Getting Oncolytic Virus Therapies Off the Ground
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector MEETING REVIEW Getting oncolytic virus therapies off the ground John C. Bell,* Brian Lichty, and David Stojdl Ottawa Regional Cancer Centre, 503 Smyth Road, Ottawa, Ontario K1H 1C4, Canada *Correspondence: [email protected] An international meeting was held on the development and application of replicating viruses for cancer therapy this past March in Banff, Alberta. In this review, using the presentations at this meeting as a backdrop, we discuss how recent scientif- ic and clinical findings are reshaping the development of oncolytic virus therapeutics. Here we identify some of the obstacles that these therapeutics face and discuss evolving strategies, both preclinically and clinically, that are facilitating oncolytic virus development. Oncolytic viruses are therapeutics that have either been natu- (University of California at San Francisco) pointed out that the rally selected or engineered to specifically grow in and kill tumor defect of L4 mRNA transport from the nucleus of Onyx 015 cells. In general, oncolytic viruses derive their specificity by infected cells can be complemented by heat shock. Indeed, it exploiting cell surface or intracellular aberrations in gene has been shown previously that E1B deleted adenoviruses are expression that arise in malignancies during tumor evolution. As cold-sensitive and replicate as well as wild-type adenovirus at David Kirn (Oxford University Medical School, UK) pointed out, 39°C (Goodrum and Ornelles, 1998). This provides an interest- while conventional chemotherapeutics are currently the best ing new wrinkle to the therapeutic application of Onyx 015, as frontline treatments available, they are limited in their utility by transient temperature spikes in patients may facilitate virus relatively narrow therapeutic windows that rapidly close as growth and killing of tumor cells. Whether this holds true or not, tumors evolve drug resistance mechanisms. New small mole- perhaps the best strategy is to create point or discrete muta- cules targeted to oncogenic proteins have greatly reduced toxi- tions in E1B that abrogate p53 degradation but permit the other city in normal tissues, but the very nature of their specificity may activities of E1B to remain intact (Shen et al., 2001). In an alter- limit their long-term usefulness. Oncolytic viruses, on the other native approach, Heise and collaborators (Heise et al., 2000) hand, are multimodality therapeutics that can be engineered to have generated an adenoviral strain with a discrete E1A-CR2 have the tumor specificity of a small molecule, the potent cell deletion that outperforms other oncolytic viruses in preclinical killing of a chemotherapeutic, the ability to arouse the host models, underscoring the idea that perhaps “less is better” immune system against tumor antigens, and an innate capacity when it comes to attenuating viral therapeutics. to stimulate the production of host cytokines that have potential The initial clinical trials with HSV oncolytic therapeutics anticancer activity. Perhaps the greatest advantage that the have proven safe, but in these studies, the maximum amount of oncolytic virus platform offers over chemical agents is its ability virus that can be produced or delivered may be limiting efficacy, to be tailored by in vitro genetic manipulation in response to pre- prompting Bob Martuza (Harvard Medical School) to coin the clinical and clinical findings. term “maximum affordable dose” as opposed to maximum toler- able dose. New engineered versions of HSV that have Are current oncolytic viruses too attenuated? increased cytolytic or fusogenic properties are being created Those developing oncolytic virus therapeutics are understand- and appear more efficacious while remaining safe (Fu and ably concerned about the safety of these new agents. The clini- Zhang, 2002; Todo et al., 2001). cal trials performed to date using a variety of oncolytic virus Many of the adenoviral vectors used for oncolytic therapy candidates demonstrate that these agents can be very safe; have deletions in viral genes that function to suppress the host however, some oncolytic viruses are so attenuated that maxi- immune response or have impaired cytolytic activity. Terry mum tolerable doses, and perhaps efficacious doses, cannot be Hermiston (Berlex Biosciences) pointed out, oncolytic viruses achieved (Markert et al., 2000; Varghese and Rabkin, 2002). not only have to be safe and tumor-selective in their growth but, The early strategies for attenuating viruses often involved dele- to be effective therapeutics, they must overcome obstacles of tion of entire genes, but in retrospect, this may have been hypoxia, host immunity, physical barriers (e.g., normal stroma), overkill. Virus gene products are often multifunctional, and it is and clearance and resistance mechanisms that may develop now recognized that it is desirable to engineer subtle mutations within the tumor milieu. This led to the idea of “arming” replicat- that delete only specific functions required for replication in nor- ing oncolytic viruses with “payloads” that will enhance virus mal cells but retaining activities required for overall efficient delivery, spread, and efficacy (Bauzon et al., 2003). As an virus replication and spread. An example is the E1B deleted example, Bill Wold (St. Louis University School of Medicine) and oncolytic adenovirus, Onyx-015. The best understood function colleagues have shown that by reinserting the viral ADP gene of E1B is the inactivation of the cellular p53 protein, an observa- (the “adenovirus death protein” which is required for efficient tion that was thought to be the cornerstone of the Onyx 015 cell lysis) they have created an oncolytic virus that is more technology (Heise et al., 1997). The E1B gene product is also cytolytic (Doronin et al., 2000, 2003) and has an increased abil- essential for the nuclear export of late transcripts that are ity to spread between cells. Another approach is to include a required for robust adenovirus replication, including the L4 transgene (e.g., TNFα or TRAIL, two apoptosis-inducing 100K transcript (Babiss et al., 1985). The 5′UTR of L4 resem- cytokines) that would enhance the cytolytic properties of the bles that of the HSP 90 mRNA, and Frank McCormick therapeutic virus (Lin et al., 2002; Rasmussen et al., 2002). CANCER CELL : JULY 2003 · VOL. 4 · COPYRIGHT © 2003 CELL PRESS 7 MEETING REVIEW These are characteristics that, when coupled with tumor selec- both increased proliferation and decreased antiviral activity. tivity, are likely to create viruses that have increased therapeutic Transcriptional targeting of viruses, by the substitution of efficacy. viral promoters with cellular promoter elements, has been wide- ly developed and reviewed extensively elsewhere (Bangma, Targeting the tumor cell surface 2000; Barnett et al., 2002; Liu, 2002; Logg et al., 2002; Nahde et Many strategies are being developed for targeting tumor cells al., 2001; Qiao et al., 2002; Savontaus et al., 2002). A new with oncolytic viruses. One approach is to use a viral agent that approach with plenty of potential is restricting virus growth to binds to a very broadly or ubiquitously expressed cell surface tumor cells based upon translational regulatory signals. Mathias antigen and restrict virus growth following entry into the cell Gromeier (Duke University) has detargeted poliovirus from non- (e.g., VSV, herpes, NDV or adenovirus). This strategy is a good dividing neuronal cells and retargeted it to malignant glioma one unless the virus receptor is lost during cancer cell evolution cells by swapping IRES elements between polio and rhinovirus- (Jee et al., 2002) or is so strongly expressed or accessible that es (Gromeier et al., 2000). It appears that the combination of a one organ can serve as a sink and bind up the majority of a ther- 3′ polio UTR sequence with a rhinovirus 5′ IRES element cre- apeutic dose. Several groups are developing ways to detarget ates a chimeric virus that is incapable of efficient translation in the adenovirus from its normal cellular receptor (the CAR or neuronal cells but is well translated in malignant cells. “coxsackie/adenovirus receptor”) and retarget tumor cell sur- faces with single chain antibodies, growth factors, or peptides It’s not only what you deliver, it’s how you deliver it (Wu et al., 2002). Using the oncolytic measles virus platform, While most oncolytic virus products are still in the early phases Stephen Russell and Roberto Cattaneo (Mayo Clinic) are close of clinical development, data from a handful of trials are provid- to achieving the goal of creating a virus that binds only to tumor ing important leads about the best way to deliver therapeutic cells. They have mapped and then mutated the amino acids viruses. Intratumoral injections of agents like Onyx-015 provid- required for effective interaction of measles virus with its two ed some early encouraging results (Khuri et al., 2000); however, natural cellular receptors, CD 46 and Slam. This mutant virus is the great hope of replicating oncolytic viruses is that they will then engineered to express single chain antibodies (ScFVs) spread and destroy systemic disease. While there have been that direct the virus to bind only to tumor cell antigens (Bucheit some reports of virus spread from injected tumors to contralat- et al., 2003; Peng et al., 2003; Schneider et al., 2002). While on eral naïve tumors in preclinical