Current Cancer Drug Targets - Volume 7, Issue 2, 2007

At first, Dr. J. C. Bell states in this issue what we should now do for the next steps and the directions for the oncolytic virus therapy of the future. He emphasizes the importance of embracing the technology accumulated so far, and of using our understanding of the molecular biology of cancer and viruses for further breakthroughs. In the new era of oncolytic virus therapy, the environment is changing from early basic research to a large number of clinical trials. Actually some of them have yielded approval of a new drug in China for example. Oncolytic virus therapy is not a mere dream, with many suffering patients waiting for relief from cancer. About 10 years ago, the dramatic debut of G207 and Onyx-015 was a giant step in the field of cancer drug therapy. In 1996, the oncolytc adenovirus, Onyx-015, was submitted and filed in the Investigational Drug Section (IDS), and only 4 years later, in 2000, phase III trials were initiated. H101 is an added E3-deletion similar in design to ONXY-015. H101 entered phase III clinical trials in 2000 in China, and 5 years later, was approved by the Chinese FDA. It took only 9 years (1996 - 2005) for the oncolytic adenovirus to be approved as a new drug. This new drug, H101, mostly showed an anti-cancer effect in combination therapy with conventional chemotherapy drugs. Sunway Biotech in Shanghai showed the rate of tumor regression (CR+PR) as follows. H101 with chemotherapy : chemotherapy alone = 78.8% : 39.6% (p value = 0.000). An adenovirus has strong capacity to cause inflammation at the spot of injection. This inflammation reflex of adenovirus can exert a strong effect on among oncolytic viruses. At present, the immune response caused by an oncolytic virus seems to be one of the important anti-cancer activities in the human body. In this issue, Dr. H. Fukuhara and Dr. T. Todo write about the issue of host immune mechanism and “armed” oncolytic HSV-1 vectors using G47δ. A host body acquires the immune response through the change of cell surface viral antigen (MHC-I), and activated CD-8, NK cells would attack tumor cells including the oncolytic virus. Thus, the strong inflammation reflex caused by the oncolytic virus may be beneficial in triggering the subsequent host immune response. They indicate that virus “oncolysates” may be useful for cancer immunotherapy. However, the capacity to induce strong inflammation might imply a dangerous aspect, should excessive high titer virus be injected into the venous tract. We must not forget the tragedy of OTC-gene therapy, which occurred at the University of Pennsylvania. Systemic injection of oncolytic virus is another topic in this special issue about Vaccinia virus and Newcastle disease virus. The capacity for systemic injection includes the possibility of inhibiting distal micro-metastasis, and is very important for advanced cancer therapy. Dr. A. M. Crompton and Dr. D. H. Kirn describe the potential of Vaccinia virus for systemic injection; and Dr. R. M. Lorence presents a very interesting phenomenon dealing with the systemic injection of Newcastle disease virus that is related to the effect of high repeat doses, and a slower infusion rate for desensitization. Those technical improvements have numerous possibilities, and may well be effective for other types of oncolytic virus as well regarding systemic injection. We also deal in this issue with HF10 clinical trials in Japan. HF10 is attenuated herpes simplex virus type-1. We show the pathological changes, caused by HF10 oncolysis in tissues. The oncolytic virus itself has a great capacity for tumor cell lysis as shown in the photographs. In the next step, we hope to perform combination therapy of HF10 with chemotherapy drugs or radiation. Some papers have stated that combination therapy of herpes oncolytic virus was expected to increase virus replication, consecutive tumor regression and survival rate in an in vivo model, but other studies mentioned that both radiation and chemotherapy diminished viral replication. Comprehension of the time-length of viral replication in a tumor site is very important for the evaluation of the therapy. It is a very key to oncolytic viral therapy......

We are very pleased and proud to be able to publish this special issue of Current Cancer Drug Targets devoted to oncolytic virus therapy covering basic and clinical research on adenovirus, vaccinia virus, herpes virus, and Newcastle disease virus. In these papers, we welcome the world's top authorities in the field who have generously contributed their latest review articles for exclusive publication in this special issue. Moreover, this issue also includes a range of opinion from government drug organizations. Here we simply wish to bring together the newest knowledge and experience in the field of cutting-edge oncolytic virus therapy for researchers and every kind of cancer therapist. The Foreword presents a historical perspective on the development of oncolytic virus together with the encouraging results of recent clinical trials (e.g., H101 has been tested in clinical trial of nearly 250 patients and approved for human use by the Chinese FDA, while PV701 has been tried in over 110 patients, as described in our special issue).

Cancer is a complex disease that often eludes successful treatment due to its propensity to evolve or adapt in the face of current therapeutic regimes. It is reasonable to suggest that sophisticated therapeutics that can attack cancers in multiple, but targeted ways, will be necessary in order to improve current success rates. It is the thesis of this article that Oncolytic Viruses (OVs), are a new generation of “smart therapeutics” for cancer with tremendous potential to revolutionize the management of what has become one of mankind's scourges. A number of viruses are being developed around the world for this purpose (one has already been approved for human use in China [1]) and I propose that it is now essential to embrace the technology and use our recent and evolving understanding of the molecular biology of cancer to fully exploit the oncolytic virus platform. In the remainder of this article I speculate on some of the next important steps in OV development and directions the platform may be headed in the future.

The current field of oncolytic virus development has evolved from, and been educated by, the route adenoviruses have taken to Phase III development in the United States (Onyx-015) and commercial approval in China (H101). Clinical development of these E1B-deleted viruses showed that a staged approach, from single-agent intratumoral injections to trials testing intravenous delivery and trials in combination with approved therapies is judicious and can be successful. Additional oncolytic products are in development, including andenovirus plus other promising platforms such as herpes simplex virus, Newcastle disease virus, reovirus and vaccinia virus. These second-generation products seek to expand clinical utility beyond the modest local efficacy of Onyx-015/H101 to potent systemic delivery and efficacy. Improvement of efficacy in metastatic cancer will depend not only on enhanced killing of tumor cells, but also on achieving intravenous delivery and better intratumoral dissemination. Many viruses inherently replicate preferentially in tumors, and engineering can increase this therapeutic index by targeting genetic features of cancers. However, both viruses and cancer cells have complex biologies. Therefore, research may reveal that there is not a single predictive factor for tumor specificity. For example, the Onyx-015 mechanism-of-selectivity has proved to be complex. Further research regarding pathway dependence for other oncolytic viruses may also reveal multiple influences on their tumor tropism.

Since the 1990s, oncolytic viruses were utilized to treat cancer patients from phase I to phase III. Oncolytic virus development in China has been keeping in step with that in other countries and even accelerated the process in some fields, especially in conducting clinical trials. H101 is one kind of oncolytic adenovirus with E1B-55KD and partial E3 deleted developed by Shanghai Sunwaybio. From 2000-2004, phase I to phase III clinical trials for treating head and neck cancer were conducted in China. Clinical data show that H101 is well tolerable and has good efficacy when combined with chemotherapy in some cancer treatment modalities. We review the clinical results and relative issues of H101 in treating cancer and discuss approaches and possible improvements for the future. Information on other oncolytic viruses developing in China is also provided.

The use of oncolytic herpes simplex virus type 1 (HSV-1) is a promising strategy for cancer treatment. Accumulating evidence indicates that, aside from the extent of replication capability within the tumor, the efficacy of an oncolytic HSV-1 depends on the extent of induction of host antitumor immune responses. Ways to modify the host immune responses toward viral oncolysis include expression of immunostimulatory molecules using oncolytic HSV-1 as a vector and co-administration of reagents that modulate immune reactions. Viral propagation may be enhanced via temporary suppression of innate immune responses. Elucidation of the role of the host immune system in oncolytic HSV-1 therapy is the key to establishing the approach as a useful clinical means for cancer treatment.

PV701 is a naturally-attenuated, non-recombinant, oncolytic strain of Newcastle disease virus that displays preclinical intravenous (IV) efficacy. PV701 is selective at killing human cancer cells versus normal human cells based on tumor specific defects in the interferon (IFN)-mediated antiviral response. This oncolytic virus displays a broad spectrum of antitumor activity in vitro and in vivo. Preclinical models successfully predicted key clinical parameters including the mechanism of toxicity, two complementary strategies (desensitization and slow infusion) to reduce toxicity, and the starting dose for phase 1 trials. In three phase 1 trials of 114 patients using IV administration of PV701, Wellstat Biologics Corporation has evaluated the effects of dose, schedule, and infusion rate for PV701. Three general classes of side effects were seen: flu-like symptoms; tumor-site-specific adverse events (AEs); and infusion reactions. The first PV701 dose desensitized the patient to the side effects of further doses, allowing a marked increase in the maximum tolerated dose for subsequent doses compared to the first dose. Tumor responses were first noted at the higher doses achieved using desensitization. In the most recent phase 1 trial of 19 patients at Hamilton, Ontario, that employed desensitization, high repeat doses, and a slower infusion rate (Hamilton Regimen), there were six responses (4 major; 2 minor) and a total of six patients with survival for at least 2 years. In addition, patient tolerability improved using the Hamilton Regimen compared to IV bolus dosing used previously. Phase 2 studies of this novel biologic agent are about to begin.

We reviewed our clinical trial using mutant herpes simplex virus “HF10”. We have evaluated the safety and effect of HF10 against recurrent breast cancer since 2003 and also applied HF10 to non-resectable pancreatic cancer since 2005. An oncolytic herpes simplex virus type 1, mutant HF10, has been isolated and evaluated for anti-tumor efficacy in syngeneic immunocompetent mouse models. From long time before clinical trial, we have found that the mutant virus can have remarkable potential to effectively treat cancer in experimental studies using animals, and that all of the surviving mice acquire resistance to rechallenge of the tumor cells. A number of studies have shown that HF10 is effective and safe for use in localized or peritoneally disseminated malignant tumors of non-neuronal origin in animals. Pilot studies using HF10 have been initiated in patients with metastatic breast cancer. For each patient, 0.5 ml HF10 diluents at various doses were injected into test nodule, and 0.5 ml sterile saline was injected into a second nodule. All patients were monitored for local and systemic adverse effects, and the nodules were excised 14 days after viral injection for histopathological studies. All patients tolerated the clinical trial well. While no adverse effects occurred, there was cancer cell death and 30-100% regression histopathologically in recurrent breast cancer. As mentioned above, intratumoral injection of mutant herpes simplex virus HF10 for recurrent metastatic breast cancer was safe and effective. Also a trial for non-resectable pancreatic cancer being carried out on the basis of the above result has proved to be innocuous and has been in progress to assess the clinical benefit and enhance the potentiality of HF10 against cancer.

Viral oncolysis, the destruction of cancer cells by replicating viruses, is a new modality of cancer therapy. This strategy involves use of viruses that are either genetically engineered to replicate preferentially in neoplastic cells, or use of viruses that display innate tropism for neoplastic cells. These viruses may also be modified to deliver transgenes to destroy cancer cells. While numerous viruses may be used for this form of cancer therapy, HSV-1 is an attractive vector for viral oncolysis due to several characteristics including its high infectivity, ease of genetic engineering, large transgene capacity, and the availability of an effective medical treatment for Herpes simplex virus infections. The HSV-1 viral genome has been manipulated to generate replication conditional viruses which target cancer cells. Although these viruses are programmed to replicate preferentially in cancer cells, there is some unintended replication in normal cells. Currently, biopsy is the gold standard for monitoring the therapeutic effects of viral oncolysis. However, a non-invasive test capable of serial monitoring of therapy during the treatment period is required for both preclinical and clinical studies. Positron emission tomography (PET) using HSV thymidine kinase as the PET reporter gene offers the desired qualities of a non-invasive test which can be easily repeated to determine the location and magnitude of viral replication and tumor lysis. We review viral oncolysis, focusing on HSV-1 viral oncolysis and therapeutic monitoring by PET.

Oncolytic viruses can selectively replicate in and lead to tumor cell lysis with minimal infection/replication potential in adjoining non-neoplastic tissue. Because of paramount safety concerns, first-generation oncolytic viruses were designed to be significantly attenuated in their lytic potential. Results from recent clinical trials have revealed the safety of this approach, but have underscored the urgency for design and testing of more tumor-selective and -potent viruses to realize the full therapeutic potential of this revolutionary treatment modality. With the discovery of various molecular/genetic changes associated with neoplasia, tumor-specific transcriptional targeting of viral virulence is being tapped to generate tumor- and tissue-specific variants. This review will focus on the various strategies exploited to generate viruses whose virulence is governed by tumorspecific transcriptional events.

Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. For targeting cancer cells, there is a need for tissue- or cell-specific promoters that can express in diverse tumor types and are silent in normal cells. Recent advances in molecular biology have fostered remarkable insights into the molecular basis of neoplasm. Telomerase activation is considered to be a critical step in carcinogenesis and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication. We constructed an attenuated adenovirus 5 vector (Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site (IRES). Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. Thus, the hTERT promoter confers competence for selective replication of Telomelysin in human cancer cells, an outcome that has important implications for the treatment of human cancers. This article reviews recent findings in this rapidly evolving field: cancer therapeutic and cancer diagnostic approaches using the hTERT promoter.

Many types of oncolytic viruses, wild-type virus, attenuated viruses and genetically-modified viruses, have been developed as an innovative cancer therapy. The strategies, nature, and technologies of oncolytic virus products are different from the conventional gene therapy products or cancer therapy products. From the regulatory aspects to ensure the safety, efficacy and quality of oncolytic viruses, there are several major points during the development, manufacturing, characterization, non-clinical study and clinical study of oncolytic viruses. The major issues include 1) virus design (wild-type, attenuated, and genetically engineered strains), 2) poof of concept in development of oncolytic virus products, 3) selectivity of oncolytic virus replication and targeting to cancer cells, 4) relevant animal models in non-clinical studies, 5) clinical safety, 6) evaluation of virus shedding. Until now, the accumulation of the information about oncolytic viruses is not enough, it may require the unique approach to ensure the safety and the development of new technology to characterize oncolytic viruses.