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At least 19 recordsLinked to original sources
PubMed2003

Pharmacologic indicators of antitumor efficacy for oncolytic virotherapy.

Central to the development of oncolytic virotherapies for cancer will be a better understanding of the parameters that influence the outcome of virotherapy to treat disseminated cancer by i.v. administration versus regional disease by local treatment. Intratumoral administration of 01/PEME, an oncolytic adenovirus, required approximately 1000-fold less dose than i.v. administration to induce similar tumor growth inhibition. Despite the short (<10 min) circulating half-life of the virus DNA, we could monitor virus distribution to the tumor site and observed virus replication by >1000-fold increase in virus DNA copies over time. There were doses of 01/PEME for which the virus DNA concentration in the tumor increased over time but did not result in antitumor efficacy. Oncolytic virus replication at a tumor site may not be a relevant indication of antitumor efficacy. Efficient distribution to the tumor site may be one of the most critical parameters for antitumor efficacy with oncolytic virotherapy.

Adenoviridae↗
PubMed2005

Oncolytic virotherapy for cancer treatment: challenges and solutions.

Advances in gene modification and viral therapy have led to the development of a variety of vectors in several viral families that are capable of replication specifically in tumor cells. Because of the nature of viral delivery, infection, and replication, this technology, oncolytic virotherapy, may prove valuable for treating cancer patients, especially those with inoperable tumors. Current limitations exist, however, for oncolytic virotherapy. They include the body's B and T cell responses, innate inflammatory reactions, host range, safety risks involved in using modified viruses as treatments, and the requirement that most currently available oncolytic viruses require local administration. Another important constraint is that genetically enhanced vectors may or may not adhere to their replication restrictions in long-term applications. Several solutions and strategies already exist, however, to minimize or circumvent many of these limitations, supporting viral oncolytic therapy as a viable option and powerful tool in the fight against cancer.

Animals↗
PubMed2004

Future directions for the field of oncolytic virotherapy: a perspective on the use of vaccinia virus.

Oncolytic virotherapy is an emerging biotherapeutic platform based on genetic engineering of viruses capable of selectively infecting and replicating within cancer cells. Such viruses have been found to be both safe and to produce antitumour effects in a number of Phase I and II clinical trials. Early work in this field has been pioneered with strains of adenovirus which, although well suited to gene therapy approaches, have displayed certain limitations in their ability to directly destroy and spread through tumour tissues, particularly after systemic administration. Investigators have subsequently been examining the feasibility of using a variety of different viruses as oncolytic agents. Vaccinia virus is perhaps the most widely administered and successful medical product in history; it displays many of the qualities thought necessary for an effective antitumour agent and is particularly well characterised in people due to its role in the eradication of smallpox. Vaccinia has a short life cycle and rapid spread, strong lytic ability, inherent systemic tumour targeting, a large cloning capacity and well-defined molecular biology. In addition, the virus produces no known disease in humans, has been delivered safely to millions of people and has already demonstrated antitumoural efficacy in trials with vaccine strains. These qualities, along with strategies for further improving the safety and antitumour effectiveness of vaccinia, will be discussed in relation to the broad spectrum of clinical experience already achieved with this virus in cancer therapy.

Antigens, Neoplasm↗
PubMed2005

Beyond oncolytic virotherapy: replication-competent retrovirus vectors for selective and stable transduction of tumors.

As cancer gene therapy employing replication-defective vectors has met with limited clinical success, there is renewed interest in using replication-competent viruses for oncolytic virotherapy. In preclinical and clinical studies, various attenuated vaccine strains and engineered virus vectors are currently being tested for their ability to achieve tumor-selective cell killing. However, significant improvements are still required in tumor selectivity, cytolytic potency, and modulating immune responses to achieve anti-tumor effects without prematurely terminating virus spread. Recently, we have developed murine leukemia virus (MLV)-based replication-competent retrovirus (RCR) vectors for highly efficient, selective, and persistent gene transfer to cancer cells, and found that such vectors may offer significant advantages as oncolytic agents. In a variety of preclinical models, RCR vectors can achieve efficient and persistent gene delivery as the virus replicates throughout an entire tumor mass after inoculation with initial multiplicities of infection as low as 0.001. When engineered to deliver suicide genes, RCR vectors achieve highly efficient and synchronized cell killing triggered by pro-drug administration, both in culture and in tumor models in vivo. Further strategies are being explored to enhance the packaging capacity, efficiency, and specificity of this vector system through the development of semi-replicative RCR vectors, adenovirus-RCR hybrids, and incorporation of tumor targeting mechanisms via modification of binding tropism and transcriptional regulation. In addition, the ability of these vectors to achieve stable transgene expression in infected tumor cells may allow therapeutic applications that move beyond oncolysis per se.

Drug Design↗
PubMed2005

Vaccinia virus and oncolytic virotherapy of cancer.

Vaccinia viruses possess many of the key attributes necessary for an ideal viral backbone for use in oncolytic virotherapy. These include a short lifecycle, with rapid cell-to-cell spread. strong lytic ability, a large cloning capacity and well-defined molecular biology. In addition, although capable of replicating in human cells, they are not considered a natural health problem and are especially well characterized. having been delivered to millions of individuals during the campaign to eradicate smallpox. A variety of tumor-targeting mutations have been described in several different vaccinia strains and the expression of a variety of different transgenes has been studied. Early clinical results using either vaccine strains or genetically modified vaccinia strains have demonstrated antitumor effects. Future prospects for the development of these viruses will be discussed.

Antineoplastic Agents↗
PubMed2005

The potential impact of hypoxia on the success of oncolytic virotherapy.

The biological properties of oncolytic viruses, in particular the ability to replicate within a tumor cell and then spread from cell to cell are highly desirable features for cancer therapy. However. several features of the tumor environment may not be conducive for efficient viral spread. Hypoxia is an important feature of solid tumors and the ability of viruses to replicate in hypoxic conditions may be a critical determinant in the success or failure of virotherapy. Turning off protein translation is a central process in the cellular adaptation to many types of stress, including viral infection and hypoxia. How a specific virus has evolved to overcome the cellular mechanisms that regulate translation in the cell under stress may be critical for the success of virotherapy.

Adenoviridae↗
PubMed2006

Oncolytic virotherapy synergism with signaling inhibitors: Rapamycin increases myxoma virus tropism for human tumor cells.

Myxoma virus is a rabbit-specific poxvirus pathogen that also exhibits a unique tropism for human tumor cells and is dramatically oncolytic for human cancer xenografts. Most tumor cell lines tested are permissive for myxoma infection in a fashion intimately tied to the activation state of Akt kinase. A host range factor of myxoma virus, M-T5, directly interacts with Akt and mediates myxoma virus tumor cell tropism. mTOR is a regulator of cell growth and metabolism downstream of Akt and is specifically inhibited by rapamycin. We report that treatment of nonpermissive human tumor cell lines, which normally restrict myxoma virus replication, with rapamycin dramatically increased virus tropism and spread in vitro. This increased myxoma replication is concomitant with global effects on mTOR signaling, specifically, an increase in Akt kinase. In contrast to the effects on human cancer cells, rapamycin does not increase myxoma virus replication in rabbit cell lines or permissive human tumor cell lines with constitutively active Akt. This indicates that rapamycin increases the oncolytic capacity of myxoma virus for human cancer cells by reconfiguring the internal cell signaling environment to one that is optimal for productive virus replication and suggests the possibility of a potentially therapeutic synergism between kinase signaling inhibitors and oncolytic poxviruses for cancer treatment.

Cell Line, Tumor↗
PubMed2003

A canine conditionally replicating adenovirus for evaluating oncolytic virotherapy in a syngeneic animal model.

Oncolytic adenoviruses, which selectively replicate in and subsequently kill cancer cells, have emerged as a promising approach for treatment of tumors resistant to other modalities. Although preclinical results have been exciting, single-agent clinical efficacy has been less impressive heretofore. The immunogenicity of adenoviruses, and consequent premature abrogation of replication, may have been a partial reason. Improving the oncolytic potency of agents has been hampered by the inability to study host-vector interactions in immune-competent systems, since human serotype adenoviruses do not productively replicate in animal tissues. Therefore, approaches such as immunomodulation, which could result in sustained replication and subsequently increased oncolysis, have not been studied. Utilizing the osteocalcin promoter for restricting the replication of a canine adenovirus to dog osteosarcoma cells, we generated and tested the first nonhuman oncolytic adenovirus. This virus effectively killed canine osteosarcoma cells in vitro and yielded a therapeutic benefit in vivo. Canine osteosarcoma is the most frequent malignant disease in large dogs, with over 8000 cases in the United States annually, and there is no curative treatment. Therefore, immunomodulation for increased oncolytic potency could be studied with clinical trials in this population. This could eventually translate into human trials.

Adenoviridae↗
PubMed2002

The oncolytic virotherapy treatment platform for cancer: unique biological and biosafety points to consider.

The field of replication-selective oncolytic viruses (virotherapy) has exploded over the last 10 years. As with many novel therapeutic approaches, initial overexuberance has been tempered by clinical trial results with first-generation agents. Although a number of significant hurdles to this approach have now been identified, novel solutions have been proposed and improvements are being made at a furious rate. This article seeks to initiate a discussion of these hurdles, approaches to overcome them, and unique safety and regulatory issues to consider.

Clinical Trials as Topic↗
PubMed2006

A conditionally replicative adenovirus that codes for a TK-GFP fusion protein (Ad5Delta24TK-GFP) for evaluation of the potency of oncolytic virotherapy combined with molecular chemotherapy.

The utility of conditionally replicative adenoviruses (CRAds) in cancer gene therapy is based on their ability to destroy tumor cells by oncolysis. However, in order to achieve adequate therapeutic response, CRAds have to spread through the tumor tissue by replication. Thus, to study the potency of these viruses to replicate and penetrate in tumors, we created a herpes simplex virus type 1 thymidine kinase-green fluorescent protein fusion gene (TK-GFP) encompassing CRAd (Ad5Delta24TK-GFP), whose tumor selectivity is mediated by a retinoblastoma (Rb)-binding site mutation. In addition, we evaluated the oncolytic efficacy of Ad5Delta24TK-GFP in combination with the TK/ganciclovir (GCV) system. Based on our results, Ad5Delta24TK-GFP replicates in cancer cells resulting in oncolysis and can efficiently penetrate into tumors. Additionally, the combination of GCV with Ad5Delta24TK-GFP augmented cell death in vitro but this was not observed in vivo: tumor growth was significantly reduced by oncolysis when compared to non-replicative virus (p<0.001), but administration of GCV did not significantly enhance oncolysis. This suggests that in certain conditions, TK/GCV-mediated cell killing may be counterproductive to replication and oncolysis, which on the other hand might be useful feature for clinical trials in case of replication-associated toxicity.

Adenoviridae↗
PubMed2005

Oncolytic virotherapy of meningiomas in vitro with replication-competent adenovirus.

OBJECTIVE: To evaluate the efficacy of the conditionally replicating adenovirus (Ad) Ad.d24 for oncolysis of benign and malignant meningiomas. METHODS: Primary meningioma cells and organotypic spheroids were cultured from tumor biopsies of 12 consecutive unselected patients. Four different Ads were constructed and tested on meningioma cells and spheroids: a replication-deficient Ad encoding the luciferase marker gene (Ad.Luc), a replication-competent Ad with complete E1 region (Ad.E1+), a replication-competent Ad encoding the luciferase gene in the E3 region (Ad.E1Luc), and a conditionally replicating Ad with an E1ACR2 deletion (Ad.d24). Replication of the latter is restricted to cells with a defective retinoblastoma pathway, whereas Ad.E1+ and Ad.E1Luc can replicate in all human cells like a wild-type Ad. Their oncolytic activity was compared in primary meningioma cells and spheroids by use of viability and outgrowth assays. RESULTS: Adenoviral penetration into organotypic meningioma spheroids was detected with the replication-competent Ad.E1Luc, whereas infection with the replication-deficient Ad.Luc was limited to the outer layer of the spheroid. Replication of the Ads and oncolysis was demonstrated in primary cell cultures of meningioma cells at high dose, i.e., greater than 50 plaque-forming units per cell. At a lower dose of 5 plaque-forming units per cell, Ad.d24 kills meningioma cells more efficiently than Ad.E1+. Infection of organotypic meningioma spheroids with Ad.d24 resulted in decreased viability and suppression of outgrowth as compared with untreated control spheroids. CONCLUSION: Infection of meningioma cells and spheroids with replication-competent Ads results in efficient oncolysis. The Ad modified to replicate selectively in retinoblast-mutant cells, Ad.d24, seemed to be an efficient oncolytic agent in benign, atypical, and malignant meningiomas.

Adenoviridae↗
PubMed2005

Oncolytic virotherapy: approaches to tumor targeting and enhancing antitumor effects.

The application of replicating viruses for the treatment of cancers represents a novel therapy that is distinct from traditional treatment modalities. It is apparent that the genetic changes that a virus produces within an infected cell in order to create an environment conducive to viral replication are often similar to the processes involved in cellular transformation. These include uncontrolled cellular proliferation, prevention of apoptosis, and resistance to host organism immune effector mechanisms. Deletions of viral genes involved in these processes have been exploited to produce viral mutants whose replication is selective for transformed cells. The use of tissue-specific transcriptional response or RNA stability elements to control the expression of critical viral genes has also resulted in targeted viruses. Work also is being undertaken to restrict or alter the tropism of viruses by altering their ability to infect certain cell types. Finally, the addition of exogenous genes can be used to increase the virus's lytic potential and/or bystander killing; to further induce the host's immune response against cancer cells; and/or to permit the controlled downregulation of viral replication if necessary. The combination of different tumor-targeting mutations in parallel with the expression of foreign genes has resulted in the evolution of second- and third-generation viruses that continue to become further distinct from their native parental strains. The movement of these viruses into the clinic has begun to demonstrate the potential of this approach in the treatment of cancers.

Apoptosis↗
PubMed2025

Infectious bursal disease virus (IBDV) as a novel oncolytic virotherapy in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most aggressive form of cancer of the central nervous system. Despite advances in immunotherapies and standard-of-care treatments for GBMs, clinical outcomes remain limited-owing to the immunosuppressive tumor microenvironment and the intrinsic resistance of GBM to conventional approaches. As a result, there is growing interest in rational combination strategies, particularly those pairing oncolytic viruses with immune-based therapies or established treatment modalities. Oncolytic viruses, by displaying conditionally enabled tumor cell-restricted replication, while stimulating antitumor immune responses and leaving healthy tissue unharmed, have the potential to reshape the therapeutic landscape in GBM and aid in achieving more durable benefits for patients. This study investigates the use of infectious bursal disease virus (IBDV) as a potential virotherapy for GBM. METHODS AND RESULTS: In vitro, IBDV infects and replicates within murine GBM cells and patient-derived GBM stem cells, inducing direct oncolysis and activating proinflammatory gene expression programs. IBDV also enhances the cytolytic activity of temozolomide (TMZ) in treated GBM cells, complementing TMZ chemotherapeutic activity. In vivo, treatment with IBDV in CT-2A GBM-bearing syngeneic mice significantly reduced tumor growth and improved survival compared with control mice. Intratumoral administration of IBDV induces a deep remodeling of the tumor immune microenvironment, reducing immunosuppressive M2-like macrophages and increasing the ratio of CD8+T cells to regulatory T cells. This reversion of immunosuppression linked to monocyte-derived macrophages has been confirmed on experimental ex vivo infections of explants derived from human GBM donors. CONCLUSION: These findings support further consideration of IBDV as a novel virotherapeutic agent for GBM.

Oncolytic Virotherapy↗
PubMed2004

Oncolytic virotherapy as a novel strategy for pancreatic cancer.

We have developed a novel gene therapy that targets genetic alterations in pancreatic cancer using oncolytic replication-selective adenoviruses in tumor cells. E1B-55kDa-deleted adenovirus (AxE1AdB) can selectively replicate in TP53-deficient human cancer cells but not cells with functional TP53. Consecutive injection with AxE1AdB markedly inhibited the growth of human pancreatic tumors in severe combined immunodeficiency disease mice. Furthermore, AxE1AdB displayed the ability to enhance gene expression as a virus vector. It is reported that uracil phosphoribosyl transferase (UPRT) overcomes 5-FU resistance. The therapeutic advantage of a replication-selective adenovirus that expresses UPRT (AxE1AdB-UPRT) was thus evaluated in an intraperitoneum-disseminated tumor model. Combined treatment with 5-FU and AxE1AdB-UPRT dramatically reduced the disseminated tumor burden without causing toxicity in normal tissues. We also clarified the process of AxE1AdB-inhibited tumor angiogenesis through the preserved E1A region: an adenoviral E1A protein binds to pRB, forcing the quiescent cell into the S phase. We constructed a double-mutant, replication-selective adenovirus (AxdAdB-3) containing a mutation in the RB-binding motif of the E1A region and a deletion of large E1B-55kDa. AxdAdB-3 swiftly induced cancer cell death in vitro and showed a potent antitumor effect in vivo. These results strongly suggest that AxdAdB-3 possesses a wider therapeutic potential than previously believed, given that most pancreatic cancers have abnormalities in both the TP53 and RB pathways.

Adenoviridae↗
PubMed2001

Oncolytic virotherapy for cancer with the adenovirus dl1520 (Onyx-015): results of phase I and II trials.

Replication-selective viral agents hold promise as a novel cancer treatment platform (virotherapy). dl1520 (Onyx-015, now CI-1042, Pfizer Corp., Groton, CT, USA), an E1B-55kD gene-deleted adenovirus, was the first such genetically engineered agent to be tested in humans. Over 250 cancer patients have now been treated on approximately ten clinical trials (phase I-III). The virus was generally well tolerated at doses of up to 2 x 10(12) particles by intratumoural, intraperitoneal, hepatic arterial and i.v. administration; no maximally-tolerated doses were identified following intra-vascular administration. Viral replication was tumour-selective and was documented after administration by all routes; however, viral replication was variable depending on tumour histology. Single agent efficacy has been relatively limited to date (0-14% local tumour regression rates). In combination with chemotherapy, however, encouraging antitumoural activity has been demonstrated. These clinical research results demonstrate the potential of this novel treatment platform, as well as the hurdles to be overcome. Novel replication-selective agents with improved potency are being developed.

Adenoviridae↗