Translation of Targeted Oncolytic Virotherapeutics from the Lab into the Clinic, and Back Again: A High-Value Iterative Loop

As our knowledge and understanding of cancer biology have exploded over the past decade, some have proposed that this is a golden age of targeted cancer therapeutics. These novel therapeutics target specific molecules and pathways in cancers. Most notably, numerous monoclonal antibodies and small-molecule tyrosine kinase inhibitors have been developed and approved for a variety of cancers. Although these agents generate billions of dollars in sales, their impact on the overall survival of patients with metastatic solid tumors is in general minimal (although rare exceptions exist).1Abou-Alfa GK Schwartz L Ricci S Amadori D Santoro A Figer A et al.Phase II study of sorafenib in patients with advanced hepatocellular carcinoma.J Clin Oncol. 2006; 24: 4293-4300Crossref PubMed Scopus (1091) Google Scholar In addition, a major driving force behind the development of these more “elegant” and targeted therapies—the promise that toxic chemotherapy could be avoided—has been undercut. In this Commentary we analyze the difference in development strategies and processes between molecular therapeutics and oncolytic virotherapeutics, and discuss how the field can benefit from a unique “iterative loop” that is feasible with the virotherapeutics class.Standard drug development typically follows a relatively slow, sequential, and unidirectional process from target identification to lead identification, lead optimization, preclinical pharmacology and toxicology, and Investigational New Drug Application (IND) filing, followed by phase I, II, and III trials, and eventually, in a small fraction of cases, to approval. The entire process can take 10 or more years before a drug is approved for a cancer market. Product approval of bevacizumab (Avastin, Genentech) for example, took approximately 10 years from identification of the target vascular endothelial growth factor molecule. Estimated costs to approval of a new chemical entity vary, but most estimates are more than $500 million. It is not at all surprising that once a molecule has been designated as an IND candidate and the costly and unidirectional process initiated, it becomes very difficult for a pharmaceutical company to justify continued product optimization. Typically the entire infrastructure is then shifted to focus on commercialization activities, and further optimization is halted.The targeted oncolytic virotherapy class may be evolving in a way that is fundamentally different from this traditional model. An iterative loop is developing that allows for clinical trial data to guide subsequent preclinical research and development activities, including product design, followed by reintroduction into the clinic and a repeat of the process. We propose that this capacity to obtain clinical data, including mechanism-of-action data, and to use it to guide product-design optimization constitutes a potential revolutionary change in drug development.This iterative loop is feasible for the targeted oncolytic virotherapy class for several reasons. First, virus species and strains represent a vast library of pharmacophores with distinctive, predictable, and diverse biologies.2Kelly E Russell SJ History of oncolytic viruses: genesis to genetic engineering.Mol Ther. 2007; 15: 651-659Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar Second, most of these virus species can be genetically engineered efficiently, resulting in enhanced safety and/or efficacy. Furthermore, therapeutic and monitoring transgenes can be inserted and expressed in a controlled fashion from the agents to improve safety, efficacy, and patient management. In addition, advances in other medical technologies, including novel imaging modalities, provide unique opportunities to examine key pharmacodynamic findings in preclinical animal models and in patients.Based on clinical findings with second-generation oncolytic viruses, hypotheses have been generated and innovative solutions proposed. The first major hurdle faced by this field was insufficient efficacy at the injected tumor site.3Kirn D Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned?.Gene Ther. 2001; 8: 89-98Crossref PubMed Scopus (301) Google Scholar,4Liu TC Galanis E Kirn D Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress.Nat Clin Pract Oncol. 2007; 4: 101-117Crossref PubMed Scopus (376) Google Scholar One hypothesis was that intratumoral spread was insufficient; proposed solutions included virus engineering for enhanced spread5Liu TC Hallden G Wang Y Brooks G Francis J Lemoine N et al.An E1B-19 kDa gene deletion mutant adenovirus demonstrates tumor necrosis factor-enhanced cancer selectivity and enhanced oncolytic potency.Mol Ther. 2004; 9: 786-803Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar and coadministration of enzymes to degrade the extracellular milieu.6McKee TD Grandi P Mok W Alexandrakis G Insin N Zimmer JP et al.Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector.Cancer Res. 2006; 66: 2509-2513Crossref PubMed Scopus (327) Google Scholar A second hypothesis was that replication duration was insufficient because of rapid immune clearance; approaches have included virus engineering for immune avoidance7Wang Y Hallden G Hill R Anand A Liu TC Francis J et al.E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models.Nat Biotechnol. 2003; 21: 1328-1335Crossref PubMed Scopus (129) Google Scholar and coadministration of immunosuppressive agents. Third, insufficient virus receptor expression on tumor cells led to engineered receptor targeting,8Gaggar A Shayakhmetov DM Lieber A CD46 is a cellular receptor for group B adenoviruses.Nat Med. 2003; 9: 1408-1412Crossref PubMed Scopus (613) Google Scholar physical modification of the virus coat, and approaches to identify tumor types most likely to respond based on molecular targets. Finally, complementary mechanisms of action were incorporated through engineered expression of therapeutic transgenes from the virus.The second major hurdle was limited systemic efficacy after intratumoral or intravenous administration. Several potential hypotheses and solutions were applied. In one approach, virus inactivation by the immune system was combated through immunosuppression and avoidance9Kambara H Saeki Y Chiocca EA Cyclophosphamide allows for in vivo dose reduction of a potent oncolytic virus.Cancer Res. 2005; 65: 11255-11258Crossref PubMed Scopus (59) Google Scholar and cell-based (“Trojan horse”) delivery.10Power AT Bell JC Cell-based delivery of oncolytic viruses: a new strategic alliance for a biological strike against cancer.Mol Ther. 2007; 15: 660-665Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar Systemic toxicity was addressed via modifications in dosing, formulation, and genetic optimization.11Laurie SA Bell JC Atkins HL Roach J Bamat MK O'Neil JD et al.A phase 1 clinical study of intravenous administration of PV701, an oncolytic virus, using two-step desensitization.Clin Cancer Res. 2006; 12: 2555-2562Crossref PubMed Scopus (84) Google Scholar Finally, the use of novel oncolytic virus species, with natural systemic blood-borne life cycles, led to enhanced systemic delivery and efficacy.12Thorne SH Hwang TH O'Gorman WE Bartlett DL Sei S Kanji F et al.Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963.J Clin Invest. 2007; 117: 3350-3358Crossref PubMed Scopus (162) Google ScholarClinical development strategies have also been developed. Key components have included a stepwise approach for administration route,3Kirn D Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned?.Gene Ther. 2001; 8: 89-98Crossref PubMed Scopus (301) Google Scholar,4Liu TC Galanis E Kirn D Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress.Nat Clin Pract Oncol. 2007; 4: 101-117Crossref PubMed Scopus (376) Google Scholar diversification of tumor types in early phases to select targets for late-stage trials, and randomized trials comparing standard of care with and without viruses or viruses versus placebo in refractory patients. Ex vivo assays to determine primary tumor tissue sensitivity have been developed and may predict treatment response.13Wang Y Thorne S Hannock J Francis J Au T Reid T et al.A novel assay to assess primary human cancer infectibility by replication-selective oncolytic adenoviruses.Clin Cancer Res. 2005; 11: 351-360PubMed Google Scholar,14Rots MG Elferink MG Gommans WM Oosterhuis D Schalk JA Curiel DT et al.An ex vivo human model system to evaluate specificity of replicating and non-replicating gene therapy agents.J Gene Med. 2006; 8: 35-41Crossref PubMed Scopus (27) Google Scholar Novel methods to determine in vivo tumor response included determination of tumor volume, density, and metabolism. Biological end points such as tumor vascularity/blood flow, viral replication, and transgene expression have been used, and mathematical modeling has been used for assessments of viral replication.15Wein LM Wu JT Kirn DH Validation and analysis of a mathematical model of a replication-competent oncolytic virus for cancer treatment: implications for virus design and delivery.Cancer Res. 2003; 63: 1317-1324PubMed Google ScholarEngineered oncolytic viruses pose unique chemistry, manufacturing, and controls issues that have been addressed. Well-characterized starting materials are required for each product, including at least three rounds of virus plaque purification. Verifying gene manipulation by sequencing the region of interest (and flanking sequences) is also now mandatory. Production of Master Cell Banks and Master Virus Banks is carried out under strict Good Manufacturing Practice and Good Laboratory Practice standards, with rigorous testing at several steps in the process. The final product also needs to be tested for identity, contamination, and potency before being used in humans. Additional regulatory chemistry, manufacturing, and controls requirements exist for third-generation oncolytic viruses, including characterizations of therapeutic and monitoring transgenes. Transgene product expression and function must be evaluated.Novel experimental therapeutics for cancer typically progress through a predictable series of developmental stages. These stages are driven as much by perception as they are by hard data. Many successfully approved therapies have followed this pathway. The stages can be categorized as follows: (1) idea development (2) unrealistic optimism (3) identification of technical difficulties and hurdles (4) unrealistic pessimism (5) problem solving, and (6) gradual progress leading to success. The development of targeted oncolytic viruses is no different from that of monoclonal antibodies or small molecules at this stage. The field is currently at stage 5 of development, where exciting iterative loops between bench and bedside are ongoing. Compared with chemotherapy or antibody- and small-molecule-based therapeutics, virotherapeutics have extremely diverse mechanisms of action, unique pharmacodynamics/pharmacokinetics, and an extensive interplay with the host. As we have demonstrated above, virotherapeutics are a novel treatment platform on which new findings in the laboratory can be translated into the clinic, and observations from clinical trials can be assessed and addressed in great detail in the laboratory. With recent advances in cancer biology, virology, and biotechnology, this therapeutic platform will continue to benefit from interdisciplinary collaboration and, as a result, will lead to breakthrough therapies for cancers. As our knowledge and understanding of cancer biology have exploded over the past decade, some have proposed that this is a golden age of targeted cancer therapeutics. These novel therapeutics target specific molecules and pathways in cancers. Most notably, numerous monoclonal antibodies and small-molecule tyrosine kinase inhibitors have been developed and approved for a variety of cancers. Although these agents generate billions of dollars in sales, their impact on the overall survival of patients with metastatic solid tumors is in general minimal (although rare exceptions exist).1Abou-Alfa GK Schwartz L Ricci S Amadori D Santoro A Figer A et al.Phase II study of sorafenib in patients with advanced hepatocellular carcinoma.J Clin Oncol. 2006; 24: 4293-4300Crossref PubMed Scopus (1091) Google Scholar In addition, a major driving force behind the development of these more “elegant” and targeted therapies—the promise that toxic chemotherapy could be avoided—has been undercut. In this Commentary we analyze the difference in development strategies and processes between molecular therapeutics and oncolytic virotherapeutics, and discuss how the field can benefit from a unique “iterative loop” that is feasible with the virotherapeutics class. Standard drug development typically follows a relatively slow, sequential, and unidirectional process from target identification to lead identification, lead optimization, preclinical pharmacology and toxicology, and Investigational New Drug Application (IND) filing, followed by phase I, II, and III trials, and eventually, in a small fraction of cases, to approval. The entire process can take 10 or more years before a drug is approved for a cancer market. Product approval of bevacizumab (Avastin, Genentech) for example, took approximately 10 years from identification of the target vascular endothelial growth factor molecule. Estimated costs to approval of a new chemical entity vary, but most estimates are more than $500 million. It is not at all surprising that once a molecule has been designated as an IND candidate and the costly and unidirectional process initiated, it becomes very difficult for a pharmaceutical company to justify continued product optimization. Typically the entire infrastructure is then shifted to focus on commercialization activities, and further optimization is halted. The targeted oncolytic virotherapy class may be evolving in a way that is fundamentally different from this traditional model. An iterative loop is developing that allows for clinical trial data to guide subsequent preclinical research and development activities, including product design, followed by reintroduction into the clinic and a repeat of the process. We propose that this capacity to obtain clinical data, including mechanism-of-action data, and to use it to guide product-design optimization constitutes a potential revolutionary change in drug development. This iterative loop is feasible for the targeted oncolytic virotherapy class for several reasons. First, virus species and strains represent a vast library of pharmacophores with distinctive, predictable, and diverse biologies.2Kelly E Russell SJ History of oncolytic viruses: genesis to genetic engineering.Mol Ther. 2007; 15: 651-659Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar Second, most of these virus species can be genetically engineered efficiently, resulting in enhanced safety and/or efficacy. Furthermore, therapeutic and monitoring transgenes can be inserted and expressed in a controlled fashion from the agents to improve safety, efficacy, and patient management. In addition, advances in other medical technologies, including novel imaging modalities, provide unique opportunities to examine key pharmacodynamic findings in preclinical animal models and in patients. Based on clinical findings with second-generation oncolytic viruses, hypotheses have been generated and innovative solutions proposed. The first major hurdle faced by this field was insufficient efficacy at the injected tumor site.3Kirn D Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned?.Gene Ther. 2001; 8: 89-98Crossref PubMed Scopus (301) Google Scholar,4Liu TC Galanis E Kirn D Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress.Nat Clin Pract Oncol. 2007; 4: 101-117Crossref PubMed Scopus (376) Google Scholar One hypothesis was that intratumoral spread was insufficient; proposed solutions included virus engineering for enhanced spread5Liu TC Hallden G Wang Y Brooks G Francis J Lemoine N et al.An E1B-19 kDa gene deletion mutant adenovirus demonstrates tumor necrosis factor-enhanced cancer selectivity and enhanced oncolytic potency.Mol Ther. 2004; 9: 786-803Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar and coadministration of enzymes to degrade the extracellular milieu.6McKee TD Grandi P Mok W Alexandrakis G Insin N Zimmer JP et al.Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector.Cancer Res. 2006; 66: 2509-2513Crossref PubMed Scopus (327) Google Scholar A second hypothesis was that replication duration was insufficient because of rapid immune clearance; approaches have included virus engineering for immune avoidance7Wang Y Hallden G Hill R Anand A Liu TC Francis J et al.E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models.Nat Biotechnol. 2003; 21: 1328-1335Crossref PubMed Scopus (129) Google Scholar and coadministration of immunosuppressive agents. Third, insufficient virus receptor expression on tumor cells led to engineered receptor targeting,8Gaggar A Shayakhmetov DM Lieber A CD46 is a cellular receptor for group B adenoviruses.Nat Med. 2003; 9: 1408-1412Crossref PubMed Scopus (613) Google Scholar physical modification of the virus coat, and approaches to identify tumor types most likely to respond based on molecular targets. Finally, complementary mechanisms of action were incorporated through engineered expression of therapeutic transgenes from the virus. The second major hurdle was limited systemic efficacy after intratumoral or intravenous administration. Several potential hypotheses and solutions were applied. In one approach, virus inactivation by the immune system was combated through immunosuppression and avoidance9Kambara H Saeki Y Chiocca EA Cyclophosphamide allows for in vivo dose reduction of a potent oncolytic virus.Cancer Res. 2005; 65: 11255-11258Crossref PubMed Scopus (59) Google Scholar and cell-based (“Trojan horse”) delivery.10Power AT Bell JC Cell-based delivery of oncolytic viruses: a new strategic alliance for a biological strike against cancer.Mol Ther. 2007; 15: 660-665Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar Systemic toxicity was addressed via modifications in dosing, formulation, and genetic optimization.11Laurie SA Bell JC Atkins HL Roach J Bamat MK O'Neil JD et al.A phase 1 clinical study of intravenous administration of PV701, an oncolytic virus, using two-step desensitization.Clin Cancer Res. 2006; 12: 2555-2562Crossref PubMed Scopus (84) Google Scholar Finally, the use of novel oncolytic virus species, with natural systemic blood-borne life cycles, led to enhanced systemic delivery and efficacy.12Thorne SH Hwang TH O'Gorman WE Bartlett DL Sei S Kanji F et al.Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963.J Clin Invest. 2007; 117: 3350-3358Crossref PubMed Scopus (162) Google Scholar Clinical development strategies have also been developed. Key components have included a stepwise approach for administration route,3Kirn D Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned?.Gene Ther. 2001; 8: 89-98Crossref PubMed Scopus (301) Google Scholar,4Liu TC Galanis E Kirn D Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress.Nat Clin Pract Oncol. 2007; 4: 101-117Crossref PubMed Scopus (376) Google Scholar diversification of tumor types in early phases to select targets for late-stage trials, and randomized trials comparing standard of care with and without viruses or viruses versus placebo in refractory patients. Ex vivo assays to determine primary tumor tissue sensitivity have been developed and may predict treatment response.13Wang Y Thorne S Hannock J Francis J Au T Reid T et al.A novel assay to assess primary human cancer infectibility by replication-selective oncolytic adenoviruses.Clin Cancer Res. 2005; 11: 351-360PubMed Google Scholar,14Rots MG Elferink MG Gommans WM Oosterhuis D Schalk JA Curiel DT et al.An ex vivo human model system to evaluate specificity of replicating and non-replicating gene therapy agents.J Gene Med. 2006; 8: 35-41Crossref PubMed Scopus (27) Google Scholar Novel methods to determine in vivo tumor response included determination of tumor volume, density, and metabolism. Biological end points such as tumor vascularity/blood flow, viral replication, and transgene expression have been used, and mathematical modeling has been used for assessments of viral replication.15Wein LM Wu JT Kirn DH Validation and analysis of a mathematical model of a replication-competent oncolytic virus for cancer treatment: implications for virus design and delivery.Cancer Res. 2003; 63: 1317-1324PubMed Google Scholar Engineered oncolytic viruses pose unique chemistry, manufacturing, and controls issues that have been addressed. Well-characterized starting materials are required for each product, including at least three rounds of virus plaque purification. Verifying gene manipulation by sequencing the region of interest (and flanking sequences) is also now mandatory. Production of Master Cell Banks and Master Virus Banks is carried out under strict Good Manufacturing Practice and Good Laboratory Practice standards, with rigorous testing at several steps in the process. The final product also needs to be tested for identity, contamination, and potency before being used in humans. Additional regulatory chemistry, manufacturing, and controls requirements exist for third-generation oncolytic viruses, including characterizations of therapeutic and monitoring transgenes. Transgene product expression and function must be evaluated. Novel experimental therapeutics for cancer typically progress through a predictable series of developmental stages. These stages are driven as much by perception as they are by hard data. Many successfully approved therapies have followed this pathway. The stages can be categorized as follows: (1) idea development (2) unrealistic optimism (3) identification of technical difficulties and hurdles (4) unrealistic pessimism (5) problem solving, and (6) gradual progress leading to success. The development of targeted oncolytic viruses is no different from that of monoclonal antibodies or small molecules at this stage. The field is currently at stage 5 of development, where exciting iterative loops between bench and bedside are ongoing. Compared with chemotherapy or antibody- and small-molecule-based therapeutics, virotherapeutics have extremely diverse mechanisms of action, unique pharmacodynamics/pharmacokinetics, and an extensive interplay with the host. As we have demonstrated above, virotherapeutics are a novel treatment platform on which new findings in the laboratory can be translated into the clinic, and observations from clinical trials can be assessed and addressed in great detail in the laboratory. With recent advances in cancer biology, virology, and biotechnology, this therapeutic platform will continue to benefit from interdisciplinary collaboration and, as a result, will lead to breakthrough therapies for cancers.

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