ABSTRACT
Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78-1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555.
ABSTRACT
Recent developments in the field of oncolytic or tumor-selective viruses have meant that the clinical applications of these agents are now being considered in more detail. Like most cancer therapies it is likely that they will be used primarily in combination with other therapeutics. Although several reports have shown that oncolytic viruses can synergize with chemotherapies within an infected cancer cell, it would be particularly important to determine whether factors released from infected cells could enhance the action of chemotherapies at a distance. Here, we demonstrate in vitro synergy between oncolytic vaccinia and taxanes. However, we also show, for the first time, that this synergy is at least partly due to the release of factors from the infected cells that are capable of sensitizing surrounding cells to chemotherapy. Several cellular factors were identified as being mediators of this bystander effect, including type I interferon released soon after infection and high-mobility group protein B1 (HMGB1) released after cell death. This represents the first description of these mechanisms for beneficial interactions between viral and traditional tumor therapies. These data may provide a direct basis for the design of clinical trials with agents currently in the clinic, as well as providing insight into the development of next generation viral vectors.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , HMGB1 Protein/metabolism , Interferons/metabolism , Neoplasms/therapy , Oncolytic Virotherapy/methods , Paclitaxel/therapeutic use , Vaccinia virus , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Cell Cycle/drug effects , Cell Death/drug effects , Cell Line, Tumor , Combined Modality Therapy , Humans , Mice , Mice, Nude , Oncolytic Viruses/physiology , Paclitaxel/pharmacology , Vaccinia virus/physiologyABSTRACT
Targeted oncolytic poxviruses hold promise for the treatment of cancer. Arming these agents with immunostimulatory cytokines (for example, granulocyte-monocyte colony-stimulating factor; GM-CSF) can potentially increase their efficacy and/or alter their safety. However, due to species-specific differences in both human GM-CSF (hGM-CSF) activity and poxviruses immune avoidance proteins, the impact of hGM-CSF expression from an oncolytic poxvirus cannot be adequately assessed in murine or rat tumor models. We developed a rabbit tumor model to assess toxicology, pharmacodynamics, oncolytic efficacy and tumor-specific immunity of hGM-CSF expressed from a targeted oncolytic poxvirus JX-963. Recombinant purified hGM-CSF protein stimulated a leukocyte response in this model that paralleled effects of the protein in humans. JX-963 replication and targeting was highly tumor-selective after i.v. administration, and intratumoral replication led to recurrent, delayed systemic viremia. Likewise, hGM-CSF was expressed and released into the blood during JX-963 replication in tumors, but not in tumor-free animals. hGM-CSF expression from JX-963 was associated with significant increases in neutrophil, monocyte and basophil concentrations in the peripheral blood. Finally, tumor-specific cytotoxic T lymphocytes (CTL) were induced by the oncolytic poxvirus, and expression of hGM-CSF from the virus enhanced both tumor-specific CTL and antitumoral efficacy. JX-963 had significant efficacy against both the primary liver tumor as well as metastases; no significant organ toxicity was noted. This model holds promise for the evaluation of immunostimulatory transgene-armed oncolytic poxviruses, and potentially other viral species.
Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Oncolytic Viruses/physiology , Poxviridae/physiology , Animals , Cells, Cultured , Disease Models, Animal , Genetic Vectors/administration & dosage , Genetic Vectors/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Injections, Intravenous , Liver Neoplasms/drug therapy , Liver Neoplasms/immunology , Oncolytic Virotherapy/methods , Oncolytic Viruses/genetics , Poxviridae/genetics , Rabbits , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
The field of molecular therapeutics is in its infancy and represents a promising and novel avenue for targeted cancer treatments. Like the small-molecule and antibody therapeutics before them, however, the genetic-based therapies will face significant research and development challenges in their maturation toward an approved cancer therapy. To facilitate this process, we outline and examine in this review the drug development process, briefly summarizing the research and development paradigms that have accompanied the recent successes of the small-molecule and antibody-based cancer therapeutics. Using this background, we compare and contrast the research and development experiences of small-molecule and antibody therapeutics with genetic-based cancer therapeutics, using oncolytic viruses as a defined example of an experimental molecular therapeutic for cancer.
Subject(s)
Antineoplastic Agents/therapeutic use , Drug Design , Genetic Therapy , Neoplasms/therapy , Clinical Trials as Topic , Humans , Neoplasms/drug therapy , Oligonucleotides/therapeutic use , Peptides/therapeutic use , Viruses/geneticsABSTRACT
In spite of aggressive surgery, irradiation and/or chemotherapy, treatment of malignant gliomas remains a major challenge in adults and children due to high treatment failure. We have demonstrated significant cell lysis and antitumour activity of the E1B-55 kDa-gene-deleted adenovirus ONYX-015 (dl1520, CI-1042; ONYX Pharmaceuticals) in subcutaneous human malignant glioma xenografts deriving from primary tumours. Here, we show the combined efficacy of this oncolytic therapy with radiation therapy. Total body irradiation (5 Gy) of athymic nude mice prior to intratumoral injections of ONYX-015 1 x 10(8) PFU daily for 5 consecutive days yielded additive tumour growth delays in the p53 mutant xenograft IGRG88. Radiation therapy was potentiated in the p53 functional tumour IGRG121 with a 'subtherapeutic' dose of 1 x 10(7) PFU daily for 5 consecutive days, inducing significant tumour growth delay, 90% tumour regression and 50% tumour-free survivors 4 months after treatment. These potentiating effects were not due to increased adenoviral infectivity or replication. Furthermore, cell lysis and induction of apoptosis, the major mechanisms for adenoviral antitumour activity, did not play a major role in the combined treatment strategy. Interestingly, the oncolytic adenovirus seemed to accelerate radiation-induced tumour fibrosis. Potentiating antitumour activity suggests the development of this combined treatment for these highly malignant tumours.
Subject(s)
Adenoviridae/genetics , Brain Neoplasms/radiotherapy , Brain Neoplasms/virology , Cell Death , Genetic Therapy , Glioma/radiotherapy , Glioma/virology , Radiation-Sensitizing Agents/pharmacology , Viral Vaccines/pharmacology , Animals , Brain Neoplasms/pathology , Female , Glioma/pathology , Mice , Mice, Nude , Neoplasms, Experimental , Transplantation, HeterologousABSTRACT
PURPOSE: Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts. PATIENTS AND METHODS: We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 x 10(9) plaque forming units (pfu), 1 x 10(10) pfu, 3 x 10(10) pfu, and 1 x 10(11) pfu. RESULTS: The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 x 10(10) pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 10(11) pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication. CONCLUSION: This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.
Subject(s)
Adenovirus E1B Proteins/genetics , Genetic Therapy/methods , Ovarian Neoplasms/therapy , Adenoviridae/physiology , Adult , Aged , Antibodies, Viral/blood , Drug Resistance, Neoplasm , Female , Genetic Therapy/adverse effects , Humans , Injections, Intraperitoneal , Middle Aged , Neoplasm Recurrence, Local , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Treatment Outcome , Tumor Suppressor Protein p53/genetics , Virus ReplicationABSTRACT
Replication-competent viruses have shown considerable promise in overcoming the inefficient gene transduction experienced by traditional gene therapy approaches to cancer treatment. The viruses infect tumor cells and replicate inside them, eventually causing lysis. Virus particles released during lysis are then able to infect other tumor cells, and, in this way, continuous rounds of infection and lysis allow the virus to spread throughout the tumor. Motivated by this novel cancer treatment, we formulate and analyse a system of partial differential equations that is essentially a radially-symmetric epidemic model embedded in a Stefan problem. We compare three, alternative virus-injection strategies: a fixed fraction of cells pre-infected with the virus are introduced throughout the entire tumor volume, within the tumor core, or within the tumor rim. For all three injection methods, simple and accurate conditions that predict whether the virus will control the tumor are derived.
Subject(s)
Genetic Therapy/methods , Models, Biological , Neoplasms/virology , Oncogenic Viruses/physiology , Virus Replication , Animals , Computer Simulation , HumansABSTRACT
ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction.
Subject(s)
Adenoviruses, Human/genetics , Cisplatin/therapeutic use , Fluorouracil/therapeutic use , Genetic Therapy/methods , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/therapy , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/therapy , Adenoviruses, Human/physiology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/therapy , Combined Modality Therapy , Female , Genetic Therapy/adverse effects , Head and Neck Neoplasms/pathology , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Virus ReplicationABSTRACT
The E1B-deleted, replication-competent ONYX-015 (dl1520) adenovirus was originally described as being able to selectively kill p53-deficient cells due to a requirement of p53 inactivation for efficient viral replication. This hypothesis has become controversial because subsequent in vitro studies have demonstrated that the host range specificity of ONYX-015 is independent of p53 gene status. Using a pair of isogenic cell lines that differ only in their p53 status, we demonstrate here that although ONYX-015 can replicate in both p53 wild-type and mutant cells in vitro, the virus demonstrates significantly greater antitumor activity against mutant p53 tumors in vivo. Moreover, ONYX-015 viral therapy can be combined with radiation to improve tumor control beyond that of either monotherapy. The results demonstrate that ONYX-015 can discern in vivo between tumors having a different p53 status and that it may be an effective neoadjuvant to radiation therapy.
Subject(s)
Adenoviridae , Genes, p53 , Neoadjuvant Therapy , Neoplasms/genetics , Neoplasms/therapy , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Humans , Mutation , Neoplasms/radiotherapy , Tumor Cells, CulturedABSTRACT
Selectively replicating viruses may offer a new approach to cancer treatment. If successful in clinical trials, these agents will constitute a new category in the antitumoral armamentarium. Many viruses are currently being studied, and an adenovirus (ONYX-015) first entered clinical trials in 1996; herpesvirus agents are scheduled to enter clinical trials in 1998. Critical issues need to be addressed if the utility of these agents is to be optimized. For each virus, the effect of antiviral immunity on antitumoral efficacy must be better understood. For all viruses, physical barriers to spread within tumors (e.g., fibrosis, pressure gradients) must be overcome. Although proof-of-concept experiments with chemotherapy and ONYX-015 have been encouraging, further studies are required to determine optimal treatment-regimen sequencing. Combination studies with radiation therapy are also underway with ONYX-015. Finally, these agents may require modification (e.g., coat modification) in order to maximize effectiveness against systemic metastases following intravenous administration.
ABSTRACT
ONYX-015 is an E1B-deleted adenovirus that replicates in and causes lysis of p53-deficient cancer cells selectively. To study the efficiency of intratumoral (i.t.) spread by ONYX-015, we infected specific fractions of tumor cells (two p53-deficient tumor lines and one p53 functional line) in vitro before subcutaneous inoculation into nude mice. Infection of as few as 5% of p53- tumor cells prevented tumor development in all cases; infection of 1% of p53- tumor cells resulted in significant growth inhibition but did not prevent tumor formation. In contrast, infection with ONYX-015 had no significant effect on p53+ tumor formation. These data suggested that replication-dependent tumor cell lysis and spread was occurring, but that tumor destruction might be improved by increasing i.t. virus distribution. Two treatment parameters were then varied to determine whether virus distribution, and consequently efficacy, could be improved. Divided i.t. injections of virus were more efficacious than a single injection of the same total dose. Likewise, increasing the volume of the viral suspension for i.t. injection allowed better distribution within the tumor mass and increased efficacy. These results have implications for the treatment of cancer patients with viral agents.
Subject(s)
Adenoviridae/genetics , Virus Replication , Adenoviridae/physiology , Animals , Female , Humans , Injections, Intralesional , Mice , Mice, Nude , Neoplasm TransplantationABSTRACT
Replication-incompetent viral vectors are being developed for the gene therapy of cancer. Although some of these may eventually be proven to have significant localized antitumoral activity, none to date have been shown to infect and cause regression of established tumors following i.v. administration. Because cancer is a systemic disease in almost all fatal cases, the lack of i.v. efficacy is a major limitation to treatment with replication-incompetent viral vectors. ONYX-015 (d11520) is an attenuated adenovirus that replicates in and causes selective lysis of cancer cells. We carried out i.v. efficacy and distribution studies in nude mice with s.c. and intraparenchymal tumor xenografts. ONYX-015 infected and replicated efficiently within tumors following i.v. administration. Viral titers in livers were relatively high 3 h after administration but decreased rapidly, becoming undetectable after 24 h. Effective antitumor doses were not associated with hepatic toxicity. Viral replication within tumors was associated with regressions in several tumor models. Selectively replicating viruses like ONYX-015 hold promise as agents to treat metastatic cancer.
Subject(s)
Adenoviridae/physiology , Defective Viruses/physiology , Genetic Therapy/methods , Genetic Vectors/administration & dosage , Neoplasms/therapy , Virus Replication , Adenoviridae/genetics , Animals , Cytopathogenic Effect, Viral , DNA, Viral/analysis , Female , Genetic Vectors/genetics , HT29 Cells/virology , Humans , In Situ Hybridization , Injections, Intravenous , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Liver Neoplasms/virology , Mice , Mice, Inbred C57BL , Mice, Nude , Neoplasms/virology , Time Factors , Transplantation, HeterologousABSTRACT
The 55-kilodalton (kDa) protein from the E1B-region of adenovirus binds to and inactivates the p53 gene, which is mutated in half of human cancers. We have previously shown that the replication and cytopathogenicity of an E1B, 55-kDa gene-attenuated adenovirus, ONYX-015, is blocked by functional p53 in RKO and U20S carcinoma lines. We now report that normal human cells were highly resistant to ONYX-015-mediated, replication-dependent cytolysis. In contrast, a wide range of human tumor cells, including numerous carcinoma lines with either mutant or normal p53 gene sequences (exons 5-9), were efficiently destroyed. Antitumoral efficacy was documented following intratumoral or intravenous administration of ONYX-015 to nude mouse-human tumor xenografts; efficacy with ONYX-015 plus chemotherapy (cisplatin, 5-fluorouracil) was significantly greater than with either agent alone.
Subject(s)
Adenovirus E1B Proteins/genetics , Capsid Proteins , Endothelium, Vascular/virology , Neoplasms, Experimental/therapy , Adenoviridae/genetics , Antigens, Viral/metabolism , Capsid/metabolism , Cells, Cultured , Chemotherapy, Adjuvant/methods , Cisplatin/administration & dosage , Epithelium/virology , Female , Fluorouracil/administration & dosage , Glioblastoma/pathology , Glioblastoma/therapy , Humans , Injections, Intralesional , Laryngeal Neoplasms/pathology , Laryngeal Neoplasms/therapy , Neoplasm Transplantation , Tumor Cells, Cultured , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/physiology , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/therapyABSTRACT
Replication-competent viruses are used as selective cancer therapeutics and the mechanisms leading to tumor-specific replication and antitumoral efficacy are now becoming apparent. The specific viruses in development include tumor-targeting herpes simplex viruses, autonomous parvoviruses, Newcastle disease viruses and adenovirus. Information is also available on antiviral immunology and viral defenses against host-mediated immunity. This approach has many potential attributes, in addition to potential hurdles that must be overcome.
Subject(s)
Neoplasms/therapy , Virus Physiological Phenomena , Virus Replication , Adenoviruses, Human/immunology , Adenoviruses, Human/physiology , Animals , Genetic Vectors/immunology , Humans , Newcastle disease virus/immunology , Newcastle disease virus/physiology , Parvovirus/immunology , Parvovirus/physiology , Simplexvirus/immunology , Simplexvirus/physiology , Viral Proteins/immunologyABSTRACT
The human adenovirus E1B gene encodes a 55-kilodalton protein that inactivates the cellular tumor suppressor protein p53. Here it is shown that a mutant adenovirus that does not express this viral protein can replicate in and lyse p53-deficient human tumor cells but not cells with functional p53. Ectopic expression of the 55-kilodalton EIB protein in the latter cells rendered them sensitive to infection with the mutant virus. Injection of the mutant virus into p53-deficient human cervical carcinomas grown in nude mice caused a significant reduction in tumor size and caused complete regression of 60 percent of the tumors. These data raise the possibility that mutant adenoviruses can be used to treat certain human tumors.