|
1
|
De S, Ehrlich M. Arrest and Attack: Microtubule-Targeting Agents and Oncolytic Viruses Employ Complementary Mechanisms to Enhance Anti-Tumor Therapy Efficacy. Genes (Basel) 2024; 15:1193. [PMID: 39336785 PMCID: PMC11431212 DOI: 10.3390/genes15091193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/25/2024] [Accepted: 09/04/2024] [Indexed: 09/30/2024] Open
Abstract
Oncolytic viruses (OVs) are promising cancer immunotherapy agents that stimulate anti-tumor immunity through the preferential infection and killing of tumor cells. OVs are currently under limited clinical usage, due in part to their restricted efficacy as monotherapies. Current efforts for enhancement of the therapeutic potency of OVs involve their combination with other therapy modalities, aiming at the concomitant exploitation of complementary tumor weaknesses. In this context, microtubule-targeting agents (MTAs) pose as an enticing option, as they perturb microtubule dynamics and function, induce cell-cycle arrest, and cause mitotic cell death. MTAs induce therapeutic benefit through cancer-cell-autonomous and non-cell-autonomous mechanisms and are a main component of the standard of care for different malignancies. However, off-target effects and acquired resistance involving distinct cellular and molecular mechanisms may limit the overall efficacy of MTA-based therapy. When combined, OVs and MTAs may enhance therapeutic efficacy through increases in OV infection and immunogenic cell death and a decreased probability of acquired resistance. In this review, we introduce OVs and MTAs, describe molecular features of their activity in cancer cells, and discuss studies and clinical trials in which the combination has been tested.
Collapse
Affiliation(s)
| | - Marcelo Ehrlich
- Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel;
| |
Collapse
|
|
2
|
Qi X. Advances in antitumour therapy with oncolytic herpes simplex virus combinations. Discov Oncol 2024; 15:302. [PMID: 39046631 PMCID: PMC11269532 DOI: 10.1007/s12672-024-01165-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 07/16/2024] [Indexed: 07/25/2024] Open
Abstract
Oncolytic Virus (OVs) is an emerging approach to tumour immunity that allows the use of natural or genetically modified viruses to specifically infect and lyse tumour cells without damaging normal cells. Oncolytic herpes simplex virus (oHSV) is one of the more widely researched and applied OVs in the field of oncology, which can directly kill tumour cells to promote anti-tumour immune responses. oHSV is one of the few viruses with good antiviral drugs, so oHSV is also more clinically safe. In recent years, in addition to monotherapy of oHSV in tumours, more and more studies have been devoted to exploring the anti-tumour effects of oHSV in combination with other therapeutic approaches. In this article we describe the progress of oHSV combination therapy against tumours in the nervous system, digestive system, reproductive system and other systems.
Collapse
Affiliation(s)
- Xuejiao Qi
- College of Basic Medical Sciences, China Three Gorges University, Yichang, Hubei, China.
| |
Collapse
|
|
3
|
Delic M, Boeswald V, Goepfert K, Pabst P, Moehler M. In vitro Characterization of Enhanced Human Immune Responses by GM-CSF Encoding HSV-1-Induced Melanoma Cells. Onco Targets Ther 2022; 15:1291-1307. [PMID: 36310770 PMCID: PMC9606445 DOI: 10.2147/ott.s350136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 09/23/2022] [Indexed: 01/24/2023] Open
Abstract
PURPOSE We studied the innate and adaptive immune response against melanoma cells after JS-1 (wild-type herpes simplex virus 1, wt HSV-1) or Talimogene laherparepvec (T-VEC) infection and evaluated the antitumoral efficacy in human melanoma cells. We analyzed the putative synergistic biological and immunological effects of JS-1 or T-VEC combined with cytostatic drugs in human tumor and immune cells. T-VEC is a genetically modified strain of HSV-1. Genetic modifications (insertion of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene) were made to attenuate the virus and increase selectivity for cancer cells. In addition to the direct oncolytic effect, we investigated the immune stimulatory effects of T-VEC by comparing it with JS-1. JS-1 is identical T-VEC except for the inserted GM-CSF gene. MATERIALS AND METHODS We analyzed the effects of T-VEC and JS-1 with cytostatic drugs in human tumor-immune cell coculture experiments. After coculture, the surface markers CD80, CD83 and CD86 were measured by fluorescence-activated cell sorting and the cytokines, interleukin (IL)-2, IL-6, tumor necrosis factor (TNF)-α and GM-CSF, by enzyme-linked immunosorbent assays. Furthermore, we analyzed the potential of the viruses to induce T cell activation, measured on the basis of CD4, CD8 and CD69. Analysis of these markers and cytokines allows for conclusions to be drawn concerning the maturation of dendritic cells (DCs) and the immunostimulatory effects of the treatment. RESULTS We documented increased activation of human cytotoxic T lymphocytes after infection by both HSV-1 strains and treatment with cytostatic drugs without significant differences between T-VEC and JS-1. CONCLUSION We demonstrated an immune response as a result of infection with both viruses, but T-VEC was in vitro not stronger than JS-1. The immunostimulatory effects of the viruses could be partially increased by chemotherapy, providing a rationale for future preclinical studies designed to explore T-VEC in combined regimens.
Collapse
Affiliation(s)
- Maike Delic
- University Medical Center of the Johannes Gutenberg University Mainz, 1st Department of Internal Medicine, Mainz, Germany,Correspondence: Maike Delic, University Medical Center of the Johannes Gutenberg University Mainz, 1st Department of Internal Medicine, Langenbeckstrasse 1, Mainz, 55131, Germany, Tel +49 6131 179803, Fax +49 6131 179657, Email
| | - Veronika Boeswald
- University Medical Center of the Johannes Gutenberg University Mainz, 1st Department of Internal Medicine, Mainz, Germany
| | - Katrin Goepfert
- University Medical Center of the Johannes Gutenberg University Mainz, 1st Department of Internal Medicine, Mainz, Germany
| | - Petra Pabst
- University Medical Center of the Johannes Gutenberg University Mainz, 1st Department of Internal Medicine, Mainz, Germany
| | - Markus Moehler
- University Medical Center of the Johannes Gutenberg University Mainz, 1st Department of Internal Medicine, Mainz, Germany
| |
Collapse
|
|
4
|
Todo T, Ino Y, Ohtsu H, Shibahara J, Tanaka M. A phase I/II study of triple-mutated oncolytic herpes virus G47∆ in patients with progressive glioblastoma. Nat Commun 2022; 13:4119. [PMID: 35864115 PMCID: PMC9304402 DOI: 10.1038/s41467-022-31262-y] [Citation(s) in RCA: 101] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 06/10/2022] [Indexed: 12/19/2022] Open
Abstract
Here, we report the results of a phase I/II, single-arm study (UMIN-CTR Clinical Trial Registry UMIN000002661) assessing the safety (primary endpoint) of G47∆, a triple-mutated oncolytic herpes simplex virus type 1, in Japanese adults with recurrent/progressive glioblastoma despite radiation and temozolomide therapies. G47Δ was administered intratumorally at 3 × 108 pfu (low dose) or 1 × 109 pfu (set dose), twice to identical coordinates within 5–14 days. Thirteen patients completed treatment (low dose, n = 3; set dose, n = 10). Adverse events occurred in 12/13 patients. The most common G47Δ-related adverse events were fever, headache and vomiting. Secondary endpoint was the efficacy. Median overall survival was 7.3 (95%CI 6.2–15.2) months and the 1-year survival rate was 38.5%, both from the last G47∆ administration. Median progression-free survival was 8 (95%CI 7–34) days from the last G47∆ administration, mainly due to immediate enlargement of the contrast-enhanced area of the target lesion on MRI. Three patients survived >46 months. One complete response (low dose) and one partial response (set dose) were seen at 2 years. Based on biopsies, post-administration MRI features (injection site contrast-enhancement clearing and entire tumor enlargement) likely reflected tumor cell destruction via viral replication and lymphocyte infiltration towards tumor cells, the latter suggesting the mechanism for “immunoprogression” characteristic to this therapy. This study shows that G47Δ is safe for treating recurrent/progressive glioblastoma and warrants further clinical development. G47Δ is a third-generation, triple-mutated oncolytic HSV-1 that has demonstrated anti-tumor efficacy in preclinical studies. Here the authors report the results of a phase I/II study of G47Δ in patients with recurrent or progressive glioblastoma.
Collapse
Affiliation(s)
- Tomoki Todo
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, and Department of Surgical Neuro-Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. .,Department of Neurosurgery, The University of Tokyo Hospital, Tokyo, Japan.
| | - Yasushi Ino
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, and Department of Surgical Neuro-Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Department of Neurosurgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Hiroshi Ohtsu
- Department of Data Science, National Center for Global Health and Medicine in Japan, Tokyo, Japan.,Leading Center for the Development and Research of Cancer Medicine, Juntendo University, Tokyo, Japan
| | - Junji Shibahara
- Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan
| | - Minoru Tanaka
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, and Department of Surgical Neuro-Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Department of Neurosurgery, The University of Tokyo Hospital, Tokyo, Japan
| |
Collapse
|
|
5
|
Spiesschaert B, Angerer K, Park J, Wollmann G. Combining Oncolytic Viruses and Small Molecule Therapeutics: Mutual Benefits. Cancers (Basel) 2021; 13:3386. [PMID: 34298601 PMCID: PMC8306439 DOI: 10.3390/cancers13143386] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/28/2021] [Accepted: 07/01/2021] [Indexed: 02/07/2023] Open
Abstract
The focus of treating cancer with oncolytic viruses (OVs) has increasingly shifted towards achieving efficacy through the induction and augmentation of an antitumor immune response. However, innate antiviral responses can limit the activity of many OVs within the tumor and several immunosuppressive factors can hamper any subsequent antitumor immune responses. In recent decades, numerous small molecule compounds that either inhibit the immunosuppressive features of tumor cells or antagonize antiviral immunity have been developed and tested for. Here we comprehensively review small molecule compounds that can achieve therapeutic synergy with OVs. We also elaborate on the mechanisms by which these treatments elicit anti-tumor effects as monotherapies and how these complement OV treatment.
Collapse
Affiliation(s)
- Bart Spiesschaert
- Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University Innsbruck, 6020 Innsbruck, Austria; (B.S.); (K.A.)
- Institute of Virology, Medical University Innsbruck, 6020 Innsbruck, Austria
- ViraTherapeutics GmbH, 6063 Rum, Austria
- Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach a.d. Riss, Germany;
| | - Katharina Angerer
- Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University Innsbruck, 6020 Innsbruck, Austria; (B.S.); (K.A.)
- Institute of Virology, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - John Park
- Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach a.d. Riss, Germany;
| | - Guido Wollmann
- Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University Innsbruck, 6020 Innsbruck, Austria; (B.S.); (K.A.)
- Institute of Virology, Medical University Innsbruck, 6020 Innsbruck, Austria
| |
Collapse
|
|
6
|
Oncolytic Herpes Simplex Virus and PI3K Inhibitor BKM120 Synergize to Promote Killing of Prostate Cancer Stem-like Cells. MOLECULAR THERAPY-ONCOLYTICS 2019; 13:58-66. [PMID: 31016228 PMCID: PMC6468160 DOI: 10.1016/j.omto.2019.03.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 03/21/2019] [Indexed: 01/08/2023]
Abstract
Novel therapies to override chemo-radiation resistance in prostate cancer (PCa) are needed. Prostate cancer sphere-forming cells (PCSCs) (also termed prostate cancer stem-like cells) likely participate in tumor progression and recurrence, and they are important therapeutic targets. We established PCSC-enriched spheres by culturing human (DU145) and murine (TRAMP-C2) PCa cells in growth factor-defined serum-free medium, and we characterized stem-like properties of clonogenicity and tumorigenicity. The efficacy of two different oncolytic herpes simplex viruses (oHSVs) (G47Δ and MG18L) in PCSCs was tested alone and in combination with radiation; chemotherapy; and inhibitors of phosphoinositide 3-kinase (PI3K), Wnt, and NOTCH in vitro; and, G47Δ was tested with the PI3K inhibitor BKM120 in a PCSC-derived tumor model in vivo. PCSCs were more tumorigenic than serum-cultured parental cells. Human and murine PCSCs were sensitive to oHSV and BKM120 killing in vitro, while the combination was synergistic. oHSV combined with radiation, docetaxel, Wnt, or NOTCH inhibitors was not. In athymic mice bearing DU145 PCSC-derived tumors, the combination of intra-tumoral G47Δ and systemic BKM120 induced complete regression of tumors in 2 of 7 animals, and it exhibited superior anti-tumor activity compared to either monotherapy alone, with no detectable toxicity. oHSV synergizes with BKM120 in killing PCSCs in vitro, and the combination markedly inhibits tumor growth, even inducing regression in vivo.
Collapse
|
|
7
|
Phan M, Watson MF, Alain T, Diallo JS. Oncolytic Viruses on Drugs: Achieving Higher Therapeutic Efficacy. ACS Infect Dis 2018; 4:1448-1467. [PMID: 30152676 DOI: 10.1021/acsinfecdis.8b00144] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Over the past 20 years there has been a dramatic expansion in the testing of oncolytic viruses (OVs) for the treatment of cancer. OVs are unique biotherapeutics that induce multimodal responses toward tumors, from direct cytopathic effects on cancer cells, to tumor associated blood vessel disruption, and ultimately potent stimulation of anti-tumor immune activation. These agents are highly targeted and can be efficacious as cancer treatments resulting in some patients experiencing complete tumor regression and even cures from OV monotherapy. However, most patients have limited responses with viral replication in tumors often found to be modest and transient. To augment OV replication, increase bystander killing of cancer cells, and/or stimulate stronger targeted anti-cancer immune responses, drug combination approaches have taken center stage for translation to the clinic. Here we comprehensively review drugs that have been combined with OVs to increase therapeutic efficacy, examining the proposed mechanisms of action, and we discuss trends in pharmaco-viral immunotherapeutic approaches currently being investigated.
Collapse
Affiliation(s)
- Michael Phan
- Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
| | - Margaret F. Watson
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
- Children’s Hospital of Eastern Ontario Research Institute, 401 Smyth Road Research Building 2, Second Floor, Room 2119, Ottawa, Ontario K1H 8L1, Canada
| | - Tommy Alain
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
- Children’s Hospital of Eastern Ontario Research Institute, 401 Smyth Road Research Building 2, Second Floor, Room 2119, Ottawa, Ontario K1H 8L1, Canada
| | - Jean-Simon Diallo
- Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
| |
Collapse
|
|
8
|
Abstract
The clinical effectiveness of immunotherapies for prostate cancer remains subpar compared with that for other cancers. The goal of most immunotherapies is the activation of immune effectors, such as T cells and natural killer cells, as the presence of these activated mediators positively correlates with patient outcomes. Clinical evidence shows that prostate cancer is immunogenic, accessible to the immune system, and can be targeted by antitumour immune responses. However, owing to the detrimental effects of prostate-cancer-associated immunosuppression, even the newest immunotherapeutic approaches fail to initiate the clinically desired antitumour immune reaction. Oncolytic viruses, originally used for their preferential cancer-killing activity, are now being recognized for their ability to overturn cancer-associated immune evasion and promote otherwise absent antitumour immunity. This oncolytic-virus-induced subversion of tumour-associated immunosuppression can potentiate the effectiveness of current immunotherapeutics, including immune checkpoint inhibitors (for example, antibodies against programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1), and cytotoxic T lymphocyte antigen 4 (CTLA4)) and chemotherapeutics that induce immunogenic cell death (for example, doxorubicin and oxaliplatin). Importantly, oncolytic-virus-induced antitumour immunity targets existing prostate cancer cells and also establishes long-term protection against future relapse. Hence, the strategic use of oncolytic viruses as monotherapies or in combination with current immunotherapies might result in the next breakthrough in prostate cancer immunotherapy.
Collapse
|
|
9
|
Simpson GR, Relph K, Harrington K, Melcher A, Pandha H. Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances. Oncolytic Virother 2016; 5:1-13. [PMID: 27579292 PMCID: PMC4996257 DOI: 10.2147/ov.s66083] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena.
Collapse
Affiliation(s)
- Guy R Simpson
- Department of Clinical and Experimental Medicine, Targeted Cancer Therapy, Faculty of Health and Medical Sciences, University of Surrey, Guildford
| | - Kate Relph
- Department of Clinical and Experimental Medicine, Targeted Cancer Therapy, Faculty of Health and Medical Sciences, University of Surrey, Guildford
| | - Kevin Harrington
- Targeted Therapy, The Institute of Cancer Research/The Royal Marsden NIHR Biomedical Research Centre, London
| | - Alan Melcher
- Targeted and Biological Therapies, Oncology and Clinical Research, Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, Leeds, UK
| | - Hardev Pandha
- Department of Clinical and Experimental Medicine, Targeted Cancer Therapy, Faculty of Health and Medical Sciences, University of Surrey, Guildford
| |
Collapse
|
|
10
|
Sokolowski NA, Rizos H, Diefenbach RJ. Oncolytic virotherapy using herpes simplex virus: how far have we come? Oncolytic Virother 2015; 4:207-19. [PMID: 27512683 PMCID: PMC4918397 DOI: 10.2147/ov.s66086] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Oncolytic virotherapy exploits the properties of human viruses to naturally cytolysis of cancer cells. The human pathogen herpes simplex virus (HSV) has proven particularly amenable for use in oncolytic virotherapy. The relative safety of HSV coupled with extensive knowledge on how HSV interacts with the host has provided a platform for manipulating HSV to enhance the targeting and killing of human cancer cells. This has culminated in the approval of talimogene laherparepvec for the treatment of melanoma. This review focuses on the development of HSV as an oncolytic virus and where the field is likely to head in the future.
Collapse
Affiliation(s)
- Nicolas As Sokolowski
- Centre for Virus Research, Westmead Millennium Institute for Medical Research, The University of Sydney, NSW, Australia
| | - Helen Rizos
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, NSW, Australia
| | - Russell J Diefenbach
- Centre for Virus Research, Westmead Millennium Institute for Medical Research, The University of Sydney, NSW, Australia
| |
Collapse
|
|
11
|
Miao L, Fraefel C, Sia KC, Newman JP, Mohamed-Bashir SA, Ng WH, Lam PYP. The potential application of a transcriptionally regulated oncolytic herpes simplex virus for human cancer therapy. Br J Cancer 2014; 110:94-106. [PMID: 24196790 PMCID: PMC3887293 DOI: 10.1038/bjc.2013.692] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 10/03/2013] [Accepted: 10/09/2013] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer therapy. METHODS Using bacterial artificial chromosome (BAC) recombineering, a cell cycle-regulatable luciferase transgene cassette was replaced with the infected cell protein 6 (ICP6) coding region (encoded for UL39 or large subunit of ribonucleotide reductase) of the HSV-1 genome. These recombinant viruses, YE-PC8, were further tested for its proliferation-dependent luciferase gene expression. RESULTS The ability of YE-PC8 to confer proliferation-dependent transgene expression was demonstrated by injecting similar amount of viruses into the tumour-bearing region of the brain and the contralateral normal brain parenchyma of the same mouse. The results showed enhanced levels of luciferase activities in the tumour region but not in the normal brain parenchyma. Similar findings were observed in YE-PC8-infected short-term human brain patient-derived glioma cells compared with normal human astrocytes. intratumoural injection of YE-PC8 viruses resulted in 77% and 80% of tumour regression in human glioma and human hepatocellular carcinoma xenografts, respectively. CONCLUSION YE-PC8 viruses confer tumour selectivity in proliferating cells and may be developed further as a feasible approach to treat human cancers.
Collapse
MESH Headings
- Animals
- Brain Neoplasms/genetics
- Brain Neoplasms/therapy
- Brain Neoplasms/virology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/therapy
- Carcinoma, Hepatocellular/virology
- Cell Cycle/genetics
- Cell Line, Tumor
- Chlorocebus aethiops
- Female
- Glioma/genetics
- Glioma/therapy
- Glioma/virology
- Herpesvirus 1, Human/genetics
- Herpesvirus 1, Human/physiology
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/therapy
- Liver Neoplasms/virology
- Luciferases/genetics
- Mice
- Mice, Nude
- Mice, SCID
- Oncolytic Virotherapy/methods
- Regulatory Elements, Transcriptional
- Transcription, Genetic
- Transgenes
- Vero Cells
- Viral Proteins/genetics
- Xenograft Model Antitumor Assays
Collapse
Affiliation(s)
- L Miao
- Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore
| | - C Fraefel
- Institute of Virology, University of Zurich, Winterthurerstrasse 266a, CH-8057, Zurich, Switzerland
| | - K C Sia
- Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore
| | - J P Newman
- Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore
| | - S A Mohamed-Bashir
- Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore
| | - W H Ng
- Department of Neurosurgery, National Neuroscience Institute, Singapore 308433, Singapore
- Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore
| | - P Y P Lam
- Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore
- Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| |
Collapse
|
|
12
|
Braidwood L, Graham SV, Graham A, Conner J. Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs. Oncolytic Virother 2013; 2:57-74. [PMID: 27512658 PMCID: PMC4918355 DOI: 10.2147/ov.s52601] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs) have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVex(GM-CSF)]), is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with "standard-of-care" drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with "standard-of-care" drugs merits further investigation, both preclinically and in the clinic. Numerous publications report such studies of oncolytic HSV in combination with other drugs, and we review their findings here. Viral interactions with cellular hosts are complex and frequently involve intracellular signaling networks, thus creating diverse opportunities for synergistic or additive combinations with many anticancer drugs. We discuss potential mechanisms that may lead to synergistic interactions.
Collapse
Affiliation(s)
- Lynne Braidwood
- Virttu Biologics Ltd, Department of Neurology, Southern General Hospital, Glasgow, UK
| | - Sheila V Graham
- MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Jarrett Building, University of Glasgow, Glasgow, UK
| | - Alex Graham
- Virttu Biologics Ltd, Department of Neurology, Southern General Hospital, Glasgow, UK
| | - Joe Conner
- Virttu Biologics Ltd, Department of Neurology, Southern General Hospital, Glasgow, UK
| |
Collapse
|
|
13
|
Liu H, Yuan SJ, Chen YT, Xie YB, Cui L, Yang WZ, Yang DX, Tian YT. Preclinical evaluation of herpes simplex virus armed with granulocyte-macrophage colony-stimulating factor in pancreatic carcinoma. World J Gastroenterol 2013; 19:5138-5143. [PMID: 23964149 PMCID: PMC3746387 DOI: 10.3748/wjg.v19.i31.5138] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Revised: 06/28/2013] [Accepted: 07/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the therapeutic efficacy and mechanisms of action of oncolytic-herpes-simplex-virus encoding granulocyte-macrophage colony-stimulating factor (HSV(GM-CSF)) in pancreatic carcinoma. METHODS Tumor blocks were homogenized in a sterile grinder in saline. The homogenate was injected into the right armpit of each mouse. After vaccination, the mice were randomly assigned into four groups: a control group, a high dose HSV(GM-CSF) group [1 × 10⁷ plaque forming units (pfu)/tumor], a medium dose HSV(GM-CSF) group (5 × 10⁶ pfu/tumor) and a low dose HSV(GM-CSF) group (5 × 10⁵ pfu/tumor). After initiation of drug administration, body weights and tumor diameters were measured every 3 d. Fifteen days later, after decapitation of the animal by cervical dislocation, each tumor was isolated, weighed and stored in 10% formaldehyde solution. The drug effectiveness was evaluated according to the weight, volume and relative volume change of each tumor. Furthermore, GM-CSF protein levels in serum were assayed by enzyme-linked immunosorbent assays at 1, 2, 3 and 4 d after injection of HSV(GM-CSF). RESULTS Injection of the recombinant mouse HSV encoding GM-CSF resulted in a significant reduction in tumor growth compared to the control group, and dose-dependent effects were observed: the relative tumor proliferation rates of the low dose, medium dose and high dose groups on 15 d after injection were 45.5%, 55.2% and 65.5%, respectively. The inhibition rates of the tumor weights of the low, middle, and high dose groups were 41.4%, 46.7% and 50.5%, respectively. Furthermore, the production of GM-CSF was significantly increased in the mice infected with HSV(GM-CSF). The increase in the GM-CSF level was more pronounced in the high dose group compared to the other two dose groups. CONCLUSION Our study provides the first evidence that HSV(GM-CSF) could inhibit the growth of pancreatic cancer. The enhanced GM-CSF expression might be responsible for the phenomenon.
Collapse
|
|
14
|
Advance in herpes simplex viruses for cancer therapy. SCIENCE CHINA-LIFE SCIENCES 2013; 56:298-305. [PMID: 23564184 DOI: 10.1007/s11427-013-4466-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Accepted: 02/27/2013] [Indexed: 02/07/2023]
Abstract
Oncolytic virotherapy is an attractive approach that uses live viruses to selectively kill cancer cells. Oncolytic viruses can be genetically engineered to induce cell lyses through virus replication and cytotoxic protein expression. Herpes simplex virus (HSV) has become one of the most widely clinically used oncolytic agent. Various types of HSV have been studied in basic or clinical research. Combining oncolytic virotherapy with chemotherapy or radiotherapy generally produces synergic action with unclear molecular mechanisms. Arming HSV with therapeutic transgenes is a promising strategy and can be used to complement conventional therapies. As an efficient gene delivery system, HSV has been successfully used to deliver various immunomodulatory molecules. Arming HSV with therapeutic genes merits further investigation for potential clinical application.
Collapse
|
|
15
|
Wennier ST, Liu J, McFadden G. Bugs and drugs: oncolytic virotherapy in combination with chemotherapy. Curr Pharm Biotechnol 2013; 13:1817-33. [PMID: 21740354 DOI: 10.2174/138920112800958850] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Accepted: 09/18/2010] [Indexed: 12/16/2022]
Abstract
Single agent therapies are rarely successful in treating cancer, particularly at metastatic or end stages, and survival rates with monotherapies alone are generally poor. The combination of multiple therapies to treat cancer has already driven significant improvements in the standard of care treatments for many types of cancers. The first combination treatments exploited for cancer therapy involved the use of several cytotoxic chemotherapy agents. Later, with the development of more targeted agents, the use of novel, less toxic drugs, in combination with the more classic cytotoxic drugs has proven advantageous for certain cancer types. Recently, the combination of oncolytic virotherapy with chemotherapy has shown that the use of these two therapies with very distinct anti-tumor mechanisms may also lead to synergistic interactions that ultimately result in increased therapeutic effects not achievable by either therapy alone. The mechanisms of synergy between oncolytic viruses (OVs) and chemotherapeutic agents are just starting to be elucidated. It is evident, however, that the success of these OV-drug combinations depends greatly on the particular OV, the drug(s) selected, and the cancer type targeted. This review summarizes the different OV-drug combinations investigated to date, including the use of second generation armed OVs, which have been studied with the specific purpose of generating synergistic interactions with particular chemotherapy agents. The known mechanisms of synergy between these OV-drug combinations are also summarized. The importance of further investigating these mechanisms of synergy will be critical in order to maximize the therapeutic efficacy of OV-drug combination therapies in the future.
Collapse
Affiliation(s)
- Sonia Tusell Wennier
- Department of Molecular Genetics and Microbiology, University of Florida, 1600 SW Archer Rd, P.O. Box 100266 Gainesville, FL 32610, USA
| | | | | |
Collapse
|
|
16
|
Concurrent chemotherapy inhibits herpes simplex virus-1 replication and oncolysis. Cancer Gene Ther 2013; 20:133-40. [PMID: 23348635 DOI: 10.1038/cgt.2012.97] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Herpes simplex virus-1 (HSV-1) replication in cancer cells leads to their destruction (viral oncolysis) and has been under investigation as an experimental cancer therapy in clinical trials as single agents, and as combinations with chemotherapy. Cellular responses to chemotherapy modulate viral replication, but these interactions are poorly understood. To investigate the effect of chemotherapy on HSV-1 oncolysis, viral replication in cells exposed to 5-fluorouracil (5-FU), irinotecan (CPT-11), methotrexate (MTX) or a cytokine (tumor necrosis factor-α (TNF-α)) was examined. Exposure of colon and pancreatic cancer cells to 5-FU, CPT-11 or MTX in vitro significantly antagonizes both HSV-1 replication and lytic oncolysis. Nuclear factor-κB (NF-κB) activation is required for efficient viral replication, and experimental inhibition of this response with an IκBα dominant-negative repressor significantly antagonizes HSV-1 replication. Nonetheless, cells exposed to 5-FU, CPT-11, TNF-α or HSV-1 activate NF-κB. Cells exposed to MTX do not activate NF-κB, suggesting a possible role for NF-κB inhibition in the decreased viral replication observed following exposure to MTX. The role of eukaryotic initiation factor 2α (eIF-2α) dephosphorylation was examined; HSV-1-mediated eIF-2α dephosphorylation proceeds normally in HT29 cells exposed to 5-FU, CPT-11 or MTX. This report demonstrates that cellular responses to chemotherapeutic agents provide an unfavorable environment for HSV-1-mediated oncolysis, and these observations are relevant to the design of both preclinical and clinical studies of HSV-1 oncolysis.
Collapse
|
|
17
|
Passer BJ, Cheema T, Wu S, Wu CL, Rabkin SD, Martuza RL. Combination of vinblastine and oncolytic herpes simplex virus vector expressing IL-12 therapy increases antitumor and antiangiogenic effects in prostate cancer models. Cancer Gene Ther 2012; 20:17-24. [PMID: 23138870 PMCID: PMC3810211 DOI: 10.1038/cgt.2012.75] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Oncolytic herpes simplex virus (oHSV)-1-based vectors selectively replicate in tumor cells causing direct killing, that is, oncolysis, while sparing normal cells. The oHSVs are promising anticancer agents, but their efficacy, when used as single agents, leaves room for improvement. We hypothesized that combining the direct oncolytic and antiangiogenic activities of the interleukin (IL)-12-secreting NV1042 oHSV with microtubule disrupting agents (MDAs) would be an effective means to enhance antitumor efficacy. Vinblastine (VB) was identified among several MDAs screened, which displayed consistent and potent cytotoxic killing of both prostate cancer and endothelial cell lines. In matrigel tube-forming assays, VB was found to be highly effective at inhibiting tube formation of human umbilical vein endothelial cells. The combination of VB with NV1023 (the parental virus lacking IL-12) or NV1042 showed additive or synergistic activity against prostate cancer cell lines, and was not due to increased oHSV replication by VB. In athymic mice bearing CWR22 prostate tumors, VB in combination with NV1042 was superior to the combination of VB plus NV1023 in reducing tumor burden, appeared to be nontoxic and resulted in a statistically significant diminution in the number of CD31(+) cells as compared with other treatment groups. In human organotypic cultures using surgical samples from radical prostatectomies, both NV1023 and NV1042 were localized specifically to the epithelial cells of prostatic glands but not to the surrounding stroma. These data highlight the therapeutic advantage of combining the dual-acting antitumor and antiangiogenic activities of oHSVs and MDAs.
Collapse
Affiliation(s)
- B J Passer
- Department of Neurosurgery, Brain Tumor Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
| | | | | | | | | | | |
Collapse
|
|
18
|
Sahin TT, Kasuya H, Nomura N, Shikano T, Yamamura K, Gewen T, Kanzaki A, Fujii T, Sugae T, Imai T, Nomoto S, Takeda S, Sugimoto H, Kikumori T, Kodera Y, Nishiyama Y, Nakao A. Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer. Cancer Gene Ther 2012; 19:229-237. [PMID: 22193629 DOI: 10.1038/cgt.2011.80] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2011] [Revised: 09/27/2011] [Accepted: 10/23/2011] [Indexed: 02/08/2023]
Abstract
Oncolytic viruses are a promising method of cancer therapy, even for advanced malignancies. HF10, a spontaneously mutated herpes simplex type 1, is a potent oncolytic agent. The interaction of oncolytic herpes viruses with the tumor microenvironment has not been well characterized. We injected HF10 into tumors of patients with recurrent breast carcinoma, and sought to determine its effects on the tumor microenvironment. Six patients with recurrent breast cancer were recruited to the study. Tumors were divided into two groups: saline-injected (control) and HF10-injected (treatment). We investigated several parameters including neovascularization (CD31) and tumor lymphocyte infiltration (CD8, CD4), determined by immunohistochemistry, and apoptosis, determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Median apoptotic cell count was lower in the treatment group (P=0.016). Angiogenesis was significantly higher in treatment group (P=0.032). Count of CD8-positive lymphocytes infiltrating the tumors was higher in the treatment group (P=0.008). We were unable to determine CD4-positive lymphocyte infiltration. An effective oncolytic viral agent must replicate efficiently in tumor cells, leading to higher viral counts, in order to aid viral penetration. HF10 seems to meet this criterion; furthermore, it induces potent antitumor immunity. The increase in angiogenesis may be due to either viral replication or the inflammatory response.
Collapse
Affiliation(s)
- T T Sahin
- Department of Surgery II, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Cheema TA, Kanai R, Kim GW, Wakimoto H, Passer B, Rabkin SD, Martuza RL. Enhanced antitumor efficacy of low-dose Etoposide with oncolytic herpes simplex virus in human glioblastoma stem cell xenografts. Clin Cancer Res 2011; 17:7383-93. [PMID: 21976549 DOI: 10.1158/1078-0432.ccr-11-1762] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE Glioblastoma (GBM) inevitably recurs despite surgery, radiation, and chemotherapy. A subpopulation of tumor cells, GBM stem cells (GSC), has been implicated in this recurrence. The chemotherapeutic agent etoposide is generally reserved for treating recurrent tumors; however, its effectiveness is limited due to acute and cumulative toxicities to normal tissues. We investigate a novel combinatorial approach of low-dose etoposide with an oncolytic HSV to enhance antitumor activity and limit drug toxicity. EXPERIMENTAL DESIGN In vitro, human GBM cell lines and GSCs were treated with etoposide alone, oncolytic herpes simplex virus (oHSV) G47Δ alone, or the combination. Cytotoxic interactions were analyzed using the Chou-Talalay method, and changes in caspase-dependent apoptosis and cell cycle were determined. In vivo, the most etoposide-resistant human GSC, BT74, was implanted intracranially and treated with either treatment alone or the combination. Analysis included effects on survival, therapy-associated adverse events, and histologic detection of apoptosis. RESULTS GSCs varied in their sensitivity to etoposide by over 50-fold in vitro, whereas their sensitivity to G47Δ was similar. Combining G47Δ with low-dose etoposide was moderately synergistic in GSCs and GBM cell lines. This combination did not enhance virus replication, but significantly increased apoptosis. In vivo, the combination of a single cycle of low-dose etoposide with G47Δ significantly extended survival of mice-bearing etoposide-insensitive intracranial human GSC-derived tumors. CONCLUSIONS The combination of low-dose etoposide with G47Δ increases survival of mice-bearing intracranial human GSC-derived tumors without adverse side effects. These results establish this as a promising combination strategy to treat resistant and recurrent GBM.
Collapse
Affiliation(s)
- Tooba A Cheema
- Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, Boston, USA
| | | | | | | | | | | | | |
Collapse
|
|
20
|
Banerjee PS, Zuniga ES, Ojima I, Carrico IS. Targeted and armed oncolytic adenovirus via chemoselective modification. Bioorg Med Chem Lett 2011; 21:4985-8. [PMID: 21669527 PMCID: PMC3413283 DOI: 10.1016/j.bmcl.2011.05.039] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Revised: 05/09/2011] [Accepted: 05/10/2011] [Indexed: 12/21/2022]
Abstract
Oncolytic adenoviruses (Ads) are an emerging alternative therapy for cancer; however, clinical trial have not yet demonstrated sufficient efficacy. When oncolytic Ads are used in combination with taxoids a synergistic increase in both cytotoxicity and viral replication is observed. In order to generate a next generation oncolytic adenovirus, virion were physically conjugated to a highly potent taxoid, SB-T-1214, and a folate targeting motif. Conjugation was enabled via the metabolic incorporation of non-canonical monosaccharides (O-GlcNAz) and amino acids (homopropargylglycine), which served as sites for chemoselective modification.
Collapse
Affiliation(s)
- Partha S. Banerjee
- Department of Chemistry and Institute of Chemical Biology and Drug Discovery, State University of New York Stony Brook, New York 11790
| | - Edison S. Zuniga
- Department of Chemistry and Institute of Chemical Biology and Drug Discovery, State University of New York Stony Brook, New York 11790
| | - Iwao Ojima
- Department of Chemistry and Institute of Chemical Biology and Drug Discovery, State University of New York Stony Brook, New York 11790
| | - Isaac S. Carrico
- Department of Chemistry and Institute of Chemical Biology and Drug Discovery, State University of New York Stony Brook, New York 11790
| |
Collapse
|
|
21
|
Abstract
The cytolytic properties of viruses can be used to treat cancer. Replication of certain viruses is favoured in cancer cells, whereas others can be modified to obtain tumour specificity. This approach has evolved to become a new discipline called virotherapy. In addition, these replication-competent (oncolytic) viruses can be adapted as vectors for cancer gene therapy. The "armed" viruses show a double mechanism of action: direct destruction of cancer cells as a consequence of the lytic viral cycle, in combination with the effect of the therapeutic gene incorporated in the viral genome. Current trends in the field include strategies to increase the oncolytic potency of existing viruses; the evaluation of new candidates; the search for synergistic effects between different viruses and conventional therapies; and a rational approach to take advantage of the interplay between the viruses and the host immune system. This review summarises the most relevant achievements in recent years.
Collapse
|
|
22
|
Heinemann L, Simpson GR, Boxall A, Kottke T, Relph KL, Vile R, Melcher A, Prestwich R, Harrington KJ, Morgan R, Pandha HS. Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer. BMC Cancer 2011; 11:221. [PMID: 21645351 PMCID: PMC3129324 DOI: 10.1186/1471-2407-11-221] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Accepted: 06/06/2011] [Indexed: 01/03/2023] Open
Abstract
Background Reovirus type 3 Dearing (T3D) has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication. Methods The effects of reovirus and chemotherapy on in vitro cytotoxicity were investigated in PC3 and Du 145 cells and the interactions between agents were assessed by combination index analysis. An Annexin V/propidium iodide fluorescence-activated cell sorting-based assay was used to determine mode of cell death. The effects of reovirus and docetaxel administered as single agent or combination therapy were tested in vivo in a murine model. The effects of docetaxel and reovirus, alone and together, on microtubule stabilisation were investigated by Western blot analysis. Results Variable degrees of synergistic cytotoxicity were observed in PC3 and Du 145 cells exposed to live reovirus and several chemotherapy agents. Combination of reovirus infection with docetaxel exposure led to increased late apoptotic/necrotic cell populations. Reovirus/docetaxel combined therapy led to reduced tumour growth and increased survival in a PC3 tumour bearing mouse model. Microtubule stabilization was enhanced in PC3 cells treated with reovirus/docetaxel combined therapy compared to other reovirus/chemotherapy combinations. Conclusions The co-administration of a variety of chemotherapeutic agents with live reovirus was able to enhance cytotoxicity synergistically in vitro. The combination of docetaxel with reovirus also delayed tumour growth and improved survival in vivo. Enhanced microtubule stabilisation following this combination treatment may, in part, explain the mechanism of synergy. These results provide evidence to support the ongoing clinical trials using these agents.
Collapse
Affiliation(s)
- Lucy Heinemann
- Oncology, Postgraduate Medical School, University of Surrey, Guildford, GU2 7WG, UK
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Naik JD, Twelves CJ, Selby PJ, Vile RG, Chester JD. Immune recruitment and therapeutic synergy: keys to optimizing oncolytic viral therapy? Clin Cancer Res 2011; 17:4214-24. [PMID: 21576084 DOI: 10.1158/1078-0432.ccr-10-2848] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Oncolytic viruses consist of a diverse range of DNA and RNA viruses traditionally thought to mediate their effects by exploiting aberrations in tumor pathways, allowing preferential viral replication in, and killing of, tumor cells. Clinical development has progressed to late-phase trials, potentially heralding their introduction into clinical practice. However, despite this promise, the activity of oncolytic viruses has yet to achieve the potential suggested in preclinical models. To address this disparity, we need to recognize the complex interaction among oncolytic viruses, tumor, chemotherapy, and host immune system, and appreciate that direct oncolysis may not be the only factor to play an important role in oncolytic virus-mediated antitumor efficacy. Although key in inactivating viruses, the host immune system can also act as an ally against tumors, interacting with oncolytic viruses under the right conditions to generate useful and long-lasting antitumor immunity. Preclinical data also suggest that oncolytic viruses show synergy with standard therapies, which may offer improved clinical response rates. Here, we explore clinical and preclinical data on clinically relevant oncolytic viruses, highlighting areas of progress, uncertainty, and translational opportunity, with respect to immune recruitment and therapeutic synergy.
Collapse
Affiliation(s)
- Jay D Naik
- Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
| | | | | | | | | |
Collapse
|
|
24
|
Gaston DC, Whitley RJ, Parker JN. Engineered herpes simplex virus vectors for antitumor therapy and vaccine delivery. Future Virol 2011. [DOI: 10.2217/fvl.11.4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Genetically modified herpes simplex viruses (HSVs) have been exploited for both antitumor therapy and vaccine delivery. These mutant viruses retain their ability to replicate and lyse permissive cells, including many tumor types, and are referred to as oncolytic HSVs. In addition, deletion of nonessential genes permits the introduction of foreign genes to augment the antitumor effect by either immune stimulation, targeting for select tumors, or expression of tumor or vaccine antigens. This article reviews the development of oncolytic HSVs as an anticancer therapy, as well as the application of HSV-1 vectors for delivery of targeted antigens or as vaccine adjuvants. The impact of these novel vectors with respect to enhanced antitumor activity and development of antitumor vaccination strategies is discussed.
Collapse
Affiliation(s)
- David C Gaston
- Medical Scientist Training Program, Department of Cell Biology, CHB 130, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Richard J Whitley
- Departments of Pediatrics, Microbiology, Medicine & Neurosurgery, CHB 303, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Jacqueline N Parker
- Departments of Pediatrics & Cell Biology, CHB 118B, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| |
Collapse
|
|
25
|
Synergistic anti-tumor effects between oncolytic vaccinia virus and paclitaxel are mediated by the IFN response and HMGB1. Gene Ther 2010; 18:164-72. [PMID: 20739958 DOI: 10.1038/gt.2010.121] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Recent developments in the field of oncolytic or tumor-selective viruses have meant that the clinical applications of these agents are now being considered in more detail. Like most cancer therapies it is likely that they will be used primarily in combination with other therapeutics. Although several reports have shown that oncolytic viruses can synergize with chemotherapies within an infected cancer cell, it would be particularly important to determine whether factors released from infected cells could enhance the action of chemotherapies at a distance. Here, we demonstrate in vitro synergy between oncolytic vaccinia and taxanes. However, we also show, for the first time, that this synergy is at least partly due to the release of factors from the infected cells that are capable of sensitizing surrounding cells to chemotherapy. Several cellular factors were identified as being mediators of this bystander effect, including type I interferon released soon after infection and high-mobility group protein B1 (HMGB1) released after cell death. This represents the first description of these mechanisms for beneficial interactions between viral and traditional tumor therapies. These data may provide a direct basis for the design of clinical trials with agents currently in the clinic, as well as providing insight into the development of next generation viral vectors.
Collapse
|
|
26
|
Castelo-Branco P, Passer BJ, Buhrman JS, Antoszczyk S, Marinelli M, Zaupa C, Rabkin SD, Martuza RL. Oncolytic herpes simplex virus armed with xenogeneic homologue of prostatic acid phosphatase enhances antitumor efficacy in prostate cancer. Gene Ther 2010; 17:805-10. [PMID: 20220784 PMCID: PMC3243306 DOI: 10.1038/gt.2010.20] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2009] [Revised: 01/05/2010] [Accepted: 01/20/2010] [Indexed: 11/09/2022]
Abstract
Prostate cancer is one of the most prevalent cancers in men. Replication-competent oncolytic herpes simplex virus (oHSV) vectors are a powerful antitumor therapy that can exert at least two effects: direct cytocidal activity that selectively kills cancer cells and induction of antitumor immunity. In addition, oHSV vectors can also function as a platform to deliver transgenes of interest. In these studies, we have examined the expression of a xenogeneic homologue of the prostate cancer antigen, prostatic acid phosphatase (PAP), with the goal of enhancing virotherapy against PAP-expressing tumors. PAP has already been used for cancer vaccination in patients with prostate cancer. Here we show that treatment with oHSV bPDelta6 expressing xenogeneic human PAP (hPAP) significantly reduces tumor growth and increases survival of C57/BL6 mice bearing mouse TRAMP-C2 prostate tumors, whereas expression of syngeneic mouse PAP (mPAP) from the same oHSV vector did not enhance antitumor activity. Treatment of mice bearing metastatic TRAMP-C2 lung tumors with oHSV-expressing hPAP resulted in fewer tumor nodules. To our knowledge, this is the first report of oncolytic viruses being used to express xenoantigens. These data lend support to the concept of combining oncolytic and immunogenic therapies as a way to improve therapy of metastatic prostate cancer.
Collapse
Affiliation(s)
- Pedro Castelo-Branco
- Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Boston, MA, United States, 02114
- Harvard Medical School, Boston, MA, United States, 02114
| | - Brent J. Passer
- Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Boston, MA, United States, 02114
- Harvard Medical School, Boston, MA, United States, 02114
| | - Jason S. Buhrman
- Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Boston, MA, United States, 02114
| | - Slawomir Antoszczyk
- Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Boston, MA, United States, 02114
- Harvard Medical School, Boston, MA, United States, 02114
| | - Melissa Marinelli
- Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Boston, MA, United States, 02114
| | - Cecil Zaupa
- Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Boston, MA, United States, 02114
- Harvard Medical School, Boston, MA, United States, 02114
| | - Samuel D Rabkin
- Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Boston, MA, United States, 02114
- Harvard Medical School, Boston, MA, United States, 02114
| | - Robert L. Martuza
- Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Boston, MA, United States, 02114
- Harvard Medical School, Boston, MA, United States, 02114
| |
Collapse
|
|
27
|
Passer BJ, Cheema T, Zhou B, Wakimoto H, Zaupa C, Razmjoo M, Sarte J, Wu S, Wu CL, Noah JW, Li Q, Buolamwini JK, Yen Y, Rabkin SD, Martuza RL. Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication. Cancer Res 2010; 70:3890-5. [PMID: 20424118 PMCID: PMC3763489 DOI: 10.1158/0008-5472.can-10-0155] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Oncolytic herpes simplex virus-1 (oHSV) vectors selectively replicate in tumor cells, where they kill through oncolysis while sparing normal cells. One of the drawbacks of oHSV vectors is their limited replication and spread to neighboring cancer cells. Here, we report the outcome of a high-throughput chemical library screen to identify small-molecule compounds that augment the replication of oHSV G47Delta. Of the 2,640-screened bioactives, 6 compounds were identified and subsequently validated for enhanced G47Delta replication. Two of these compounds, dipyridamole and dilazep, interfered with nucleotide metabolism by potently and directly inhibiting the equilibrative nucleoside transporter-1 (ENT1). Replicative amplification promoted by dipyridamole and dilazep were dependent on HSV mutations in ICP6, the large subunit of ribonucleotide reductase. Our results indicate that ENT1 antagonists augment oHSV replication in tumor cells by increasing cellular ribonucleoside activity.
Collapse
Affiliation(s)
- Brent J Passer
- Departments of Neurosurgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Kanai R, Wakimoto H, Cheema T, Rabkin SD. Oncolytic herpes simplex virus vectors and chemotherapy: are combinatorial strategies more effective for cancer? Future Oncol 2010; 6:619-34. [PMID: 20373873 PMCID: PMC2904234 DOI: 10.2217/fon.10.18] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Despite aggressive treatments, including chemotherapy and radiotherapy, cancers often recur owing to resistance to conventional therapies. Oncolytic viruses such as oncolytic herpes simplex virus (oHSV) represent an exciting biological approach to cancer therapy. A range of viral mutations has been engineered into HSV to engender oncolytic activity. While oHSV as a single agent has been tested in a number of cancer clinical trials, preclinical studies have demonstrated enhanced efficacy when it is combined with cytotoxic anticancer drugs. Among the strategies that will be discussed in this article are combinations with standard-of-care chemotherapeutics, expression of prodrug-activating enzymes to enhance chemotherapy and small-molecule inhibitors. The combination of oHSV and chemotherapy can achieve much more efficient cancer cell killing than either single agent alone, often through synergistic interactions. This can be clinically important not just for improving efficacy but also for permitting lower and less toxic chemotherapeutic doses. The viral mutations in an oHSV vector often determine the favorability of its interactions with chemotherapy, just as different cancer cells, due to genetic alterations, vary in their response to chemotherapy. As chemotherapeutics are often the standard of care, combining them with an investigational new drug, such as oHSV, is clinically easier than combining multiple novel agents. As has become clear for most cancer therapies, multimodal treatments are usually more effective. In this article, we will discuss the recent progress of these combinatorial strategies between virotherapy and chemotherapy and future directions.
Collapse
Affiliation(s)
- Ryuichi Kanai
- Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, & Harvard Medical School, Boston, MA, USA
| | - Hiroaki Wakimoto
- Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, & Harvard Medical School, Boston, MA, USA
| | - Tooba Cheema
- Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, & Harvard Medical School, Boston, MA, USA
| | - Samuel D Rabkin
- Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, & Harvard Medical School, Boston, MA, USA, Tel.: +1 617 726 6817, Fax: +1 617 643 3422
| |
Collapse
|
|
29
|
Ottolino-Perry K, Diallo JS, Lichty BD, Bell JC, McCart JA. Intelligent design: combination therapy with oncolytic viruses. Mol Ther 2009; 18:251-63. [PMID: 20029399 DOI: 10.1038/mt.2009.283] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Metastatic cancer remains an incurable disease in the majority of cases and thus novel treatment strategies such as oncolytic virotherapy are rapidly advancing toward clinical use. In order to be successful, it is likely that some type of combination therapy will be necessary to have a meaningful impact on this disease. Although it may be tempting to simply combine an oncolytic virus with the existing standard radiation or chemotherapeutics, the long-term goal of such treatments must be to have a rational, potentially synergistic combination strategy that can be safely and easily used in the clinical setting. The combination of oncolytic virotherapy with existing radiotherapy and chemotherapy modalities is reviewed along with novel biologic therapies including immunotherapies, in order to help investigators make intelligent decisions during the clinical development of these products.
Collapse
Affiliation(s)
- Kathryn Ottolino-Perry
- Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, Ontario, Canada
| | | | | | | | | |
Collapse
|