibitors, monoclonal antibodies against tumor antigens, or checkpoint inhibitors. Recently, oncolytic viruses (OVs) have come to the forefront as a viable option for cancer immunotherapy, especially for "cold" tumors, which are known to inhabit an immunologically suppressive tumor microenvironment. Desired characteristics of viruses are selected through genetic attenuation of uncontrolled virulence, and some genes are replaced with ones that enhance conditional viral replication within tumor cells. Treatment with OVs must overcome various hurdles such as premature viral suppression by the host's immune system and the dense stromal barrier. Currently, clinical studies investigate the efficacy of OVs in conjunction with various anti-cancer therapeutics, including radiotherapy, chemotherapy, immune checkpoint inhibitors, and monoclonal antibodies. Thus, future research should explore how cancer therapeutics work synergistically with certain OVs in order to create more effective combination therapies and improve patient outcomes.

Advances in tumor immunotherapy and gene therapy

<p indent="0mm">As emerging tumor immunotherapy and gene therapy products such as immune checkpoint inhibitors, oncolytic viruses and chimeric antigen receptor T (CAR-T) cells approved for clinical use, tumor immunotherapy and gene therapy have revolutionized the treatment of some solid tumors and blood tumors. On a global scale to obtain authoritative organization and leading experts of broad consensus, tumor immunotherapy and gene therapy are becoming the first-line treatment for a wide variety of tumor treatment. However, this field is still facing some questions to be solved, including the immunotherapy-related adverse reactions and the non-significant efficacy of oncolytic virus, and CAR-T cells should break through the treatment of solid tumors and reduce the expensive price. Aiming at these key scientific issues, the research teams from West China Hospital of Sichuan University have made a series of achievements from disease molecular network to drug discovery, development and translation based on innovative biotechnology. Herein, this paper briefly reviews the progress of tumor immunotherapy and gene therapy in recent years from West China Hospital of Sichuan University. We look forward to the 130th anniversary of the establishment of West China Hospital as an opportunity to continue to make more world-class achievements and benefit the society in the future.