Viruses For Treatment Of Cancer Research Articles

Breaking Barriers: A Future Perspective on Glioblastoma Therapy with mRNA-Based Immunotherapies and Oncolytic Viruses.

The use of mRNA-based immunotherapies that leverage the genomes of oncolytic viruses holds significant promise in addressing glioblastoma (GBM), an exceptionally aggressive neurological tumor. We explore the significance of mRNA-based platforms in the area of immunotherapy, introducing an innovative approach to mitigate the risks associated with the use of live viruses in cancer treatment. The ability to customize oncolytic virus genome sequences enables researchers to precisely target specific cancer cells, either through viral genome segments containing structural proteins or through a combination of regions with oncolytic potential. This strategy may enhance treatment effectiveness while minimizing unintended impacts on non-cancerous cells. A notable case highlighted here pertains to advanced findings regarding the application of the Zika virus (ZIKV) in GBM treatment. ZIKV, a member of the family Flaviviridae, shows oncolytic properties against GBM, opening novel therapeutic avenues. We explore intensive investigations of glioblastoma stem cells, recognized as key drivers in GBM initiation, progression, and resistance to therapy. However, a comprehensive elucidation of ZIKV's underlying mechanisms is imperative to pave the way for ZIKV-based clinical trials targeting GBM patients. This investigation into harnessing the potential of oncolytic-virus genomes for mRNA-based immunotherapies underscores its noteworthy implications, potentially paving the way for a paradigm shift in cancer treatment strategies.

A review of oncolytic viruses in cancer treatment

A review of oncolytic viruses in cancer treatment

Abstract 6542: CAL1 vaccinia virus as oncolytic agent and potential use of cell-based platform to enhance its therapeutic effects

Abstract Background: Oncolytic virotherapy is a promising immuno-oncology approach that has not realized its potential due to rapid elimination by humoral immunity mediated by complement and neutralizing antibodies. We propose to use an adipose-derived mesenchymal stemcell-based platform,where the virus can be protected and amplified and potentiated inside the stem cells in order to minimize the clearance by anti-viral immunity. ACAM2000, the smallpox vaccine currently licensed in the U.S., is a clonal derivative of Dryvax® with reduced virulence and a well-documented safety profile in humans. This vaccinia virus strain can potentially be used as an oncolytic virus for cancer treatment. In this study, we evaluate the ability of ACAM2000 to (1) selectively kill cancer cells, (2) to be genetically modified without affecting its natural tumor selectivity, and to (3) determine if a stem cell-based platform can protect the virus from inactivation and potentiate its anti-tumor effects. Methods: ACAM2000 was amplified in CV1 cells and named CAL1. CAL1 was tested for its ability to replicate and selectively kill various human prostate cancer cell lines in vitro and in vivo. Additionally, CAL1 was loaded into adipose-derived mesenchymal stem cells to generate a new therapeutic agent called SuperNova1 (SNV1). Both CAL1 and SNV1 were tested for their ability to kill cancer cells in the presence of active complement and neutralizing antibodies in cell culture as well as in mice. Furthermore, CAL1 was used as the backbone to generate derivative CAL2 viruses using CRISPR/Cas9 technology to insert the gene encoding the fluorescent protein TurboFP into the intergenic locus between ORF-157 and ORF-158 of CAL1 without disrupting any existing CAL1 ORFs. Results: We showed that in vitro CAL1 preferentially infected, amplified in and lysed tumor cells and was also able to cause tumor regression in vivo without signs of toxicity. Furthermore, we demonstrated that the backbone of CAL1 can be used to engineer recombinant viruses, CAL2, that carry therapeutic genes without additionally attenuating the ability of the virus to amplify or kill tumor cells. SNV1 significantly enhanced protection of CAL1 virus from clearance by the immune system, leading to higher therapeutic efficacy. Furthermore, SNV1 provided instantly active viral particles for immediate infection and simultaneous release of therapeutic proteins in the injected tumors. Conclusions: CAL1 could be used as an oncolytic agent. We show here that a major advantage of using a cell-based platform to deliver and potentiate oncolytic vaccinia virus is the prevention of viral inactivation by the humoral immune system resulting in enhanced oncolytic viral therapy. Citation Format: Duong H. Nguyen, Thomas Herrmann, Ashley Alamillo, Forrest Neuharth, Alberto Gomez, Ivelina Minev, Barbara Härtl, Laura Schneider, Boris Minev, Dobrin Draganov, Antonio F. Santidrian. CAL1 vaccinia virus as oncolytic agent and potential use of cell-based platform to enhance its therapeutic effects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6542.

Enhancement of the therapeutic effects of oncolytic vaccinia virus by using autologous and allogeneic cell-based delivery platforms.

e15271 Background: Clinical trials with oncolytic viruses for cancer treatment have shown limited efficacy due to viruses’ rapid clearance by patients’ innate and adaptive immune systems. In a recent first-in-human clinical trial, we confirmed the safety and feasibility of our approach to enhance oncolytic vaccinia virus (OVV) delivery and improve tumor targeting by utilizing an autologous cell-based cell delivery system (auto-OVV). We also developed an allogeneic cell-based platform (SuperNova1c - SNV1c) aiming to protect and potentiate OVV’s antitumor effects in large patient populations. Methods: We evaluated the immunomodulatory potential of auto-OVV by an extensive time-course analysis of cytokines in patients’ plasma (Luminex profiling) and peripheral blood immune cells (flow cytometry). We also analyzed the ability of SNV1c to protect the OVV from antibody/complement inactivation in vitro and in vivo following intratumoral injection in various mouse tumors. The immune cell infiltrations of the injected tumors were also analyzed. Results: Therapy with auto-OVV induced a coordinated activation of cytokine, T cell and NK responses in patients as early as 1 day, peaking around 1-week and lasting for up to 1-month post treatment. Effective OVV amplification in cancer patients correlated with significant changes of multiple innate and adaptive immune parameters. Patient stratification into groups with transient versus persistent viral DNA was linked to opposing and mutually exclusive patterns of robust activation of NK versus T cell responses, respectively. SNV1c showed significantly enhanced protection of OVV in vitro and led to statistically significant tumor growth inhibition as compared to control non-treated tumors or to naked OVV-treated tumors. Importantly, local administration of SNV1c induced systemic therapeutic effects. Five days after SNV1c administration, tumor infiltrating lymphocytes from both treated and untreated tumors showed increased CD4 and CD8 T-cell infiltrations, decreased Tregs, and improved effector to Treg ratios, associated with tumor growth inhibition at both treated and untreated tumor sites. Conclusions: This study establishes the timeline of treatment-related immunological changes and identifies potential immunological correlates associated with the OVV persistence in vivo. We also demonstrate the ability of our cell-based platforms to protect and potentiate OVV by circumventing innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy.

Use of stem cells as carriers of oncolytic viruses for cancer treatment.

Therapeutic application of stem cells and oncolytic viruses in cancer treatment has rapidly increased in the last decade. Oncolytic viruses are considered as a new class of anticancer agents because of their ability to selectively infect and destroy cancer cells. Furthermore, regarding the specific migratory capacity of stem cells, they can be used as carriers or vectors targeting metastatic cancer. Promising results have been reported regarding the use of stem cells and oncolytic viruses as a therapeutic approach for the treatment of metastatic cancer. The present review aimed to determine the approaches involved in the use of the tumor-homing capacity of stem cells for cancer treatment.

Effect of the oncolytic ECHO-7 virus Rigvir® on the viability of cell lines of human origin in vitro.

Background: The role of oncolytic viruses in cancer treatment is increasingly studied. The first oncolytic virus (Rigvir®, ECHO-7) was registered in Latvia over a decade ago. In a recent retrospective study Rigvir® decreased mortality 4.39-6.57-fold in stage IB-IIC melanoma patients. The aims of the present study are to test the effect of Rigvir® on cell line viability in vitro and to visualize the cellular presence of Rigvir® by immunocytochemistry.Methods: The cytolytic effect of Rigvir® on the viability of FM-9, RD, AGS, A549, HDFa, HPAF‑II, MSC, MCF7, HaCaT, and Sk-Mel-28 cell lines was measured using live cell imaging. PBMC viability was measured using flow cytometry. The presence of ECHO-7 virus was visualized using immunocytochemistry. Statistical difference between treatment groups was calculated using two-way ANOVA.Results: Rigvir® (10%, volume/volume) reduced cell viability in FM-9, RD, AGS, A549, HDFa, HPAF‑II and MSC cell lines by 67-100%. HaCaT cell viability was partly affected while Rigvir® had no effect on MCF7, Sk-Mel-28 and PBMC viability. Detection of ECHO-7 by immunocytochemistry in FM-9, RD, AGS, A549, HDFa, HPAF-II and Sk-Mel-28 cell lines suggests that the presence of Rigvir® in the cells preceded or coincided with the time of reduction of cell viability. Rigvir® (10%) had no effect on live PBMC count.Conclusions: The results suggest that Rigvir® in vitro reduces the viability of cells of human melanoma, rhabdomyosarcoma, gastric adenocarcinoma, lung carcinoma, pancreas adenocarcinoma but not in PBMC. The presence of Rigvir® in the sensitive cells was confirmed using anti-ECHO-7 antibodies. The present results suggest that a mechanism of action for the clinical benefit of Rigvir® is its cytolytic properties. The present results suggest that the effect of Rigvir® could be tested in other cancers besides melanoma. Further studies of possible Rigvir® entry receptors are needed.

Apoptin as a potential viral gene oncotherapeutic agent.

The use of viruses for treatment of cancer overcomes the bottlenecks of chemotherapy and radiotherapy. Several viruses and their proteins have been evaluated for oncolytic effect. The VP3 protein (apoptin) of chicken anemia virus is one such protein with an inherent ability to lyse cancer and transformed cells while leaving normal cells unharmed. In the present study, the apoptosis inducing potential of VP3 protein of CAV was evaluated in human cervical cancer cell line (HeLa). It was found that in VP3-induced apoptosis, caspase-dependent intrinsic pathway plays an important role with the cleavage of poly (ADP-ribose) polymerase (PARP) and there was no evidence of involvement of death receptor-mediated extrinsic pathway. The results of this study provide intuitive information and strengthen the candidacy of apoptin as a viral oncotherapeutic agent.

Viruses in cancer treatment

Soon after the discovery that viruses cause human disease, started the idea of using viruses to treat cancer. After the initial indiscriminate use, crude preparations of each novel virus in the early twentieth century, a second wave of virotherapy blossomed in the 60s with purified and selected viruses. Responses were rare and short-lived. Immune rejection of the oncolytic viruses was identified as the major problem and virotherapy was abandoned. During the past two decades virotherapy has re-emerged with engineered viruses, with a trend towards using them as tumor-debulking immunostimulatory agents combined with radio or chemotherapy. Currently, oncolytic Reovirus, Herpes, and Vaccinia virus are in late phase clinical trials. Despite the renewed hope, efficacy will require improving systemic tumor targeting, overcoming stroma barriers for virus spread, and selectively stimulating immune responses against tumor antigens but not against the virus. Virotherapy history, viruses, considerations for clinical trials, and hurdles are briefly overviewed.

Integrin targeted oncolytic adenoviruses Ad5‐D24‐RGD and Ad5‐RGD‐D24‐GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors

The safety of oncolytic viruses for treatment of cancer has been shown in clinical trials while antitumor efficacy has often remained modest. As expression of the coxsackie-adenovirus receptor may be variable in advanced tumors, we developed Ad5-D24-RGD, a p16/Rb pathway selective oncolytic adenovirus featuring RGD-4C modification of the fiber. This allows viral entry through alpha-v-beta integrins frequently highly expressed in advanced tumors. Advanced tumors are often immunosuppressive which results in lack of tumor eradication despite abnormal epitopes being present. Granulocyte-macrophage colony stimulating factor (GMCSF) is a potent activator of immune system with established antitumor properties. To stimulate antitumor immunity and break tumor associated immunotolerance, we constructed Ad5-RGD-D24-GMCSF, featuring GMCSF controlled by the adenoviral E3 promoter. Preliminary safety of Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of human cancer was established. Treatments with Ad5-D24-RGD (N = 9) and Ad5-RGD-D24-GMCSF (N = 7) were well tolerated. Typical side effects were grade 1-2 fatigue, fever and injection site pain. 77% (10/13) of evaluable patients showed virus in circulation for at least 2 weeks. In 3 out of 6 evaluable patients, disease previously progressing stabilized after a single treatment with Ad5-RGD-D24-GMCSF. In addition, 2/3 patients had stabilization or reduction in tumor marker levels. All patients treated with Ad5-D24-RGD showed disease progression in radiological analysis, although 3/6 had temporary reduction or stabilization of marker levels. Induction of tumor and adenovirus specific immunity was demonstrated with ELISPOT in Ad5-RGD-D24-GMCSF treated patients. RGD modified oncolytic adenoviruses with or without GMCSF seem safe for further clinical development.

Engineering oncolytic viruses to exploit tumor specific defects in innate immune signaling pathways

Background: The use of oncolytic viruses for treatment of cancer marks a significant alteration in the battle between host and virus. Viruses are confronted by cellular innate immune responses and contain an armamentarium of immunomodulatory proteins that suppress innate immunity. Tumorigenesis can result in impairment of innate immune responses. Viruses engineered to be vulnerable to normal responses may mediate tumor-specific killing with minimal off-target toxicity. Objective: To examine the mechanisms by which mammalian cells respond to viral infections in normal versus cancer cells and how viruses overcome these responses and to illustrate how this knowledge is used to develop physiologically targeted oncolytic viruses. Methods: Literature describing studies investigating innate responses to virus infections, cancer-specific molecular defects, immunosuppressive viral products and design of oncolytic viruses is extensively reviewed, and pertinent concepts are distilled and developed. Results/conclusion: Innate responses to viral infections are complex involving i) viral detection; ii) induction of interferon and other cytokines; and iii) establishment of an antiviral state. Oncolytic viruses are engineered to be susceptible to antiviral responses in normal cells. Cancers can be partially vulnerable to these viruses because they have defective antiviral responses but the antitumor potency of physiologically targeted viruses may be significantly diminished.

Viruses in Treatment of Cancer

Viruses in Treatment of Cancer

Viruses in Treatment of Cancer

Viruses in Treatment of Cancer