editorial
© The American Society of Gene & Cell Therapy
doi:10.1038/mt.2015.94
Oncolytic Treatment for Cancer Recommended for Approval
T
he recent recommendation by members
of the US Food and Drug Administration’s (FDA’s) Oncologic Drugs Advisory Committee and Cellular, Tissue, and Gene Therapies Advisory Committee in favor of approval of the oncolytic immunotherapy talimogene laherparepvec (T-VEC) ushers in a new era of gene therapy in the United States. The final approval from the FDA, anticipated before October of this year, will fulfill the promise of oncolytic immunotherapy but will also raise many immediate challenges. T-VEC is an attenuated, replication-competent, oncolytic herpes simplex 1 virus engineered to produce the immunostimulatory cytokine granulocyte–macrophage colony-stimulating factor (GM-CSF) within the tumor. This virus-based immunotherapy both effects local tumor lysis and stimulates a systemic immunoreactivity to the cancer. Clinical testing of the agent in the OPTiM study involved 436 patients with unresected stage IIIB/C and IV melanoma who were randomized at a 2:1 ratio to receive intralesional T-VEC or subcutaneous GM-CSF. Administration of T-VEC produced a significant extension in durable response rates (TVEC, 16% vs. GM-CSF, 2%), which was the primary end point. The objective response rate was 26% vs. 6%, with a complete response rate of 11% vs. 1%, for T-VEC and GM-CSF, respectively. Of note, there was an extension in overall survival (a secondary end point) of 4.4-months with T-VEC vs. GM-CSF. Taking live, replication-competent viruses to human testing involves all of the complex issues surrounding production, quality control, and release criteria for biological agents that are inherently mutable. The mechanism of action of these agents differs from those of previous agents in that in vivo replication occurs after administration. This complicates the relationship of administered dose to tumor exposure. Whereas administration of attenuated viruses as vaccines at low dose produces little risk for the public, administration of cancer-therapeutic doses can result in significant shedding of potentially infectious virus. Such shedding must be tracked, and adverse effects on the patient and contacts must be monitored. Complicating matters is the fact that viral titers, if the targeted tumors are very permissive, may peak within days after administration. We will need rapid viral assays—perhaps ones that can
Molecular Therapy vol. 23 no. 7 july 2015
be performed remotely—to help identify secondary replication and shedding to correlate with response and toxicity of treatments. Regulations should not be so onerous, however, that they render delivery of potentially lifesaving treatments impractical or unaffordable. We must also consider that patients with natural herpetic sores are not quarantined, and most strains of oncolytic virus are attenuated and therefore safer than their wild-type counterparts. There are effective antiviral treatments for many of the viruses being tested in the clinic, including acyclovir and antiviral immunoglobulin. However, we will need rigorous guidelines for treatment with these antiviral agents when toxicity is encountered, so as to minimize risks of these agents while at the same time avoiding administration of antivirals so prematurely that they neutralize any potential anticancer efficacy. Hospitals and clinics will also face challenges inherent in administering, storing, transporting, and disposing of the virus. There will be a need to protect potentially immunocompromised patients and pregnant personnel. Local biosafety committees will need to determine the roles of infectious-disease consultations for each type of therapy. Hospitals and health systems will need to decide if they will offer such therapies or refer patients to specialized viral treatment centers. The greatest challenge will be optimization of viral production. In an age when small molecules and antibodies that cost dollars to produce are charged at thousands of dollars a dose, what are reasonable charges for viruses that cost tens of thousands of dollars to produce? Increasing the purity and yield of the production processes should reduce the cost of these agents so as to allow their use not only in the United States and other advanced economies but also in the developing world, where cancer is an even bigger killer. Despite these challenges, these are exciting times in the field of oncolytic virotherapy and gene therapy. Approval of T-VEC will not only translate into clinical benefit for patients with metastatic melanoma but also serve as a precedent for development of other gene therapies and possibly spur the creation of the clinical infrastructure necessary for this important new class of therapeutic.
Yuman Fong
Editor-in-Chief, Molecular Therapy — Oncolytics
1131
© The American Society of Gene & Cell Therapy
doi:10.1038/mt.2015.94
Oncolytic Treatment for Cancer Recommended for Approval
T
he recent recommendation by members
of the US Food and Drug Administration’s (FDA’s) Oncologic Drugs Advisory Committee and Cellular, Tissue, and Gene Therapies Advisory Committee in favor of approval of the oncolytic immunotherapy talimogene laherparepvec (T-VEC) ushers in a new era of gene therapy in the United States. The final approval from the FDA, anticipated before October of this year, will fulfill the promise of oncolytic immunotherapy but will also raise many immediate challenges. T-VEC is an attenuated, replication-competent, oncolytic herpes simplex 1 virus engineered to produce the immunostimulatory cytokine granulocyte–macrophage colony-stimulating factor (GM-CSF) within the tumor. This virus-based immunotherapy both effects local tumor lysis and stimulates a systemic immunoreactivity to the cancer. Clinical testing of the agent in the OPTiM study involved 436 patients with unresected stage IIIB/C and IV melanoma who were randomized at a 2:1 ratio to receive intralesional T-VEC or subcutaneous GM-CSF. Administration of T-VEC produced a significant extension in durable response rates (TVEC, 16% vs. GM-CSF, 2%), which was the primary end point. The objective response rate was 26% vs. 6%, with a complete response rate of 11% vs. 1%, for T-VEC and GM-CSF, respectively. Of note, there was an extension in overall survival (a secondary end point) of 4.4-months with T-VEC vs. GM-CSF. Taking live, replication-competent viruses to human testing involves all of the complex issues surrounding production, quality control, and release criteria for biological agents that are inherently mutable. The mechanism of action of these agents differs from those of previous agents in that in vivo replication occurs after administration. This complicates the relationship of administered dose to tumor exposure. Whereas administration of attenuated viruses as vaccines at low dose produces little risk for the public, administration of cancer-therapeutic doses can result in significant shedding of potentially infectious virus. Such shedding must be tracked, and adverse effects on the patient and contacts must be monitored. Complicating matters is the fact that viral titers, if the targeted tumors are very permissive, may peak within days after administration. We will need rapid viral assays—perhaps ones that can
Molecular Therapy vol. 23 no. 7 july 2015
be performed remotely—to help identify secondary replication and shedding to correlate with response and toxicity of treatments. Regulations should not be so onerous, however, that they render delivery of potentially lifesaving treatments impractical or unaffordable. We must also consider that patients with natural herpetic sores are not quarantined, and most strains of oncolytic virus are attenuated and therefore safer than their wild-type counterparts. There are effective antiviral treatments for many of the viruses being tested in the clinic, including acyclovir and antiviral immunoglobulin. However, we will need rigorous guidelines for treatment with these antiviral agents when toxicity is encountered, so as to minimize risks of these agents while at the same time avoiding administration of antivirals so prematurely that they neutralize any potential anticancer efficacy. Hospitals and clinics will also face challenges inherent in administering, storing, transporting, and disposing of the virus. There will be a need to protect potentially immunocompromised patients and pregnant personnel. Local biosafety committees will need to determine the roles of infectious-disease consultations for each type of therapy. Hospitals and health systems will need to decide if they will offer such therapies or refer patients to specialized viral treatment centers. The greatest challenge will be optimization of viral production. In an age when small molecules and antibodies that cost dollars to produce are charged at thousands of dollars a dose, what are reasonable charges for viruses that cost tens of thousands of dollars to produce? Increasing the purity and yield of the production processes should reduce the cost of these agents so as to allow their use not only in the United States and other advanced economies but also in the developing world, where cancer is an even bigger killer. Despite these challenges, these are exciting times in the field of oncolytic virotherapy and gene therapy. Approval of T-VEC will not only translate into clinical benefit for patients with metastatic melanoma but also serve as a precedent for development of other gene therapies and possibly spur the creation of the clinical infrastructure necessary for this important new class of therapeutic.
Yuman Fong
Editor-in-Chief, Molecular Therapy — Oncolytics
1131
