REVIEW | doi:10.20944/preprints202112.0484.v1
Online: 30 December 2021 (12:32:40 CET)
Cell death by apoptosis is a major cellular response, in the control of tissue homeostasis and as a defense mechanism in case of cellular aggression like an infection. Cell self-destruction is part of antiviral responses, aimed at limiting the spread of a virus. Although it may contribute to the deleterious effects in infectious pathology, apoptosis remains a key mechanism for viral clearance and resolution of infection. The control mechanisms of cell death processes by viruses have been extensively studied. Apoptosis can be triggered by different viral determinants, through different pathways, as a result of virally induced cell stresses and innate immune responses. Zika virus (ZIKV) induces Zika disease in humans which has caused severe neurological forms, birth defects and microcephaly in newborns during the last epidemics. ZIKV also surprised by revealing an ability to persist in the genital tract and in semen, thus being sexually transmitted. Mechanisms of diverting antiviral responses such as the interferon response, the role of cytopathic effects and apoptosis in the etiology of the disease have been widely studied and debated. In this review, we examined the interplay between ZIKV infection of different cell types and apoptosis and how the virus deals with this cellular response. We illustrate a duality in the effects of ZIKV-controlled apoptosis, depending on whether it occurs too early or too late, respectively in neuropathogenesis, or in long-term viral persistence. We further discuss a prospective role for apoptosis in ZIKV-related therapies, and the use of ZIKV as an oncolytic agent.
REVIEW | doi:10.20944/preprints202109.0366.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Docetaxel; Paclitaxel; Oncolytic Poliovirus; PVSRIPO; Sipuleucel
Online: 21 September 2021 (14:21:19 CEST)
Among the leading causes of cancer mortality, prostatic adenocarcinoma (PaC) is at second to lung carcinoma, but it is the most commonly happening non-cutaneous malignancy in elderly men in the world. Therapeutic options for PaC depend on age, growth & stage of malignancy, the desired outcomes and shortcomings of available treatment, estimated cost and patient compliance. Patients older than 60 years with a sluggish localized tumor may be placed on active surveillance, otherwise go with transurethral resection of the prostate (TURP), prostate artery embolization (PAE) and pelvic lymphadenectomy with/without radiation therapy. For metastatic PC androgen-deprivation therapy is an option with or without surgery. These agents decline the body’s testosterone production or block its activity by gonadotropin- releasing hormone (GnRH) analogues including leuprolide acetate and goserelin acetate implant. The hormone’s activity can be stopped by androgens antagonist such as flutamide, bicalutamide and nilutamide along with chemotherapeutic agents, such as taxanes (e.g., docetaxel, paclitaxel) but after all the disease relapses in 20-30% of patients. So, new immunological or vaccine-based therapeutic moieties have been investigated to meet the objective of providing selectivity to cancerous cells and desired therapeutic outcomes with less/no harmful effects to normal cells. The chimeric version, oncolytic poliovirus and human rhinovirus i.e. PVSRIPO is most promising feature in cancer therapeutics and activate innate immunity by neutrophils infiltration via PAMP & DAMP pathways while Sipuleucel-T expresses major histocompatibility complex (MHC) which can stimulate CD4+ helper T-cells and CD8+ cytotoxic T-cells and ultimately activate the acquired immunity against cancer cells. In this article, we have discussed the role of genetic predisposition and chemotherapeutic approaches including oncolytic poliovirus for the treatment of PaC in order to better understanding of tumor biology and mechanisms involved in chemotherapeutic drugs based resistance.
REVIEW | doi:10.20944/preprints202008.0658.v1
Subject: Life Sciences, Virology Keywords: glioma; oncolytic virus; glioblastoma; virotherapy; brain tumor
Online: 30 August 2020 (11:17:24 CEST)
Glioma tumors are one of the most devastating cancer types. Of the different glioma tumors, glioblastoma is the most advanced stage with the worst prognosis. Current therapies are still unable to provide an effective cure. Recent advantages in oncolytic immunotherapy have generated great expectations in the cancer therapy field. The use of oncolytic viruses (OV) in cancer treatment is one of those immune-therapeutic alternatives. OV have a double oncolytic action by both, directly destroying the cancer cells, sparing the patient’s life, and stimulating a tumor specific immune response to revert the ability of tumors to escape the control of the immune system. OV are one promising alternative to conventional therapies in glioma tumor treatment. Several clinical trials have proven the feasibility to use some viruses to specifically infect tumors eluding undesired toxic effects in the patient. Here we have revisited the literature in order to describe the main OV proposed so far as therapeutic alternatives to destroy glioma cells in vitro and trigger tumor destruction in vivo. Some clinical trials are exploring the use of this therapy as an alternative were other approaches provide limited hope.
ARTICLE | doi:10.20944/preprints202103.0779.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Adenovirus; Oncolytic; Virotherapy; Targeting; αvβ6 integrin; Systemic delivery
Online: 31 March 2021 (15:30:59 CEST)
Background: We previously developed a refined, tumor selective adenovirus, Ad5NULL-A20, har-boring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a marker of aggressive epithelial cancers. Methods: To ascertain the selectivity of Ad5NULL-A20 for αvβ6 positive tumor cell lines of pancreatic and breast cancer origin, we performed reporter gene and cell viability assays. Biodistribution of viral vectors in mice harboring xenografts with low, medium, and high αvβ6 levels was quantified by qPCR for viral genomes 48 hours post intravenous administration. Results: Ad5NULL-A20 vector transduced cells in an αvβ6 selective manner, whilst cell killing me-diated by oncolytic Ad5NULL-A20 was αvβ6 selective. Biodistribution analysis following intrave-nous administration into mice bearing breast cancer xenografts demonstrated that Ad5NULL-A20 resulted in significantly reduced liver accumulation coupled with increased tumor accumulation compared to Ad5 in all three models, with tumor: liver ratios improved as a function of αvβ6 expression. Conclusions: Ad5NULL-A20 based virotherapies efficiently target αvβ6 integrin positive tumors following intravenous administration, validating the potential of Ad5NULL-A20 for systemic ap-plications, enabling tumor selective overexpression of virally encoded therapeutic transgenes.
REVIEW | doi:10.20944/preprints201805.0273.v2
Subject: Life Sciences, Virology Keywords: adenovirus; oncolytic; targeting; virotherapy; cancer; αvβ6 integrin; immunotherapy; tropism
Online: 15 June 2018 (05:14:24 CEST)
The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.
REVIEW | doi:10.20944/preprints202105.0007.v1
Subject: Life Sciences, Biochemistry Keywords: Glioblastoma; Oncolytic Virus; Blood Brain Barrier; Tumor Microenvironment; Tumor Heterogeneity
Online: 3 May 2021 (11:01:14 CEST)
Glioblastoma is one of the most difficult tumor types to treat with conventional therapy options like tumor debulking, chemo and radiotherapy. Immunotherapeutic agents like oncolytic viruses, immune checkpoint inhibitors and chimeric antigen receptor T cells have revolutionized cancer therapy, but their success in glioblastoma remains limited and further optimization of immunotherapies is needed. Several oncolytic viruses have demonstrated ability to infect tumors and trigger anti-tumor immune responses in malignant glioma patients. Leading the pack, oncolytic herpesvirus, first in its class, awaits an approval for treating malignant glioma from MHLW, the federal authority of Japan. Nevertheless, some major hurdles like the blood brain barrier, immunosuppressive tumor microenvironment, and tumor heterogeneity can engender suboptimal efficacy in malignant glioma. In this review, we discuss the current status of malignant glioma therapies with a focus on oncolytic viruses in clinical trials. Furthermore, we discuss the obstacles faced by oncolytic viruses in malignant glioma patients and strategies that are being used to overcome these limitations to 1) optimize delivery of oncolytic viruses beyond the blood brain barrier; 2) trigger inflammatory immune responses in and around tumors; and 3) use of multimodal therapies in combination to tackle tumor heterogeneity, with an end goal of optimizing the therapeutic outcome of oncolytic virotherapy.
REVIEW | doi:10.20944/preprints202010.0084.v2
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: adenovirus; oncolytic; virotherapy; targeting; immunotherapy; immunogenic cell death; αvβ6 integrin
Online: 3 November 2020 (08:19:31 CET)
More people are surviving longer with cancer. Whilst this can be partially attributed to advances in early detection of cancers, there is little doubt that the improvement in survival statistics is also due to the expansion in the spectrum of treatments available for efficacious treatment. Transformative amongst those are immunotherapies, which have proven effective agents for treating immunogenic forms of cancer, though immunologically “cold” tumour types remain refractive. Oncolytic viruses, such as those based on adenovirus have great potential as anti-cancer agents and have seen a resurgence of interest in recent years. Amongst their many advantages is their ability to induce immunogenic cell death (ICD) of infected tumour cells, thus providing the alluring potential to synergize with immunotherapies by turning immunologically “cold” tumours “hot”. Additionally, enhanced immune mediated cell killing can be promoted through the local overexpression of immunological transgenes, encoded from within the engineered viral genome. To achieve this full potential requires the development of refined, tumour selective “precision virotherapies” that are extensively engineered to prevent off-target up take via native routes of infection, and targeted to infect and replicate uniquely within malignantly transformed cells. Here, we review the latest advances towards this holy grail within the adenoviral field.
REVIEW | doi:10.20944/preprints201707.0045.v1
Subject: Life Sciences, Other Keywords: oncolytic virotherapy; combination therapy; mathematical model; immune system; cancer; immunotherapy
Online: 17 July 2017 (13:01:09 CEST)
After decades of research, oncolytic virotherapy has recently advanced to clinical application, and currently a multitude of novel agents and combination treatments are being evaluated for cancer therapy. Oncolytic agents preferentially replicate in tumor cells, inducing tumor cell lysis and complex anti-tumor effects, such as innate and adaptive immune responses and the destruction of tumor vasculature. With the availability of different vector platforms and the potential of both genetic engineering and combination regimens to enhance particular aspects of safety and efficacy, the identification of optimal treatments for patient subpopulations or even individual patients becomes a top priority. Mathematical modeling can provide support in this arena by making use of experimental and clinical data to generate hypotheses about the mechanisms underlying complex biology and, ultimately, predict optimal treatment protocols. Increasingly complex models can be applied to account for therapeutically relevant parameters such as components of the immune system. In this review, we describe current developments in oncolytic virotherapy and mathematical modeling to discuss the benefit of integrating different modeling approaches into biological and clinical experimentation. Conclusively, we propose a mutual combination of these fields of research for more efficient development and effective treatments.
REVIEW | doi:10.20944/preprints202106.0680.v1
Subject: Behavioral Sciences, Other Keywords: patient activation; patient engagement, behavioral health change; self-administered therapy, oral oncolytic
Online: 28 June 2021 (15:32:14 CEST)
Oncology clinical pharmacists are uniquely positioned to make interventions to increase patient activation and engagement. To accomplish this goal, pharmacists can target health system-related, provider-related, and patient-related factors to help enhance patient-centered care and drive behavioral health changes. Interventions that pharmacists must tackle include educating team members and patients on the medication acquisition process, communicating urgency of treatment, optimizing workflows, facilitating guideline recommendations, preventing, and managing treatment toxicities, and promoting patient self-advocacy through education and shared decision-making. As crucial members of the healthcare team, oncology clinical pharmacists can simplify highly complex treatment regimens to facilitate and optimize patients’ ownership of their care. This review will focus on the example of venetoclax treatment in acute myeloid leukemia to demonstrate the impact that pharmacists provide that leads to behavioral change of patients and clinicians.
ARTICLE | doi:10.20944/preprints202008.0028.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Oncolytic virus; Mesenchymal stem cell; Prodrug activation; P53 mutant tumor; Colorectal cancer
Online: 2 August 2020 (12:31:32 CEST)
Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. Methods: MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Results: Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-Adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. Conclusion: This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.
REVIEW | doi:10.20944/preprints201804.0359.v1
Subject: Biology, Other Keywords: oncolytic virus; in situ autovaccination; cytokine; immune checkpoint inhibitor; immune co-stimulator
Online: 27 April 2018 (09:18:37 CEST)
With the progress of immunotherapy in cancer, oncolytic viruses (OVs) are getting more and more attention during the past decade. Due to their cancer-selective and immunogenic property, OVs are considered ideal candidates to be combined with immunotherapy to increase both specificity and efficacy in cancer treatment. OVs preferentially replicate in and lyse cancer cells, generating pathogen-associated molecular patterns (PAMPs) and danger (damage)-associated molecular patterns (DAMPs). These signals trigger innate immune response to modulate the solid tumor microenvironment, resulting in in situ autovaccination leading to adaptive anti-virus and anti-tumor immunity. Here, we summarize the conceptual updates of oncolytic virotherapy, immunotherapy, and the strategies to enhance the virus-mediated anti-tumor immune response, including: 1. Arm OVs with cytokines to modulated innate and adaptive immunity; 2. Combine OVs with immune checkpoint inhibitors to release T cell inhibition; 3. Combine OVs with immune co-stimulators to enhance T cell activation.
REVIEW | doi:10.20944/preprints202107.0064.v1
Subject: Life Sciences, Biochemistry Keywords: virotherapy; oncolytic viruses; gliomas; pancreatic cancer; adenoviruses; parvoviruses; enteroviruses; blood-brain barrier; tropism; transgene
Online: 2 July 2021 (14:23:22 CEST)
The idea of using the lytic power of viruses against the malignant cells has been entertained for many decades. However, oncolytic viruses (OV) gained broad attention as an emerging anti-cancer therapy only recently with the successful implementation of the oncolytic herpesvirus to treat advanced melanoma. OVs offer an attractive therapeutic combination of tumor-specific cell lysis together with immune stimulation, yet the latter effect is less well studied. Nevertheless, OVs can be envisaged as potential in situ tumor vaccines. The therapeutic potential of OVs can be instigated further by using the molecular biological and biotechnological tools to modify the existing viruses for their optimal tumor selectivity and enhanced immune stimulation. Furthermore, OVs can be readily combined with other therapeutic agents to increase the efficacy of the existing therapeutic schemes. In this review, we discuss biotechnological advances in the development of therapeutic applications of OVs in Russia. Particular emphasis is made on the OV-mediated treatment of glioblastoma. In addition, we highlight the challenges of oncolytic virotherapy, and describe the strategies to optimize current approaches to improve clinical outcomes.
REVIEW | doi:10.20944/preprints202208.0220.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Molecular switches; oncolytic vectors; patient-specific ubiquitous mutations; targeted therapy; multi-region sequencing; molecular biology
Online: 11 August 2022 (11:50:12 CEST)
Most existing cancer therapies negatively affect normal tissue as well as cancerous tissue. A potentially effective strategy for treating cancer that precludes off-target damage and could be an option for most patients would involve targeting one or more mutations that are ubiquitous in the given patient’s tumor(s). To effect this strategy, one would employ multi-region sequencing of a patient’s primary tumor and metastases to seek out mutations that are shared between all or at least most regions. Once the target or targets are known, one would ideally rapidly generate a molecular switch for at least one of said ubiquitous mutations that can distinguish the mutated DNA, RNA, or protein from the wild-type version and subsequently trigger a therapeutic response. I propose that the therapeutic response involve the replication of an oncolytic virus or intracellular bacterium, as any mutation can theoretically be detected by a vector that enters the cell - and automatic propagation could be very helpful. Moreover, the mutation “signal” can be easily enhanced through transcriptional and translational (if the target is an intracellular protein) enhancement. Importantly, RNA may make the best target for the molecular switches in terms of amplification of the signal and ease of targeting.
REVIEW | doi:10.20944/preprints202012.0239.v1
Subject: Medicine & Pharmacology, Allergology Keywords: glioblastoma; high-grade glioma; refractory glioma; virotherapy; oncolytic viruses; neuro-oncology; refractory glioblastoma; chimeric viruses; clinical trials
Online: 9 December 2020 (20:13:56 CET)
As new treatment modalities are being explored in neuro-oncology, viruses are emerging as a promising class of therapeutics. Virotherapy consists of introduction of either wild-type or engineered viruses to the site of disease, where they exert anti-tumor effect. These viruses can either be non-lytic, in which case they are used to deliver gene therapy, or lytic, which induce tumor cell lysis and subsequent host immunologic response. Replication-competent viruses can then go on to further infect and lyse neighboring glioma cells. This treatment paradigm is being explored extensively in both preclinical and clinical studies for a variety of indications. Virus-based therapies are advantageous due to the natural susceptibility of glioma cells to viral infection, which improves therapeutic selectivity. Furthermore, lytic viruses expose glioma antigens to the host immune system and subsequently stimulate an immune response that specifically targets tumor cells. This review surveys the current landscape of oncolytic virotherapy clinical trials in high-grade glioma, summarizes preclinical experiences, identifies challenges associated with this modality across multiple trials, and highlights potential to integrate this therapeutic strategy into promising combinatory approaches.
REVIEW | doi:10.20944/preprints202010.0623.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Glioblastoma; Neural Stem Cells; Mesenchymal Stem Cells; Stem Cell Therapy; Enzyme/Prodrug Therapy; Oncolytic Virotherapy; Nanoparticles; TRAIL; Cytokine Therapy
Online: 29 October 2020 (15:51:04 CET)
The potential of Neural Stem Cells (NSCs) to provide therapeutic benefit for a variety of neurological disorders, including brain malignancies, has been long recognized and has inspired many scientists to design, test and successfully demonstrate that NSCs are efficient and effective therapeutic agents. Glioblastoma, the deadliest form of primary brain tumor, despite extensive and sustained efforts to find better therapies, remains a disease without cure, with a median survival after diagnosis of less than two years. Treatment resistance in glioblastoma is in large part attributed to limitations in the delivery and distribution of therapeutic agents administered either systemically or directly into the tumor due to the highly invasive nature of this cancer and its abnormal intratumoral vasculature. Stem Cells (SCs) have an innate tumor-tropic migratory behavior, can be modified to deliver a variety of therapeutic agents and efficiently distribute their cargo into brain tumors, pursuing invading streams of tumor cells, deep into the brain parenchyma. Over the last twenty years, numerous preclinical trials have demonstrated the feasibility and efficacy of SCs as antiglioma agents, leading to the development of trials to test these therapies in the clinic. In this review we present and analyze these studies and discuss mechanisms underlying their beneficial effect, highlighting experimental progress, limitations and the emergence of promising new therapeutic avenues. We hope to increase awareness of the advantages of using SCs for the treatment of glioblastoma and inspire further studies that will lead to accelerated implementation of effective therapies.
REVIEW | doi:10.20944/preprints202112.0525.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: colorectal cancer; immunotherapy; checkpoint blockade; adoptive cell therapy; monoclonal antibodies; oncolytic viruses; anti-cancer vaccines; cytokine; T cell; NK cell
Online: 31 December 2021 (15:14:39 CET)
Though early-stage colorectal cancer has a high 5-year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair proficient patients to immunotherapy.