Pediatr Blood Cancer 2015;62:739–740
HIGHLIGHT
by Gregory K. Friedman, MD*
Attack of the Cancer-Killing Viruses: Clinical Application of Oncolytic Virotherapy in Children
O
ncolytic virotherapy, which employs cytolytic viruses to infect and kill cancer cells, is a nascent field that offers great promise at targeting pediatric malignancies, yet challenges to the effective application of this therapy still exist. Oncolytic viruses are attractive cancer therapies because of their potential to target and kill cancer cells and create an antitumor immune response while sparing normal cells which results in less toxicity than conventional therapies. Furthermore, the method of cell killing by oncolytic viruses differs from conventional therapies and enables viruses to potentially elude mechanisms of chemotherapy and radiation resistance. Human pathogenic viruses such as herpes simplex virus-1 (HSV) or adenovirus contain genetically engineered mutations that prevent or limit replication in normal cells but permit replication in tumor cell. Non-pathogenic or mildly pathogenic viruses like Seneca Valley virus or reovirus may kill tumor cells that contain defective interferon responses or altered signaling pathways. To enhance the oncolytic effect, therapeutic foreign genes can be expressed in some engineered, armed viruses. These foreign genes can be used to improve viral replication in tumor cells, to augment the antitumor response elicited by the virus through the production of immune stimulating cytokines, or to target the tumor microenvironment. Preclinical studies have shown that a variety of RNA and DNA viruses can effectively target pediatric solid tumors, including chemotherapy and radiation-resistant cancer stem cells [1,2]. These studies have led to several pediatric clinical trials. Recent issues of Pediatric Blood & Cancer highlight the advancement of oncolytic virotherapy to clinical application in children with reports on the first cooperative group phase I trials of oncolytic viruses. Both trials proved the feasibility and safety of this approach in children. Burke et al. described the clinical use of Seneca Valley virus (NTX-010), a single-stranded RNA virus in the Picornaviridae family, which does not cause disease in humans but effectively killed a variety of pediatric solid tumors in preclinical studies [3–5]. The virus was safely administered intravenously at multiple dose levels, combined with oral cyclophosphamide, and given in two doses 21 days apart in children with recurrent or refractory solid tumors. There was a single dose limiting toxicity (DLT) (grade 3 pain) at dose level 1 and a few grade 3 or 4 related adverse events that were manageable. All patients cleared the virus from blood and stool within three weeks and nearly all developed neutralizing antibodies, which appeared to limit applicability as there were no objective responses. However, 10 of 16 patients had stable disease at the time of disease re-evaluation, suggesting that further studies with Seneca Valley virus are warranted.
C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25366 Published online 7 February 2015 in Wiley Online Library (wileyonlinelibrary.com).
Kolb et al. reported on the use of intravenous reovirus (Reolysin), a double stranded RNA virus in the Reoviridae family which causes mild to no gastrointestinal or respiratory symptoms and selectively replicated in Ras-activated pediatric cancer cells in preclinical studies [6,7]. Reovirus was safely administered alone for five consecutive days of a 28-day cycle or combined with oral cyclophosphamide in 24 patients with relapsed/refractory extracranial solid tumors. There were no DLTs although grade 5 respiratory failure and a thromboembolic event were reported in the setting of disease progression. No virus was detected in the saliva or stool, and the average time of reovirus viremia clearance was 6.5 days with no viremia seen after day 17. Similar to the Burke et al. study, no objective responses were seen, although there were three patients with stable disease who received a second cycle. In addition to these trials, several other pediatric oncolytic virotherapy trials are being conducted at a limited number of institutions. JX-594 (Pexa-Vec), a double-stranded vaccinia virus in the poxvirus family which possesses a thymidine kinase gene deletion to provide replication selectivity to tumor cells and a GM-CSF gene insertion to stimulate a systemic antitumor immune response, has been safely injected intratumorally in six pediatric patients [8]. Toxicities were grade 3, and four of six patients had stable disease in the injected target lesion with imaging evidence suggestive of an anti-tumor response in one patient. Trials of intratumoral oncolytic HSV (HSV1716), a double-stranded DNA, cytolytic virus with deletion of the virulence gene g134.5, are ongoing in patients with recurrent non-central nervous system (CNS) solid tumors (ClinicalTrials.gov identifier NCT00931931) and CNS tumors (NCT02031965). An intravenous cohort has been added to the non-CNS trial. Although the phase I trials reported in Pediatric Blood & Cancer were not designed to determine efficacy, significant responses were not seen. Developing effective viruses remains the primary challenge for researchers. Defining which viruses are most Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama Conflict of interest: Nothing to declare.
Correspondence to: Gregory K. Friedman, Children’s of Alabama, 1600 7th Avenue South, ACC 512, Birmingham, AL 35233. E-mail: [email protected] Received 30 October 2014; Accepted 31 October 2014
740
Friedman
efficacious for treating different tumor types, identifying tumor biomarkers that can help distinguish patients most likely to respond to a specific virus, and determining mechanisms of therapeutic resistance to virotherapy are critical as tumor genotype and phenotype heterogeneity may limit viral efficacy. To maximize virotherapy, a better understanding of the tumor microenvironment and how it can be disrupted to enhance viral cell killing and boost the antitumor immune response are needed. The ideal balance between the oncolytic effect of the virus and the immune response engendered by the virus must be elucidated. Determining the most effective ways to deliver each class of virus to tumor cells is essential for targeting both local and metastatic disease. Lastly, oncolytic virotherapy combination approaches with convention chemotherapy and radiation, small molecule inhibitors, monoclonal antibodies, and/or other viruses with different mechanisms of attack are likely to work synergistically and provide a greater treatment effect than virus alone. Thus, combination strategies must be developed and tested. As the important questions of feasibility and safety of utilizing oncolytic viruses in children are being answered with recent and current trials, researchers can focus on overcoming
Pediatr Blood Cancer DOI 10.1002/pbc
the various challenges that still exist, so that more effective viruses and treatment regimens incorporating viruses can be designed.
REFERENCES 1. Hammill AM, Conner J, Cripe TP. Oncolytic virotherapy reaches adolescence. Pediatr Blood Cancer 2010:55:1253–1263. 2. Friedman GK, Cassady KA, Beierle EA, Markert JM, Gillespie GY. Targeting pediatric cancer stem cells with oncolytic virotherapy. Pediatr Res 2012:71:500–510. 3. Burke MJ, Ahern C, Weigel BJ, Poirier JT, Rudin CM, Chen Y, Cripe TP, Bernhardt MB, Blaney SM. Phase I trial of seneca valley virus (NTX-010) in children with relapsed/refractory solid tumors: A report of the children’s oncology group. Pediatr Blood Cancer 2014. 4. Reddy PS, Burroughs KD, Hales LM, Ganesh S, Jones BH, Idamakanti N, Hay C, Li SS, Skele KL, Vasko AJ, Yang J, Watkins DN, Rudin CM, Hallenbeck PL. Seneca valley virus, a systemically deliverable oncolytic picornavirus, and the treatment of neuroendocrine cancers. J Natl Cancer I 2007:99:1623–1633. 5. Morton CL, Houghton PJ, Kolb EA, Gorlick R, Reynolds CP, Kang MH, Maris JM, Keir ST, Wu J, Smith MA. Initial testing of the replication competent seneca valley virus (NTX-010) by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 2010:55:295–303. 6. Hingorani P, Zhang WD, Lin JA, Liu L, Guha C, Kolb EA. Systemic administration of reovirus (reolysin) inhibits growth of human sarcoma xenografts. Cancer 2011:117:1764–1774. 7. Kolb EA, Sampson V, Stabley D, Walter A, Sol-Church K, Cripe T, Hingorani P, Ahern CH, Weigel BJ, Zwiebel J, Blaney SM. A phase I trial and viral clearance study of reovirus (Reolysin) in children with relapsed or refractory extra-cranial solid tumors: A Children’s Oncology Group phase I consortium report. Pediatr Blood Cancer 2014. 8. Cripe TP, Ngo MC, Geller JI, Louis CU, Currier MA, Racadio JM, Towbin AJ, Rooney CM, Pelusio A, Moon A, Hwang T, Burke JM, Kirn DH, Bell JC, Breitbach CJ. Phase I study of intratumoral Pexa-Vec (JX -594), an oncolytic and immunotherapeutic vaccinia virus, in pediatric cancer patients. Mol Ther 2015.
HIGHLIGHT
by Gregory K. Friedman, MD*
Attack of the Cancer-Killing Viruses: Clinical Application of Oncolytic Virotherapy in Children
O
ncolytic virotherapy, which employs cytolytic viruses to infect and kill cancer cells, is a nascent field that offers great promise at targeting pediatric malignancies, yet challenges to the effective application of this therapy still exist. Oncolytic viruses are attractive cancer therapies because of their potential to target and kill cancer cells and create an antitumor immune response while sparing normal cells which results in less toxicity than conventional therapies. Furthermore, the method of cell killing by oncolytic viruses differs from conventional therapies and enables viruses to potentially elude mechanisms of chemotherapy and radiation resistance. Human pathogenic viruses such as herpes simplex virus-1 (HSV) or adenovirus contain genetically engineered mutations that prevent or limit replication in normal cells but permit replication in tumor cell. Non-pathogenic or mildly pathogenic viruses like Seneca Valley virus or reovirus may kill tumor cells that contain defective interferon responses or altered signaling pathways. To enhance the oncolytic effect, therapeutic foreign genes can be expressed in some engineered, armed viruses. These foreign genes can be used to improve viral replication in tumor cells, to augment the antitumor response elicited by the virus through the production of immune stimulating cytokines, or to target the tumor microenvironment. Preclinical studies have shown that a variety of RNA and DNA viruses can effectively target pediatric solid tumors, including chemotherapy and radiation-resistant cancer stem cells [1,2]. These studies have led to several pediatric clinical trials. Recent issues of Pediatric Blood & Cancer highlight the advancement of oncolytic virotherapy to clinical application in children with reports on the first cooperative group phase I trials of oncolytic viruses. Both trials proved the feasibility and safety of this approach in children. Burke et al. described the clinical use of Seneca Valley virus (NTX-010), a single-stranded RNA virus in the Picornaviridae family, which does not cause disease in humans but effectively killed a variety of pediatric solid tumors in preclinical studies [3–5]. The virus was safely administered intravenously at multiple dose levels, combined with oral cyclophosphamide, and given in two doses 21 days apart in children with recurrent or refractory solid tumors. There was a single dose limiting toxicity (DLT) (grade 3 pain) at dose level 1 and a few grade 3 or 4 related adverse events that were manageable. All patients cleared the virus from blood and stool within three weeks and nearly all developed neutralizing antibodies, which appeared to limit applicability as there were no objective responses. However, 10 of 16 patients had stable disease at the time of disease re-evaluation, suggesting that further studies with Seneca Valley virus are warranted.
C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25366 Published online 7 February 2015 in Wiley Online Library (wileyonlinelibrary.com).
Kolb et al. reported on the use of intravenous reovirus (Reolysin), a double stranded RNA virus in the Reoviridae family which causes mild to no gastrointestinal or respiratory symptoms and selectively replicated in Ras-activated pediatric cancer cells in preclinical studies [6,7]. Reovirus was safely administered alone for five consecutive days of a 28-day cycle or combined with oral cyclophosphamide in 24 patients with relapsed/refractory extracranial solid tumors. There were no DLTs although grade 5 respiratory failure and a thromboembolic event were reported in the setting of disease progression. No virus was detected in the saliva or stool, and the average time of reovirus viremia clearance was 6.5 days with no viremia seen after day 17. Similar to the Burke et al. study, no objective responses were seen, although there were three patients with stable disease who received a second cycle. In addition to these trials, several other pediatric oncolytic virotherapy trials are being conducted at a limited number of institutions. JX-594 (Pexa-Vec), a double-stranded vaccinia virus in the poxvirus family which possesses a thymidine kinase gene deletion to provide replication selectivity to tumor cells and a GM-CSF gene insertion to stimulate a systemic antitumor immune response, has been safely injected intratumorally in six pediatric patients [8]. Toxicities were grade 3, and four of six patients had stable disease in the injected target lesion with imaging evidence suggestive of an anti-tumor response in one patient. Trials of intratumoral oncolytic HSV (HSV1716), a double-stranded DNA, cytolytic virus with deletion of the virulence gene g134.5, are ongoing in patients with recurrent non-central nervous system (CNS) solid tumors (ClinicalTrials.gov identifier NCT00931931) and CNS tumors (NCT02031965). An intravenous cohort has been added to the non-CNS trial. Although the phase I trials reported in Pediatric Blood & Cancer were not designed to determine efficacy, significant responses were not seen. Developing effective viruses remains the primary challenge for researchers. Defining which viruses are most Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama Conflict of interest: Nothing to declare.
Correspondence to: Gregory K. Friedman, Children’s of Alabama, 1600 7th Avenue South, ACC 512, Birmingham, AL 35233. E-mail: [email protected] Received 30 October 2014; Accepted 31 October 2014
740
Friedman
efficacious for treating different tumor types, identifying tumor biomarkers that can help distinguish patients most likely to respond to a specific virus, and determining mechanisms of therapeutic resistance to virotherapy are critical as tumor genotype and phenotype heterogeneity may limit viral efficacy. To maximize virotherapy, a better understanding of the tumor microenvironment and how it can be disrupted to enhance viral cell killing and boost the antitumor immune response are needed. The ideal balance between the oncolytic effect of the virus and the immune response engendered by the virus must be elucidated. Determining the most effective ways to deliver each class of virus to tumor cells is essential for targeting both local and metastatic disease. Lastly, oncolytic virotherapy combination approaches with convention chemotherapy and radiation, small molecule inhibitors, monoclonal antibodies, and/or other viruses with different mechanisms of attack are likely to work synergistically and provide a greater treatment effect than virus alone. Thus, combination strategies must be developed and tested. As the important questions of feasibility and safety of utilizing oncolytic viruses in children are being answered with recent and current trials, researchers can focus on overcoming
Pediatr Blood Cancer DOI 10.1002/pbc
the various challenges that still exist, so that more effective viruses and treatment regimens incorporating viruses can be designed.
REFERENCES 1. Hammill AM, Conner J, Cripe TP. Oncolytic virotherapy reaches adolescence. Pediatr Blood Cancer 2010:55:1253–1263. 2. Friedman GK, Cassady KA, Beierle EA, Markert JM, Gillespie GY. Targeting pediatric cancer stem cells with oncolytic virotherapy. Pediatr Res 2012:71:500–510. 3. Burke MJ, Ahern C, Weigel BJ, Poirier JT, Rudin CM, Chen Y, Cripe TP, Bernhardt MB, Blaney SM. Phase I trial of seneca valley virus (NTX-010) in children with relapsed/refractory solid tumors: A report of the children’s oncology group. Pediatr Blood Cancer 2014. 4. Reddy PS, Burroughs KD, Hales LM, Ganesh S, Jones BH, Idamakanti N, Hay C, Li SS, Skele KL, Vasko AJ, Yang J, Watkins DN, Rudin CM, Hallenbeck PL. Seneca valley virus, a systemically deliverable oncolytic picornavirus, and the treatment of neuroendocrine cancers. J Natl Cancer I 2007:99:1623–1633. 5. Morton CL, Houghton PJ, Kolb EA, Gorlick R, Reynolds CP, Kang MH, Maris JM, Keir ST, Wu J, Smith MA. Initial testing of the replication competent seneca valley virus (NTX-010) by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 2010:55:295–303. 6. Hingorani P, Zhang WD, Lin JA, Liu L, Guha C, Kolb EA. Systemic administration of reovirus (reolysin) inhibits growth of human sarcoma xenografts. Cancer 2011:117:1764–1774. 7. Kolb EA, Sampson V, Stabley D, Walter A, Sol-Church K, Cripe T, Hingorani P, Ahern CH, Weigel BJ, Zwiebel J, Blaney SM. A phase I trial and viral clearance study of reovirus (Reolysin) in children with relapsed or refractory extra-cranial solid tumors: A Children’s Oncology Group phase I consortium report. Pediatr Blood Cancer 2014. 8. Cripe TP, Ngo MC, Geller JI, Louis CU, Currier MA, Racadio JM, Towbin AJ, Rooney CM, Pelusio A, Moon A, Hwang T, Burke JM, Kirn DH, Bell JC, Breitbach CJ. Phase I study of intratumoral Pexa-Vec (JX -594), an oncolytic and immunotherapeutic vaccinia virus, in pediatric cancer patients. Mol Ther 2015.
