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Gilead pushes towards pangenotypic and shorter HCV treatments p575
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Amgen’s T-Vec (talimogene laherparepvec) is set to become the first oncolytic virus to gain approval in a Western jurisdiction, following the recent 22–1 vote in favor of approval in melanoma from an expert panel drawn from the US Food and Drug Administration (FDA)’s Cellular, Tissue and Gene Therapies Advisory Committee and Oncologic Drugs Advisory Committee. The near unanimity of the vote belied both the critical tone of the FDA documentation released in advance of the April 29 panel meeting and the doubtful stance adopted by several FDA reviewers during the hearing. Its forthcoming approval will be a milestone for this form of cancer immunotherapy, which has had a long and checkered history. The FDA’s deadline for a decision under the Prescription Drug User Fee Act is October 27. “It’s very important for the field that any virus gets approved,” says Oliver Ebert, assistant medical director and group leader at the Department of Internal Medicine, School of Medicine at the Technical University of Munich. “It’s a first step.” Although there is little doubt that T-Vec is safe, its efficacy and its utility—as a monotherapy, at least—are limited. When set against the potency of antibody drugs targeting immune checkpoints, its direct and indirect immuno stimulatory effects against cancer are modest. Paradoxically, however, the advent of immune checkpoint inhibitors has given this technology a boost—preliminary data indicate that T-Vec has more potential when administered in combination with such agents. Initial sales forecasts for T-Vec are low. New York-based investment bank Cowen and Company puts its annual sales potential in melanoma at no more than $200 million, given the limited patient population the product addresses. “This is because patients with melanoma that is advanced enough to be unresectable, but not advanced enough to require aggressive systemic approaches, are uncommon,” Eric Schmidt, Cowen’s managing director and senior research analyst wrote in a quarterly review of Thousand Oaks, California–based Amgen earlier this year. The panel assessed T-Vec on the basis of results from an open-label phase 3 trial, called
Nature Reviews Cancer 14, 565 (2014)
First oncolytic virus edges towards approval in surprise vote
Coupling oncolytic viruses (OV) with new immunotherapies such as checkpoint inhibitors and CAR-T cells has given the field a boost.
OPTiM, in 436 patients with advanced, unresectable melanoma. These were assigned, in a 2:1 ratio, to have T-Vec injected directly into lesions located on or just beneath the surface of the skin or within the lymph nodes, or a control therapy, the immunostimulatory cytokine granulocyte macrophage colony-stimulating factor (GM-CSF). The primary endpoint was the rate of durable response—defined as a complete or a partial response—lasting for a minimum of six months. Those in the T-Vec arm achieved a durable response rate of 16%, versus 2% for those in the control arm. Median overall survival was 23.3 months for the T-Vec arm versus 18.9 months for the control arm. The systemic effects of T-Vec, measured by its impact on distal, noninjected lesions, were minimal. Just 9% (16/177) of visceral, noninjected lesions exhibited a complete response to therapy during the study; 22% (212/981) of nonvisceral, noninjected lesions did. In contrast, 64.3%(1,361/2,116) of injected lesions shrunk by at least 50%; 47% of the total (995/2,116) were completely resolved. The FDA was critical of this assessment, however, as some of the noninjected lesions included in the analysis “appeared to be too small for reliable assessment.” Moreover, Amgen failed to back up its imaging data with any supporting immunological biomarker data pointing to a clinical response. In T-Vec’s favor, it has a relatively benign safety profile, in marked contrast to immune checkpoint inhibitors, which can have severe, immune-related side effects. What’s more, it appears to have a synergistic effect when administered with immune checkpoint
nature biotechnology volume 33 NUMBER 6 juNE 2015
inhibitors. Melanoma patients on T-Vec plus the cytotoxic T-lymphocyte antigen 4 (CTLA4) blocker Yervoy (ipilimumab; Bristol-Myers Squibb, New York) attained an objective response rate of 56% and a complete response rate of 33% in a phase 1b study, as reported at the HemOnc Today meeting in New York on April 23. “The responses were certainly much greater than I would expect from ipilimumab alone,” says Dmitriy Zamarin, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. Moreover, no dose-limiting toxicities were observed. A phase 2 trial comparing the combination with Yervoy, which is recruiting 200 patients, is ongoing. As Nature Biotechnology went to press, preliminary data from a combination of T-Vec and the programmed cell death 1 (PD-1) inhibitor Keytruda (pembrolizumab) were due to be unveiled at the American Society of Clinical Oncology meeting in Chicago. A phase 3 trial of this combination is already underway. In combination settings, the main function of T-Vec—and potentially other oncolytic viruses (Table 1)—is to create an inflammatory milieu within the tumor microenvironment. Patients with a pre-existing immune response to a tumor tend to have a better response to immune checkpoint modulation therapy than those who have none. But drumming up widespread infection to prompt cancer cells—the goal of oncolytic virus developers for decades—is not very realistic, says Zamarin, as the virus can be quickly cleared by the immune system. Malcolm McColl, CEO of Sydney-based Viralytics concurs. His company is testing both intravenous and 569
NEWS
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© 2015 Nature America, Inc. All rights reserved.
Table 1 Oncolytic viruses in clinical development Agent
Developer
Description
Lead indications
Clinical status
Oncorine (H101)
Shanghai Sunway Biotech (Shanghai)
Recombinant human adenovirus type 5 with E1B deletion conferring conditional replication in p53-deficient cancer cells
Head and neck cancer, lung cancer, liver cancer, advanced cancers with malignant pleural and peritoneal effusions
Approved in China 2005
Talimogene laherparepvec (T-Vec)
Amgen
Modified HSV-1 carrying ICP34.5 and ICP47 deletions, expressing US11 as an immediate early gene and GM-CSF
Metastatic melanoma
FDA review
Reolysin, a variant of reovirus
Oncolytics Biotech (Calgary, Canada)
Wild-type double-stranded RNA virus
Head and neck cancer
Phase 3
CG0070
Cold Genesys (Newport Beach, California)
Adenovirus expressing GM-CSF
Bladder cancer
Phase 2/3
Pexastimogene devacirepvec (Pexa-Vec, JX-594)
SillaJen (Busan, South Korea)
Modified vaccinia virus with thymidine kinase deletion and GM-CSF insertion
Hepatocellular carcinoma
Phase 2b
Cavatak
Viralytics
Unmodified Coxsackie virus A21
Unresectable melanoma
Phase 2
Enadenotucirev
PsiOxus Therapeutics (Abingdon, UK)
Chimeric adenovirus based on Ad3 and Ad11p, obtained through directed evolution
Colorectal cancer, bladder cancer, ovarian cancer
Phase 1/2
GL-ONC1
Genelux (San Diego)
Attenuated vaccinia virus, Lister strain
Solid tumors
Phase 1/2
ParvOryx
ORYX (Baldham, Germany)
Parvovirus H1 (wild-type rat virus)
Glioblastoma multiforme
Phase 1/2a
Seprehevir (HSV1716)
VIRTTU Biologics (Glasgow, UK)
Mutant HSV virus with deletions in RL1 gene encoding protein ICP34.5
Malignant pleural mesothelioma, highgrade glioma, solid tumors
Phase 1/2a
DNX-2401
DNAtrix (Houston)
Glioblastoma Modified adenovirus with a deletion in the retinoblastoma-binding domain of the E1A protein and encoding an integrinbinding RGD-4C peptide
Phase 1b
Oncolytic vesicular stomatitis virus (VSV)
MedImmune, Omnis Pharma
Recombinant VSV expressing interferon-β Sorafenib-refractory liver cancer
Phase 1
ONCOS-102
Oncos Therapeutics (Helsinki, Finland)
Chimeric adenovirus encoding GM-CSF
Phase 1
TBI-1401 (HF10)
Takara Bio (Otsu, Shiga, Japan)
Spontaneously attenuated HSV-1 mutant
Solid tumors with superficial lesions
Phase 1
VCN-01
VCN Biosciences (Barcelona, Spain)
Oncolytic adenovirus expressing PH20 hyaluronidase to break down tumor extracellular matrix
Advanced solid tumors, advanced pancreatic cancer
Phase 1
Soft tissue sarcoma, mesothelioma, ovarian cancer
Source: clinicaltrials.gov, company websites
intratumoral administration routes with an unmodified Coxsackie virus (Cavatak) selected for its activity. The goal in either setting is the same, to direct an immune response against the tumor, regardless of the administration route. A small-scale trial of the virus in combination with Yervoy is also underway, and others are in the offing. “I think it’s all going to play out as a combination therapy,” McColl says. Within those combinations, which virus represents the best option for cancer immunotherapy remains an open question for now, given the immaturity of the field. T-Vec is based on a strain of herpes simplex virus 1 (HSV-1) that has been genetically modified to both express GM-CSF and ensure it grows selectively in cancer cells. But virus size and tissue tropism—which can be altered by pseudotyping to improve selectivity for cancer cells—immunogenicity and cancer-cell-killing potency all contribute to the activity of a given virus. E a r l i e r t h i s y e a r, L o n d o n - b a s e d AstraZeneca’s MedImmune arm entered a development agreement with Rochester,
570
Minnesota–based Omnis Pharmaceuticals, based on the latter’s vesicular stomatitis virus (VSV), developed by Omnis founder Stephen Russell of the Mayo Clinic, in Rochester. “This virus is a very potent virus—it replicates very fast,” says Ebert. To alleviate potential toxicity in noncancerous cells, it has been modified to express the anti-viral cytokine interferon-β. Ebert’s laboratory recently published preclinical research on an alternative strategy for ensuring the safety of VSV (Cancer Gene Ther. doi:10.1038/cgt.2015.23, 1 May 2015). “We found that adding the STAT3 signal transducer and activator of transcription 3 inhibitor can protect normal cells from virus-induced toxicity,” he says. STAT3, a transcription factor whose constitutive overexpression is associated with many tumor types, is already a target for investigational drugs, and its co-administration with VSV could allow higher doses of the virus to be administered. Zamarin and colleagues have demonstrated in a mouse melanoma model that
intratumoral delivery of Newcastle disease virus, an avian pathogen that is largely harmless in humans, can lead to infiltration of distant tumors by activated lymphocytes, even in the absence of viral spread (Sci. Transl. Med. 6, 226ra32, 2014). This renders the tumors sensitive to Yervoy therapy. Zamarin’s group is now working on a ‘good manufacturing process’, with a view to taking this concept into the clinic, although he first aims to modify the virus with an immunoactive payload that would further enhance the immunogenicity of the virus. The line between oncolytic viruses and viral vaccines is already blurred. Eventually, they could become complex systems encompassing several activities within one construct. These remain preclinical concepts that have yet to enter the clinic, however. In the meantime, compelling data from trials of combination therapies could finally bring oncolytic viruses from the margins to the mainstream of cancer immunotherapy. Cormac Sheridan Dublin
volume 33 NUMBER 6 juNE 2015 nature biotechnology
Gilead pushes towards pangenotypic and shorter HCV treatments p575
Alnylam’s RNAi therapy in amyloid disease p577
npg
© 2015 Nature America, Inc. All rights reserved.
Amgen’s T-Vec (talimogene laherparepvec) is set to become the first oncolytic virus to gain approval in a Western jurisdiction, following the recent 22–1 vote in favor of approval in melanoma from an expert panel drawn from the US Food and Drug Administration (FDA)’s Cellular, Tissue and Gene Therapies Advisory Committee and Oncologic Drugs Advisory Committee. The near unanimity of the vote belied both the critical tone of the FDA documentation released in advance of the April 29 panel meeting and the doubtful stance adopted by several FDA reviewers during the hearing. Its forthcoming approval will be a milestone for this form of cancer immunotherapy, which has had a long and checkered history. The FDA’s deadline for a decision under the Prescription Drug User Fee Act is October 27. “It’s very important for the field that any virus gets approved,” says Oliver Ebert, assistant medical director and group leader at the Department of Internal Medicine, School of Medicine at the Technical University of Munich. “It’s a first step.” Although there is little doubt that T-Vec is safe, its efficacy and its utility—as a monotherapy, at least—are limited. When set against the potency of antibody drugs targeting immune checkpoints, its direct and indirect immuno stimulatory effects against cancer are modest. Paradoxically, however, the advent of immune checkpoint inhibitors has given this technology a boost—preliminary data indicate that T-Vec has more potential when administered in combination with such agents. Initial sales forecasts for T-Vec are low. New York-based investment bank Cowen and Company puts its annual sales potential in melanoma at no more than $200 million, given the limited patient population the product addresses. “This is because patients with melanoma that is advanced enough to be unresectable, but not advanced enough to require aggressive systemic approaches, are uncommon,” Eric Schmidt, Cowen’s managing director and senior research analyst wrote in a quarterly review of Thousand Oaks, California–based Amgen earlier this year. The panel assessed T-Vec on the basis of results from an open-label phase 3 trial, called
Nature Reviews Cancer 14, 565 (2014)
First oncolytic virus edges towards approval in surprise vote
Coupling oncolytic viruses (OV) with new immunotherapies such as checkpoint inhibitors and CAR-T cells has given the field a boost.
OPTiM, in 436 patients with advanced, unresectable melanoma. These were assigned, in a 2:1 ratio, to have T-Vec injected directly into lesions located on or just beneath the surface of the skin or within the lymph nodes, or a control therapy, the immunostimulatory cytokine granulocyte macrophage colony-stimulating factor (GM-CSF). The primary endpoint was the rate of durable response—defined as a complete or a partial response—lasting for a minimum of six months. Those in the T-Vec arm achieved a durable response rate of 16%, versus 2% for those in the control arm. Median overall survival was 23.3 months for the T-Vec arm versus 18.9 months for the control arm. The systemic effects of T-Vec, measured by its impact on distal, noninjected lesions, were minimal. Just 9% (16/177) of visceral, noninjected lesions exhibited a complete response to therapy during the study; 22% (212/981) of nonvisceral, noninjected lesions did. In contrast, 64.3%(1,361/2,116) of injected lesions shrunk by at least 50%; 47% of the total (995/2,116) were completely resolved. The FDA was critical of this assessment, however, as some of the noninjected lesions included in the analysis “appeared to be too small for reliable assessment.” Moreover, Amgen failed to back up its imaging data with any supporting immunological biomarker data pointing to a clinical response. In T-Vec’s favor, it has a relatively benign safety profile, in marked contrast to immune checkpoint inhibitors, which can have severe, immune-related side effects. What’s more, it appears to have a synergistic effect when administered with immune checkpoint
nature biotechnology volume 33 NUMBER 6 juNE 2015
inhibitors. Melanoma patients on T-Vec plus the cytotoxic T-lymphocyte antigen 4 (CTLA4) blocker Yervoy (ipilimumab; Bristol-Myers Squibb, New York) attained an objective response rate of 56% and a complete response rate of 33% in a phase 1b study, as reported at the HemOnc Today meeting in New York on April 23. “The responses were certainly much greater than I would expect from ipilimumab alone,” says Dmitriy Zamarin, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. Moreover, no dose-limiting toxicities were observed. A phase 2 trial comparing the combination with Yervoy, which is recruiting 200 patients, is ongoing. As Nature Biotechnology went to press, preliminary data from a combination of T-Vec and the programmed cell death 1 (PD-1) inhibitor Keytruda (pembrolizumab) were due to be unveiled at the American Society of Clinical Oncology meeting in Chicago. A phase 3 trial of this combination is already underway. In combination settings, the main function of T-Vec—and potentially other oncolytic viruses (Table 1)—is to create an inflammatory milieu within the tumor microenvironment. Patients with a pre-existing immune response to a tumor tend to have a better response to immune checkpoint modulation therapy than those who have none. But drumming up widespread infection to prompt cancer cells—the goal of oncolytic virus developers for decades—is not very realistic, says Zamarin, as the virus can be quickly cleared by the immune system. Malcolm McColl, CEO of Sydney-based Viralytics concurs. His company is testing both intravenous and 569
NEWS
npg
© 2015 Nature America, Inc. All rights reserved.
Table 1 Oncolytic viruses in clinical development Agent
Developer
Description
Lead indications
Clinical status
Oncorine (H101)
Shanghai Sunway Biotech (Shanghai)
Recombinant human adenovirus type 5 with E1B deletion conferring conditional replication in p53-deficient cancer cells
Head and neck cancer, lung cancer, liver cancer, advanced cancers with malignant pleural and peritoneal effusions
Approved in China 2005
Talimogene laherparepvec (T-Vec)
Amgen
Modified HSV-1 carrying ICP34.5 and ICP47 deletions, expressing US11 as an immediate early gene and GM-CSF
Metastatic melanoma
FDA review
Reolysin, a variant of reovirus
Oncolytics Biotech (Calgary, Canada)
Wild-type double-stranded RNA virus
Head and neck cancer
Phase 3
CG0070
Cold Genesys (Newport Beach, California)
Adenovirus expressing GM-CSF
Bladder cancer
Phase 2/3
Pexastimogene devacirepvec (Pexa-Vec, JX-594)
SillaJen (Busan, South Korea)
Modified vaccinia virus with thymidine kinase deletion and GM-CSF insertion
Hepatocellular carcinoma
Phase 2b
Cavatak
Viralytics
Unmodified Coxsackie virus A21
Unresectable melanoma
Phase 2
Enadenotucirev
PsiOxus Therapeutics (Abingdon, UK)
Chimeric adenovirus based on Ad3 and Ad11p, obtained through directed evolution
Colorectal cancer, bladder cancer, ovarian cancer
Phase 1/2
GL-ONC1
Genelux (San Diego)
Attenuated vaccinia virus, Lister strain
Solid tumors
Phase 1/2
ParvOryx
ORYX (Baldham, Germany)
Parvovirus H1 (wild-type rat virus)
Glioblastoma multiforme
Phase 1/2a
Seprehevir (HSV1716)
VIRTTU Biologics (Glasgow, UK)
Mutant HSV virus with deletions in RL1 gene encoding protein ICP34.5
Malignant pleural mesothelioma, highgrade glioma, solid tumors
Phase 1/2a
DNX-2401
DNAtrix (Houston)
Glioblastoma Modified adenovirus with a deletion in the retinoblastoma-binding domain of the E1A protein and encoding an integrinbinding RGD-4C peptide
Phase 1b
Oncolytic vesicular stomatitis virus (VSV)
MedImmune, Omnis Pharma
Recombinant VSV expressing interferon-β Sorafenib-refractory liver cancer
Phase 1
ONCOS-102
Oncos Therapeutics (Helsinki, Finland)
Chimeric adenovirus encoding GM-CSF
Phase 1
TBI-1401 (HF10)
Takara Bio (Otsu, Shiga, Japan)
Spontaneously attenuated HSV-1 mutant
Solid tumors with superficial lesions
Phase 1
VCN-01
VCN Biosciences (Barcelona, Spain)
Oncolytic adenovirus expressing PH20 hyaluronidase to break down tumor extracellular matrix
Advanced solid tumors, advanced pancreatic cancer
Phase 1
Soft tissue sarcoma, mesothelioma, ovarian cancer
Source: clinicaltrials.gov, company websites
intratumoral administration routes with an unmodified Coxsackie virus (Cavatak) selected for its activity. The goal in either setting is the same, to direct an immune response against the tumor, regardless of the administration route. A small-scale trial of the virus in combination with Yervoy is also underway, and others are in the offing. “I think it’s all going to play out as a combination therapy,” McColl says. Within those combinations, which virus represents the best option for cancer immunotherapy remains an open question for now, given the immaturity of the field. T-Vec is based on a strain of herpes simplex virus 1 (HSV-1) that has been genetically modified to both express GM-CSF and ensure it grows selectively in cancer cells. But virus size and tissue tropism—which can be altered by pseudotyping to improve selectivity for cancer cells—immunogenicity and cancer-cell-killing potency all contribute to the activity of a given virus. E a r l i e r t h i s y e a r, L o n d o n - b a s e d AstraZeneca’s MedImmune arm entered a development agreement with Rochester,
570
Minnesota–based Omnis Pharmaceuticals, based on the latter’s vesicular stomatitis virus (VSV), developed by Omnis founder Stephen Russell of the Mayo Clinic, in Rochester. “This virus is a very potent virus—it replicates very fast,” says Ebert. To alleviate potential toxicity in noncancerous cells, it has been modified to express the anti-viral cytokine interferon-β. Ebert’s laboratory recently published preclinical research on an alternative strategy for ensuring the safety of VSV (Cancer Gene Ther. doi:10.1038/cgt.2015.23, 1 May 2015). “We found that adding the STAT3 signal transducer and activator of transcription 3 inhibitor can protect normal cells from virus-induced toxicity,” he says. STAT3, a transcription factor whose constitutive overexpression is associated with many tumor types, is already a target for investigational drugs, and its co-administration with VSV could allow higher doses of the virus to be administered. Zamarin and colleagues have demonstrated in a mouse melanoma model that
intratumoral delivery of Newcastle disease virus, an avian pathogen that is largely harmless in humans, can lead to infiltration of distant tumors by activated lymphocytes, even in the absence of viral spread (Sci. Transl. Med. 6, 226ra32, 2014). This renders the tumors sensitive to Yervoy therapy. Zamarin’s group is now working on a ‘good manufacturing process’, with a view to taking this concept into the clinic, although he first aims to modify the virus with an immunoactive payload that would further enhance the immunogenicity of the virus. The line between oncolytic viruses and viral vaccines is already blurred. Eventually, they could become complex systems encompassing several activities within one construct. These remain preclinical concepts that have yet to enter the clinic, however. In the meantime, compelling data from trials of combination therapies could finally bring oncolytic viruses from the margins to the mainstream of cancer immunotherapy. Cormac Sheridan Dublin
volume 33 NUMBER 6 juNE 2015 nature biotechnology
