Review
Cancer selective adenoviruses

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Abstract

Ten years ago Frank McCormick proposed dl1520 as an oncolytic adenovirus. Although great as an inspiration for better oncolytic viruses it was far from a good product. As Onyx-015, it underwent a wish-fulfilling clinical development program seizing the opportunity left by its p53-targeted non-replicative counterpart Ad-p53. Now, facing a skeptical environment, more selective and potent oncolytic adenoviruses await their clinical opportunity. However, advance in key issues remains elusive, such as, selectivity or retargeting at the level of cell receptors to improve pharmacokinetics. Preclinical models and a few clinical data on biodistribution show that only a minimal proportion of the injected dose reaches the tumors after systemic administration. Once in the tumor, the virus must overcome barriers to efficient spread imposed by stroma and immune responses. Arming the oncolytic virus with transgenes is a natural combination of virotherapy and gene therapy strategies. Transgenes that increase virus production or cellular spread may help to overcome these barriers. Cytotoxic transgenes can help to eliminate tumor cells but need to be compatible with efficient virus replication. These challenges require a careful approach to clinical development and a great deal of collaboration to launch clinical tests with a virus backbone that contains intellectual property from multiple sources.

Introduction

For oncologists viruses do not have the appeal of drugs. Viruses cause diseases and drugs cure them. More selective drugs are available in oncology with prospects of high efficacy and low toxicity. A drug is smaller and much more simple than a virus and intuitively it appears less toxic. However there are two things that drugs can not do. First drugs can inhibit an active target but cannot detect or replace the missing function of a protein. That is, they do not act upon the absence of a target. In cancer, tumor suppressors are missing targets central to the progression of the disease. Inactivation of oncogenes is seldom enough to stop cancer progression. Second, a drug does not amplify itself. This means that a very high concentration is needed to reach every tumor cell. At such concentration toxicity to tissues that proliferate such as bone marrow is difficult to avoid. This shortcoming of conventional drugs have prompted a few oncologists to seek for the magic bullet of immunotherapy. The immune response effector cells should amplify themselves until all the target tumor cells are destroyed. However tumors evolve in the presence of these cells and hence they are selected to evade them. Despite the complexity of a virus, virotherapy is a rational approach to circumvent these limitations.

Virus therapy or virotherapy of cancer is an old theme. Almost every virus has been injected into humans in an attempt to treat cancer since early clinical observations of spontaneous cures after viral infections. However a new age of virotherapy was initiated by Frank McCormick proposing the use of dl1520 for cancer treatment. Previously virotherapy went through different phases. Initially all viruses that propagated in tumors were used. Then research focused on a few viruses that have a natural tropism for cancer cells. This tropism was associated mainly to the property of tumor cells to allow the continuous propagation of IFN-sensitive viruses, such as Newcastle Disease Virus. Genetic engineering techniques and a better understanding of how viruses use cell metabolism, allowed the rational design of oncolytic viruses. Pioneers crippled nucleotide metabolism genes of herpes simplex virus to achieve a certain level of tumor-selective replication (Martuza et al., 1991). However, McCormick’s proposal improved the prospects of selectivity and efficacy because the virus modifications targeted the genetic defects that cause cancer (Bischoff et al., 1996). Unfortunately, dl1520 was not only taken as a great conceptual leap to inspire more selective oncolytic viruses but as a product itself, with high expectations of clinical success backed by daring investments.

Section snippets

The case of dl1520 or Onyx-015

Adenovirus early proteins have several functions aimed to activate the S-phase of the cell cycle (Fig. 1). The main control is at the level of E2F release from the E2F-pRb complex that occurs when E1a 12s and 13s proteins bind to pRB. The released E2F can activate the transcription of cyclin E, cyclin A and other cell cycle progression genes. p53 could counterbalance this activation inducing the expression of p21, and inhibitor of cyclin E and cyclin A dependent kinases. To avoid this cellular

The case of CV706

The trend initiated with Onyx-015 was soon spurred with CV706. CV706 is an adenovirus 5 (Ad5) that contains the enhancer and promoter of the prostate-specific antigen (PSA) gene upstream of the E1a adenovirus gene (Rodriguez et al., 1997). It is the first adenovirus designed for virotherapy of cancer. E1a is the first gene expressed from the adenovirus genome and controls the expression of other virus genes. The control of E1a under the PSA promoter results in a virus that is only turned on in

A current model backbone

Onyx-015 and CV716 have inspired a myriad of novel oncolytic adenoviruses. The former represents the idea of deleting virus functions that are dispensable in tumors. The latter represents the idea of inserting exogenous DNA sequences to make an oncolytic vector. A classification of these alternatives as type 1 and type 2 conditionally replicative viruses has been proposed but it is clear that a proper oncolytic virus will embody a combination of deletions and insertions (Fig. 2).

Among

Arming the backbone

Among the insertions that can be done in the tumor-selective adenovirus backbone, transgenes deserve special mention. An oncolytic virus with a transgene embodies the fusion of virotherapy and gene therapy. Cancer gene therapy has used non-replicative adenoviruses to deliver transgenes in different therapeutic approaches. Clinical failure with tumor suppressors and prodrug-converting genes has been attributed to poor transduction. It is true that a replicating vector can multiply the transfer

Working together

Even if the best armed backbone is assembled, gene-virotherapy will benefit from the help of other cancer treatments. Adenovirotherapy has demonstrated synergy with chemotherapy and radiotherapy, for example. However, one of the obstacles to assemble a good adenovirus backbone is just commercial. It is very expensive to produce the GLP preclinical studies and the GMP virus for clinical development. These steps need industry investment, and industry invests when intellectual property is clear.

Acknowledgements

The work from the author’s laboratory mentioned in this review has been supported by the Theradpox STREP grant from the 6th FP Contract LSHB-CT-2005-018700, the BIO-2005-08682-C03-01 grant from the Spanish Ministry of Education and Science and funding from Oncolytics Biotech Inc. I Thank Manel Cascallo and Juan Fueyo for their extensive collaborations. I also thank Cristina Balague for style corrections and Stefano Indraccolo for the invitation to write this review.

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