|
1
|
Ammour Y, Nikolaeva E, Sagimbaeva O, Shamsutdinov P, Astapenko A, Zhelaeva Y, Gavrilova M, Susova O, Mitrofanov A, Bekyashev A, Nasedkina T, Svitich O, Faizuloev E, Zverev V. Human Melanoma and Glioblastoma Cells Express Cathepsins Supporting Reovirus Moscow Strain Infection. Viruses 2024; 16:1944. [PMID: 39772250 PMCID: PMC11680368 DOI: 10.3390/v16121944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
This study evaluates the oncolytic potential of the Moscow strain of reovirus against human metastatic melanoma and glioblastoma cells. The Moscow strain effectively infects and replicates within human melanoma cell lines and primary glioblastoma cells, while sparing non-malignant human cells. Infection leads to the selective destruction of neoplastic cells, mediated by functional viral replication. A positive correlation was identified between viral RNA accumulation and tumor cell death, with no replication observed in non-malignant cells. This study highlights the critical roles of cathepsins B, L, and S as mediators of the oncolytic process. The pharmacological inhibition of these enzymes significantly attenuated reovirus-induced cytotoxicity in melanoma and glioblastoma cells. Conversely, PKR production analysis revealed minimal activation in reovirus-infected tumor cells, suggesting that the hyperactivation of the RAS-signaling pathway and subsequent PKR inhibition do not directly contribute to the selective efficacy of reovirus. Moreover, infected tumor cells exhibited features of both apoptotic and non-apoptotic death, emphasizing the intricate mechanisms of reovirus-mediated oncolysis. These findings underscore the therapeutic promise of the Moscow strain of reovirus as a selective and potent oncolytic agent for targeting melanoma and glioblastoma cells.
Collapse
Affiliation(s)
- Yulia Ammour
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia;
| | - Eugenia Nikolaeva
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Olesya Sagimbaeva
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Pavel Shamsutdinov
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Anastasia Astapenko
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Yulia Zhelaeva
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Marina Gavrilova
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Olga Susova
- N.N. Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation, 115478 Moscow, Russia; (O.S.); (A.M.); (A.B.)
| | - Aleksey Mitrofanov
- N.N. Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation, 115478 Moscow, Russia; (O.S.); (A.M.); (A.B.)
| | - Ali Bekyashev
- N.N. Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation, 115478 Moscow, Russia; (O.S.); (A.M.); (A.B.)
| | - Tatiana Nasedkina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia;
| | - Oxana Svitich
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, 119146 Moscow, Russia
| | - Evgeny Faizuloev
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Vitaly Zverev
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, 119146 Moscow, Russia
| |
Collapse
|
|
2
|
Lee WS, Lee SJ, Lee HJ, Yang H, Go EJ, Gansukh E, Song KH, Xiang X, Park DG, Alain T, Chon HJ, Kim C. Oral reovirus reshapes the gut microbiome and enhances antitumor immunity in colon cancer. Nat Commun 2024; 15:9092. [PMID: 39438458 PMCID: PMC11496807 DOI: 10.1038/s41467-024-53347-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 10/02/2024] [Indexed: 10/25/2024] Open
Abstract
The route of oncolytic virotherapy is pivotal for immunotherapeutic efficacy in advanced cancers. In this preclinical study, an oncolytic reovirus (RC402) is orally administered to induce antitumor immunity. Oral reovirus treatment shows no gross toxicities and effectively suppresses multifocal tumor lesions. Orally administered reovirus interacts with the host immune system in the Peyer's patch of the terminal ileum, increases IgA+ antibody-secreting cells in the lamina propria through MAdCAM-1+ blood vessels, and reshapes the gut microbiome. Oral reovirus promotes antigen presentation, type I/II interferons, and T cell activation within distant tumors, but does not reach or directly infect tumor cells beyond the gastrointestinal tract. In contrast to intratumoral reovirus injection, the presence of the gut microbiome, Batf3+ dendritic cells, type I interferons, and CD8+ T cells are indispensable for orally administered reovirus-induced antitumor immunity. Oral reovirus treatment is most effective when combined with αPD-1(L1) and/or αCTLA-4, leading to complete colon tumor regression and protective immune memory. Collectively, oral reovirus virotherapy is a feasible and effective immunotherapeutic strategy in preclinical studies.
Collapse
Affiliation(s)
- Won Suk Lee
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi-do, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University, Seongnam, Gyeonggi-do, Republic of Korea
| | - Seung Joon Lee
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi-do, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University, Seongnam, Gyeonggi-do, Republic of Korea
| | - Hye Jin Lee
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi-do, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University, Seongnam, Gyeonggi-do, Republic of Korea
| | - Hannah Yang
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi-do, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University, Seongnam, Gyeonggi-do, Republic of Korea
| | - Eun-Jin Go
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi-do, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University, Seongnam, Gyeonggi-do, Republic of Korea
| | | | | | - Xiao Xiang
- Department of Biochemistry, Microbiology, and Immunology, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
| | - Dong Guk Park
- Virocure Inc., Seoul, Republic of Korea
- Department of Surgery, School of Medicine, Dankook University, Cheonan, Republic of Korea
| | - Tommy Alain
- Department of Biochemistry, Microbiology, and Immunology, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
| | - Hong Jae Chon
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi-do, Republic of Korea.
- Laboratory of Translational Immuno-Oncology, CHA University, Seongnam, Gyeonggi-do, Republic of Korea.
| | - Chan Kim
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi-do, Republic of Korea.
- Laboratory of Translational Immuno-Oncology, CHA University, Seongnam, Gyeonggi-do, Republic of Korea.
| |
Collapse
|
|
3
|
Zhang J, Liu K, Zhu Z, Shang S, Wei D, Zheng Y, Zhang L, Liang Y, Ju D, Yuan J. Innovative strategies in genitourinary cancer: the role of oncolytic viruses. Front Oncol 2024; 14:1461324. [PMID: 39464707 PMCID: PMC11502293 DOI: 10.3389/fonc.2024.1461324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 09/09/2024] [Indexed: 10/29/2024] Open
Abstract
Urinary tumors pose a significant health threat because of their high prevalence and recurrence rates. Despite the availability of various treatment options, many patients poorly respond to traditional therapies, highlighting the urgent need for alternative approaches. Oncolytic viruses are promising therapeutic agents. These viruses exploit the unique characteristics of cancer cells to specifically target and destroy them, thereby triggering potent antitumor immune responses. This review delves into recent advancements and future prospects of oncolytic viruses, focusing on their application in renal, bladder, and prostate cancers. By discussing practical implications and the potential of different viruses, including the cowpox virus, adenovirus, measles virus, coxsackievirus, and reovirus, we pave the way for further exploration and refinement of this exciting field.
Collapse
Affiliation(s)
- Jie Zhang
- College of Life Sciences, Northwest University, Xi’an, Shaanxi, China
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Kepu Liu
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Zheng Zhu
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Shihao Shang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Di Wei
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yu Zheng
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Lei Zhang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Ying Liang
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Dongen Ju
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Jianlin Yuan
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| |
Collapse
|
|
4
|
Welsh OL, Roth AN, Sutherland DM, Dermody TS. Sequence polymorphisms in the reovirus σ1 attachment protein modulate encapsidation efficiency and replication in mice. J Virol 2024; 98:e0030524. [PMID: 38771042 PMCID: PMC11237452 DOI: 10.1128/jvi.00305-24] [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: 02/16/2024] [Accepted: 04/23/2024] [Indexed: 05/22/2024] Open
Abstract
Many functions of viral attachment proteins are established, but less is known about the biological importance of viral attachment protein encapsidation efficiency. The mammalian orthoreovirus (reovirus) σ1 attachment protein forms filamentous trimers that incorporate into pentamers of the λ2 capsid protein. Reovirus strains vary in the efficiency of σ1 encapsidation onto progeny virions, which influences viral stability during entry into cells and the efficacy of tumor cell lysis. While the role of σ1 encapsidation has been evaluated in studies using cultured cells, the contribution of attachment protein encapsidation efficiency to viral infection in animals is less clear. Polymorphisms in reovirus σ1 at residues 22 and 249 have been implicated in viral dissemination in mice and susceptibility to proteolysis in the murine intestine, respectively. To determine whether these residues contribute to σ1 encapsidation efficiency, we engineered σ1 mutant viruses with single- and double-residue substitutions at sites 22 and 249. We found that substitutions at these sites alter the encapsidation of σ1 and that reoviruses encapsidating higher amounts of σ1 bind cells more avidly and have a modest replication advantage in a cell-type-specific manner relative to low σ1-encapsidating reoviruses. Furthermore, we found that a high σ1-encapsidating reovirus replicates and disseminates more efficiently in mice relative to a low σ1-encapsidating reovirus. These findings provide evidence of a relationship between viral attachment protein encapsidation efficiency and viral replication in cell culture and animal hosts. IMPORTANCE Viral attachment proteins can serve multiple functions during viral replication, including attachment to host cells, cell entry and disassembly, and modulation of host immune responses. The relationship between viral attachment protein encapsidation efficiency and viral replication in cells and animals is poorly understood. We engineered and characterized a panel of reoviruses that differ in the capacity to encapsidate the σ1 attachment protein. We found that strains encapsidating σ1 with higher efficiency bind cells more avidly and replicate and spread more efficiently in mice relative to those encapsidating σ1 with lower efficiency. These results highlight a function for σ1 attachment protein capsid abundance in viral replication in cells and animals, which may inform future use of reovirus as an oncolytic therapeutic.
Collapse
Affiliation(s)
- Olivia L. Welsh
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Institute of Infection, Inflammation, and Immunity, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alexa N. Roth
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Institute of Infection, Inflammation, and Immunity, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Danica M. Sutherland
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Institute of Infection, Inflammation, and Immunity, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Terence S. Dermody
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Institute of Infection, Inflammation, and Immunity, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| |
Collapse
|
|
5
|
Groeneveldt C, Kinderman P, Griffioen L, Rensing O, Labrie C, van den Wollenberg DJ, Hoeben RC, Coffey M, Loghmani H, Verdegaal EM, Welters MJ, van der Burg SH, van Hall T, van Montfoort N. Neutralizing Antibodies Impair the Oncolytic Efficacy of Reovirus but Permit Effective Combination with T cell-Based Immunotherapies. Cancer Immunol Res 2024; 12:334-349. [PMID: 38194598 PMCID: PMC10911706 DOI: 10.1158/2326-6066.cir-23-0480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 10/31/2023] [Accepted: 01/05/2024] [Indexed: 01/11/2024]
Abstract
Reovirus type 3 Dearing (Reo), manufactured for clinical application as pelareorep, is an attractive anticancer agent under evaluation in multiple phase 2 clinical trials for the treatment of solid tumors. It elicits its anticancer efficacy by inducing both oncolysis and intratumoral T-cell influx. Because most people have been preexposed to Reo, neutralizing antibodies (NAb) are prevalent in patients with cancer and might present a barrier to effective Reo therapy. Here, we tested serum of patients with cancer and healthy controls (n = 100) and confirmed that Reo NAbs are present in >80% of individuals. To investigate the effect of NAbs on both the oncolytic and the immunostimulatory efficacy of Reo, we established an experimental mouse model with Reo preexposure. The presence of preexposure-induced NAbs reduced Reo tumor infection and prevented Reo-mediated control of tumor growth after intratumoral Reo administration. In B cell-deficient mice, the lack of NAbs provided enhanced tumor growth control after Reo monotherapy, indicating that NAbs limit the oncolytic capacity of Reo. In immunocompetent mice, intratumoral T-cell influx was not affected by the presence of preexposure-induced NAbs and consequently, combinatorial immunotherapy strategies comprising Reo and T-cell engagers or checkpoint inhibitors remained effective in these settings, also after a clinically applied regimen of multiple intravenous pelareorep administrations. Altogether, our data indicate that NAbs hamper the oncolytic efficacy of Reo, but not its immunotherapeutic capacity. Given the high prevalence of seropositivity for Reo in patients with cancer, our data strongly advocate for the application of Reo as part of T cell-based immunotherapeutic strategies.
Collapse
Affiliation(s)
- Christianne Groeneveldt
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Priscilla Kinderman
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Lisa Griffioen
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Olivia Rensing
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Camilla Labrie
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Rob C. Hoeben
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Matt Coffey
- Oncolytics Biotech Incorporated, Calgary, Canada
| | | | - Els M.E. Verdegaal
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Marij J.P. Welters
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Sjoerd H. van der Burg
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Thorbald van Hall
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Nadine van Montfoort
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| |
Collapse
|
|
6
|
Rao MFS, Ahmed B, Qadir MI. Oncolytic Virotherapy: An Advanced Microbial Approach for the Management of Cancer. Crit Rev Eukaryot Gene Expr 2024; 34:1-13. [PMID: 37824388 DOI: 10.1615/critreveukaryotgeneexpr.2023048962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2023]
Abstract
Destruction of the tumor (cancerous) cells may be caused by live viruses, which have replicative ability and replicate selectively in tumor cells, known as oncolytic virotherapy. In comparison of conservative cancer therapy, tumor-selective replicating viruses have more advantages. These viruses have introduced new methodologies for the human cancer treatment. Numerous strategies are used in development of virotherapeutics. Virotherapy is not unusual concept, but modern advances in technology of genetic modification of oncolytic viruses have improved the ability of targeting tumor cells more specifically, it triggered the development of novel ammunition to fight cancer. An effective virotherapeutic approach with oncolytic viruses exhibits the feasibility and safety under clinical approach. New strategies are being explored to overcome basic obstacles and challenges in virotherapy. Administration of oncolytic viruses, logically, will successfully augment new treatments against many kinds of tumors. Some encouraging antitumor responses shown by combination therapy are provoking strong immunity against established cancer. Chief developments in oncolytic virotherapy have seen in past several years. Significant understandings have been provided by findings on the interface among immune comebacks and viruses, whereas potential results have shown in clinical trials.
Collapse
Affiliation(s)
| | - Bilal Ahmed
- University of Science And Technology of Fujairah, UAE; School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Muhammad Imran Qadir
- Institute of Molecular Biology & Biotechnology, Bahauddin Zakariya University, Multan, Pakistan
| |
Collapse
|
|
7
|
Cristi F, Walters M, Narayan N, Agopsowicz K, Hitt MM, Shmulevitz M. Improved oncolytic activity of a reovirus mutant that displays enhanced virus spread due to reduced cell attachment. Mol Ther Oncolytics 2023; 31:100743. [PMID: 38033400 PMCID: PMC10685048 DOI: 10.1016/j.omto.2023.100743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 10/31/2023] [Indexed: 12/02/2023] Open
Abstract
Wild-type reovirus serotype 3 Dearing (T3wt), a non-pathogenic intestinal virus, has shown promise as a cancer therapy in clinical trials, but it would benefit from an increased potency. Given that T3wt is naturally adapted to the intestinal environment (rather than tumors), we genetically modified reovirus to improve its infectivity in cancer cells. Various reovirus mutants were created, and their oncolytic potency was evaluated in vitro using plaque size as a measure of virus fitness in cancer cells. Notably, Super Virus 5 (SV5), carrying five oncolytic mutations, displayed the largest plaques in breast cancer cells among the mutants tested, indicating the potential for enhancing oncolytic potency through the combination of mutations. Furthermore, in a HER2+ murine breast cancer model, mice treated with SV5 exhibited superior tumor reduction and increased survival compared with those treated with PBS or T3wt. Intriguingly, SV5 did not replicate faster than T3wt in cultured cells but demonstrated a farther spread relative to T3wt, attributed to its reduced attachment to cancer cells. These findings highlight the significance of increased virus spread as a crucial mechanism for improving oncolytic virus activity. Thus, genetic modifications of reovirus hold the potential for augmenting its efficacy in cancer therapy.
Collapse
Affiliation(s)
- Francisca Cristi
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB T6G 2E1, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton AB T6G 2E1, Canada
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Maiah Walters
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Nashae Narayan
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Kate Agopsowicz
- Department of Oncology, University of Alberta, Edmonton AB T6G 1Z2, Canada
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Mary M. Hitt
- Department of Oncology, University of Alberta, Edmonton AB T6G 1Z2, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton AB T6G 2E1, Canada
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Maya Shmulevitz
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB T6G 2E1, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton AB T6G 2E1, Canada
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton AB T6G 2E1, Canada
| |
Collapse
|
|
8
|
Hu M, Liao X, Tao Y, Chen Y. Advances in oncolytic herpes simplex virus and adenovirus therapy for recurrent glioma. Front Immunol 2023; 14:1285113. [PMID: 38022620 PMCID: PMC10652401 DOI: 10.3389/fimmu.2023.1285113] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Recurrent glioma treatment is challenging due to molecular heterogeneity and treatment resistance commonly observed in these tumors. Researchers are actively pursuing new therapeutic strategies. Oncolytic viruses have emerged as a promising option. Oncolytic viruses selectively replicate within tumor cells, destroying them and stimulating the immune system for an enhanced anticancer response. Among Oncolytic viruses investigated for recurrent gliomas, oncolytic herpes simplex virus and oncolytic adenovirus show notable potential. Genetic modifications play a crucial role in optimizing their therapeutic efficacy. Different generations of replicative conditioned oncolytic human adenovirus and oncolytic HSV have been developed, incorporating specific modifications to enhance tumor selectivity, replication efficiency, and immune activation. This review article summarizes these genetic modifications, offering insights into the underlying mechanisms of Oncolytic viruses' therapy. It also aims to identify strategies for further enhancing the therapeutic benefits of Oncolytic viruses. However, it is important to acknowledge that additional research and clinical trials are necessary to establish the safety, efficacy, and optimal utilization of Oncolytic viruses in treating recurrent glioblastoma.
Collapse
Affiliation(s)
- Mingming Hu
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - XuLiang Liao
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Tao
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yaohui Chen
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
9
|
Zhu X, Fan C, Xiong Z, Chen M, Li Z, Tao T, Liu X. Development and application of oncolytic viruses as the nemesis of tumor cells. Front Microbiol 2023; 14:1188526. [PMID: 37440883 PMCID: PMC10335770 DOI: 10.3389/fmicb.2023.1188526] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/18/2023] [Indexed: 07/15/2023] Open
Abstract
Viruses and tumors are two pathologies that negatively impact human health, but what occurs when a virus encounters a tumor? A global consensus among cancer patients suggests that surgical resection, chemotherapy, radiotherapy, and other methods are the primary means to combat cancer. However, with the innovation and development of biomedical technology, tumor biotherapy (immunotherapy, molecular targeted therapy, gene therapy, oncolytic virus therapy, etc.) has emerged as an alternative treatment for malignant tumors. Oncolytic viruses possess numerous anti-tumor properties, such as directly lysing tumor cells, activating anti-tumor immune responses, and improving the tumor microenvironment. Compared to traditional immunotherapy, oncolytic virus therapy offers advantages including high killing efficiency, precise targeting, and minimal side effects. Although oncolytic virus (OV) therapy was introduced as a novel approach to tumor treatment in the 19th century, its efficacy was suboptimal, limiting its widespread application. However, since the U.S. Food and Drug Administration (FDA) approved the first OV therapy drug, T-VEC, in 2015, interest in OV has grown significantly. In recent years, oncolytic virus therapy has shown increasingly promising application prospects and has become a major research focus in the field of cancer treatment. This article reviews the development, classification, and research progress of oncolytic viruses, as well as their mechanisms of action, therapeutic methods, and routes of administration.
Collapse
Affiliation(s)
- Xiao Zhu
- Zhejiang Provincial People's Hospital Affiliated to Hangzhou Medical College, Hangzhou Medical College, Hangzhou, China
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
- Department of Biological and Chemical Sciences, New York Institute of Technology—Manhattan Campus, New York, NY, United States
| | - Chenyang Fan
- Department of Clinical Medicine, Medicine and Technology, School of Zunyi Medical University, Zunyi, China
| | - Zhuolong Xiong
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Mingwei Chen
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Zesong Li
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital(Shenzhen Institute of Translational Medicine), Shenzhen, China
| | - Tao Tao
- Department of Gastroenterology, Zibo Central Hospital, Zibo, China
| | - Xiuqing Liu
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| |
Collapse
|
|
10
|
Groeneveldt C, van den Ende J, van Montfoort N. Preexisting immunity: Barrier or bridge to effective oncolytic virus therapy? Cytokine Growth Factor Rev 2023; 70:1-12. [PMID: 36732155 DOI: 10.1016/j.cytogfr.2023.01.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023]
Abstract
Oncolytic viruses (OVs) represent a highly promising treatment strategy for a wide range of cancers, by mediating both the direct killing of tumor cells as well as mobilization of antitumor immune responses. As many OVs circulate in the human population, preexisting OV-specific immune responses are prevalent. Indeed, neutralizing antibodies (NAbs) are abundantly present in the human population for commonly used OVs, such as Adenovirus type 5 (Ad5), Herpes Simplex Virus-1 (HSV-1), Vaccinia virus, Measles virus, and Reovirus. This review discusses (pre)clinical evidence regarding the effect of preexisting immunity against OVs on two distinct aspects of OV therapy; OV infection and spread, as well as the immune response induced upon OV therapy. Combined, this review provides evidence that consideration of preexisting immunity is crucial in realizing the full potential of the highly promising therapeutic implementation of OVs. Future investigation of current gaps in knowledge highlighted in this review should yield a more complete understanding of this topic, ultimately allowing for better and more personalized OV therapies.
Collapse
Affiliation(s)
- Christianne Groeneveldt
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
| | - Jasper van den Ende
- Master Infection & Immunity, Utrecht University, 3584 CS Utrecht, the Netherlands
| | - Nadine van Montfoort
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA, Leiden, the Netherlands
| |
Collapse
|
|
11
|
Generation and Quantification of Cytotoxic Lymphocytes Following Oncolytic Virus Infection of Multi-cellular Tumor Spheroids. Methods Mol Biol 2023; 2614:139-149. [PMID: 36587124 DOI: 10.1007/978-1-0716-2914-7_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Oncolytic viruses (OVs) rapidly and specifically replicate in and kill tumor cells. OV-targeted infection of malignant cells has the potential to create an "inflammatory storm" that stimulates both innate and adaptive anti-tumor immune responses. The generation of anti-tumor immunity following OV treatment has been shown to be crucial for effective therapy. Therefore, establishing methodologies to measure the generation of anti-tumor T cell responses following OV infection in in vitro assays, which better mimic the complexity of the human tumor microenvironment (TME), will be critical to harness the full potential of OV therapy. Such experimental platforms will accelerate the development of next-generation OVs that are capable of overcoming immunosuppressive networks found within the tumor microenvironment. Here we describe a method that was designed to test the generation and quantification of human tumor-specific T cells following OV infection of 3D tumor spheroids cultured with or without fibroblasts.
Collapse
|
|
12
|
Fang C, Xiao G, Wang T, Song L, Peng B, Xu B, Zhang K. Emerging Nano-/Biotechnology Drives Oncolytic Virus-Activated and Combined Cancer Immunotherapy. RESEARCH 2023; 6:0108. [PMID: 37040283 PMCID: PMC10079287 DOI: 10.34133/research.0108] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 03/15/2023] [Indexed: 04/05/2023]
Abstract
Oncolytic viruses (OVs) as one promising antitumor methods have made important contributions to tumor immunotherapy, which arouse increasing attention. They provide the dual mechanisms including direct killing effect toward tumor cells and immune activation for elevating antitumor responses, which have been proved in many preclinical studies. Especially, natural or genetically modified viruses as clinical immune preparations have emerged as a new promising approach objective to oncology treatment. The approval of talimogene laherparepvec (T-VEC) by the U.S. Food and Drug Administration (FDA) for the therapy of advanced melanoma could be considered as a milestone achievement in the clinical translation of OV. In this review, we first discussed the antitumor mechanisms of OVs with an emphasis on targeting, replication, and propagation. We further outlined the state of the art of current OVs in tumor and underlined the activated biological effects especially including immunity. More significantly, the enhanced immune responses based on OVs were systematically discussed from different perspectives such as combination with immunotherapy, genetic engineering of OVs, integration with nanobiotechnology or nanoparticles, and antiviral response counteraction, where their principles were shed light on. The development of OVs in the clinics was also highlighted to analyze the actuality and concerns of different OV applications in clinical trials. At last, the future perspectives and challenges of OVs as an already widely accepted treatment means were discussed. This review will provide a systematic review and deep insight into OV development and also offer new opportunities and guidance pathways to drive the further clinical translation.
Collapse
Affiliation(s)
- Chao Fang
- Central Laboratory and Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine,
Tongji University, No. 301 Yan-chang-zhong Road, Shanghai 200072, China
| | - Gaozhe Xiao
- National Center for International Research of Bio-targeting Theranostics,
Guangxi Medical University, No. 22 Shuangyong Road 22, Nanning, Guangxi 530021, China
| | - Taixia Wang
- Central Laboratory and Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine,
Tongji University, No. 301 Yan-chang-zhong Road, Shanghai 200072, China
| | - Li Song
- Central Laboratory and Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine,
Tongji University, No. 301 Yan-chang-zhong Road, Shanghai 200072, China
| | - Bo Peng
- Central Laboratory and Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine,
Tongji University, No. 301 Yan-chang-zhong Road, Shanghai 200072, China
| | - Bin Xu
- Department of Urology, Shanghai Ninth People’s Hospital,
Shanghai Jiaotong University School of Medicine, No. 639 Zhizaoju Road, Huangpu, Shanghai 200011, China
| | - Kun Zhang
- Central Laboratory and Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine,
Tongji University, No. 301 Yan-chang-zhong Road, Shanghai 200072, China
- National Center for International Research of Bio-targeting Theranostics,
Guangxi Medical University, No. 22 Shuangyong Road 22, Nanning, Guangxi 530021, China
| |
Collapse
|
|
13
|
Liu X, Zhang J, Feng K, Wang S, Chen L, Niu S, Lu Q, Fang Y. Efficacy and safety of oncolytic virus combined with chemotherapy or immune checkpoint inhibitors in solid tumor patients: A meta-analysis. Front Pharmacol 2022; 13:1023533. [PMID: 36452227 PMCID: PMC9702820 DOI: 10.3389/fphar.2022.1023533] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/24/2022] [Indexed: 08/29/2023] Open
Abstract
Background: In recent years, several clinical trials have focused on oncolytic virus (OVs) combined with chemotherapy or immune checkpoint inhibitors (ICIs) in solid tumor patients, which showed encouraging effects. However, few studies have concentrated on the summary on the safety and efficacy of the combined treatments. Therefore, we conducted this meta-analysis to explore the safety and curative effect of the combined therapy. Methods: We searched the PubMed, Cochrane Library, Embase, and Clinicaltrials.gov databases to comprehensively select articles on OVs combined with chemotherapy or ICIs for the solid tumor treatment. Overall survival (OS), progression-free survival (PFS), 1-year survival rate, 2-year survival rate, objective response rate (ORR), and adverse events (AEs) were the outcomes. Results: Fifteen studies with 903 patients were included in this meta-analysis. The pooled ORR was 32% [95% confidence interval (CI): 27-36%, I2 = 24.9%, p = 0.239]. Median OS and median PFS were 6.79 months (CI: 4.29-9.30, I2 = 62.9%, p = 0.044) and 3.40 months (CI: 2.59-4.22, I2 = 0.0%, p = 0.715), respectively. The 1-year survival rate was 38% (CI: 0.29-0.47, I2 = 62.9%, p = 0.044), and the 2-year survival rate was 24% (CI: 12-37%, I2 = 0.0%, p = 0.805). The most common AEs were fever (63%, CI: 57-69%, I2 = 2.3%, p = 0.402), fatigue (58%, CI: 51-65%, I2 = 49.2%, p = 0.096), chill (52%, CI: 43-60%, I2 = 0.0%, p = 0.958), and neutropenia (53%, CI: 47-60%, I2 = 0.0%, p = 0.944). Conclusion: OVs combined with ICIs showed a better efficacy than OVs combined with chemotherapy, which lends support to further clinical trials of OVs combined with ICIs. In addition, OVs combined with pembrolizumab can exert increased safety and efficacy. The toxicity of grades ≥3 should be carefully monitored and observed. However, high-quality, large-scale clinical trials should be completed to further confirm the efficacy and safety of OVs combined with ICIs. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/login.php], identifier [RD42022348568].
Collapse
Affiliation(s)
- Xiangxing Liu
- Department of Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Jiaojiao Zhang
- Department of Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Keqing Feng
- Department of Clinical Pharmacy, Ocean University of China, Qingdao, China
| | - Simin Wang
- Department of Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Liming Chen
- Nursing Department, Peking University People’s Hospital, Beijing, China
| | - Suping Niu
- Clinical Trial Institution, Scientific Research Department, Peking University People’s Hospital, Beijing, China
| | - Qian Lu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Yi Fang
- Clinical Trial Institution, Peking University People’s Hospital, Beijing, China
| |
Collapse
|
|
14
|
Mussafi O, Mei J, Mao W, Wan Y. Immune checkpoint inhibitors for PD-1/PD-L1 axis in combination with other immunotherapies and targeted therapies for non-small cell lung cancer. Front Oncol 2022; 12:948405. [PMID: 36059606 PMCID: PMC9430651 DOI: 10.3389/fonc.2022.948405] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/22/2022] [Indexed: 12/13/2022] Open
Abstract
It has been widely acknowledged that the use of immune checkpoint inhibitors (ICI) is an effective therapeutic treatment in many late-stage cancers. However, not all patients could benefit from ICI therapy. Several biomarkers, such as high expression of PD-L1, high mutational burden, and higher number of tumor infiltration lymphocytes have shown to predict clinical benefit from immune checkpoint therapies. One approach using ICI in combination with other immunotherapies and targeted therapies is now being investigated to enhance the efficacy of ICI alone. In this review, we summarized the use of other promising immunotherapies and targeted therapies in combination with ICI in treatment of lung cancers. The results from multiple animals and clinical trials were reviewed. We also briefly discussed the possible outlooks for future treatment.
Collapse
Affiliation(s)
- Ofek Mussafi
- Department of Cardiothoracic Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
- The Pq Laboratory of BiomeDx/Rx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY, United States
| | - Jie Mei
- Department of Oncology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Wenjun Mao
- Department of Cardiothoracic Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Yuan Wan
- The Pq Laboratory of BiomeDx/Rx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY, United States
| |
Collapse
|
|
15
|
Samson A, West EJ, Carmichael J, Scott KJ, Turnbull S, Kuszlewicz B, Dave RV, Peckham-Cooper A, Tidswell E, Kingston J, Johnpulle M, da Silva B, Jennings VA, Bendjama K, Stojkowitz N, Lusky M, Prasad K, Toogood GJ, Auer R, Bell J, Twelves CJ, Harrington KJ, Vile RG, Pandha H, Errington-Mais F, Ralph C, Newton DJ, Anthoney A, Melcher AA, Collinson F. Neoadjuvant Intravenous Oncolytic Vaccinia Virus Therapy Promotes Anticancer Immunity in Patients. Cancer Immunol Res 2022; 10:745-756. [PMID: 35439304 PMCID: PMC9381099 DOI: 10.1158/2326-6066.cir-21-0171] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 08/09/2021] [Accepted: 04/15/2022] [Indexed: 01/07/2023]
Abstract
Improving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases or metastatic melanoma were treated with a single intravenous infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec-associated side effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells. Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with IFNα secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anticancer immunity. In the 2 patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of presurgical oncolytic vaccinia virus-based therapies to stimulate anticancer immunity and increase the chances to cure patients with cancer.
Collapse
Affiliation(s)
- Adel Samson
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom.,Corresponding Author: Adel Samson, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom. Phone: 011-3343-8449; E-mail:
| | - Emma J. West
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | - Jonathan Carmichael
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | - Karen J. Scott
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | - Samantha Turnbull
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | - Bethany Kuszlewicz
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | - Rajiv V. Dave
- Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | | | - Emma Tidswell
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | | | | | - Barbara da Silva
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | - Victoria A. Jennings
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | | | | | | | - K.R. Prasad
- Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | | | - Rebecca Auer
- Ontario Health Research Institute, Ottawa, Canada
| | - John Bell
- Ontario Health Research Institute, Ottawa, Canada
| | - Chris J. Twelves
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | | | | | | | - Fiona Errington-Mais
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | - Christy Ralph
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | - Darren J. Newton
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | - Alan Anthoney
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | | | - Fiona Collinson
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| |
Collapse
|
|
16
|
Schuelke MR, Gundelach JH, Coffey M, West E, Scott K, Johnson DR, Samson A, Melcher A, Vile RG, Bram RJ. Phase I trial of sargramostim/pelareorep therapy in pediatric patients with recurrent or refractory high-grade brain tumors. Neurooncol Adv 2022; 4:vdac085. [PMID: 35821679 PMCID: PMC9268737 DOI: 10.1093/noajnl/vdac085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background Brain tumors are the leading cause of cancer death for pediatric patients. Pelareorep, an immunomodulatory oncolytic reovirus, has intravenous efficacy in preclinical glioma models when preconditioned with GM-CSF (sargramostim). We report a phase I trial with the primary goal of evaluating the safety of sargramostim/pelareorep in pediatric patients with recurrent or refractory high-grade brain tumors and a secondary goal of characterizing immunologic responses. Methods The trial was open to pediatric patients with recurrent or refractory high-grade brain tumors (3 + 3 cohort design). Each cycle included 3 days of subcutaneous sargramostim followed by 2 days of intravenous pelareorep. Laboratory studies and imaging were acquired upon recruitment and periodically thereafter. Results Six patients participated, including three glioblastoma, two diffuse intrinsic pontine glioma, and one medulloblastoma. Two pelareorep dose levels of 3 × 108 and 5 × 108 tissue culture infectious dose 50 (TCID50) were assessed. One patient experienced a dose limiting toxicity of persistent hyponatremia. Common low-grade (1 or 2) adverse events included transient fatigue, hypocalcemia, fever, flu-like symptoms, thrombocytopenia, and leukopenia. High-grade (3 or 4) adverse events included neutropenia, lymphopenia, leukopenia, hypophosphatemia, depressed level of consciousness, and confusion. All patients progressed on therapy after a median of 32.5 days and died a median of 108 days after recruitment. Imaging at progression did not show evidence of pseudoprogression or inflammation. Correlative assays revealed transient but consistent changes in immune cells across patients. Conclusions Sargramostim/pelareorep was administered to pediatric patients with recurrent or refractory high-grade brain tumors. Hyponatremia was the only dose limiting toxicity (DLT), though maximum tolerated dose (MTD) was not determined.
Collapse
Affiliation(s)
- Matthew R Schuelke
- Medical Scientist Training Program, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Matt Coffey
- Oncolytics Biotech, Calgary, Alberta, Canada
| | - Emma West
- Faculty of Medicine and Health, Leeds Institute of Medical Research, University of Leeds, St James' University Hospital, Leeds, UK
| | - Karen Scott
- Faculty of Medicine and Health, Leeds Institute of Medical Research, University of Leeds, St James' University Hospital, Leeds, UK
| | - Derek R Johnson
- Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Adel Samson
- Faculty of Medicine and Health, Leeds Institute of Medical Research, University of Leeds, St James' University Hospital, Leeds, UK
| | - Alan Melcher
- The Institute of Cancer Research/Royal Marsden, National Institute for Health Research Biomedical Research Centre, London, UK
| | - Richard G Vile
- Faculty of Medicine and Health, Leeds Institute of Medical Research, University of Leeds, St James' University Hospital, Leeds, UK
| | - Richard J Bram
- Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
|
17
|
Roulstone V, Mansfield D, Harris RJ, Twigger K, White C, de Bono J, Spicer J, Karagiannis SN, Vile R, Pandha H, Melcher A, Harrington K. Antiviral antibody responses to systemic administration of an oncolytic RNA virus: the impact of standard concomitant anticancer chemotherapies. J Immunother Cancer 2021; 9:jitc-2021-002673. [PMID: 34301814 PMCID: PMC8728387 DOI: 10.1136/jitc-2021-002673] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2021] [Indexed: 01/19/2023] Open
Abstract
Background Oncolytic reovirus therapy for cancer induces a typical antiviral response to this RNA virus, including neutralizing antibodies. Concomitant treatment with cytotoxic chemotherapies has been hypothesized to improve the therapeutic potential of the virus. Chemotherapy side effects can include immunosuppression, which may slow the rate of the antiviral antibody response, as well as potentially make the patient more vulnerable to viral infection. Method Reovirus neutralizing antibody data were aggregated from separate phase I clinical trials of reovirus administered as a single agent or in combination with gemcitabine, docetaxel, carboplatin and paclitaxel doublet or cyclophosphamide. In addition, the kinetics of individual antibody isotypes were profiled in sera collected in these trials. Results These data demonstrate preserved antiviral antibody responses, with only moderately reduced kinetics with some drugs, most notably gemcitabine. All patients ultimately produced an effective neutralizing antibody response. Conclusion Patients’ responses to infection by reovirus are largely unaffected by the concomitant drug treatments tested, providing confidence that RNA viral treatment or infection is compatible with standard of care treatments.
Collapse
Affiliation(s)
| | - David Mansfield
- Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
| | - Robert J Harris
- St John's Institute of Dermatology, Guy's Hospital, London, UK
| | - Katie Twigger
- Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
| | - Christine White
- Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
| | - Johann de Bono
- Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
| | - James Spicer
- St John's Institute of Dermatology, Guy's Hospital, London, UK
| | | | - Richard Vile
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Hardev Pandha
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Alan Melcher
- Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
| | - Kevin Harrington
- Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
| |
Collapse
|
|
18
|
Role of Myeloid Cells in Oncolytic Reovirus-Based Cancer Therapy. Viruses 2021; 13:v13040654. [PMID: 33920168 PMCID: PMC8070345 DOI: 10.3390/v13040654] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/06/2021] [Accepted: 04/08/2021] [Indexed: 12/11/2022] Open
Abstract
Oncolytic reovirus preferentially targets and kills cancer cells via the process of oncolysis, and additionally drives clinically favorable antitumor T cell responses that form protective immunological memory against cancer relapse. This two-prong attack by reovirus on cancers constitutes the foundation of its use as an anticancer oncolytic agent. Unfortunately, the efficacy of these reovirus-driven antitumor effects is influenced by the highly suppressive tumor microenvironment (TME). In particular, the myeloid cell populations (e.g., myeloid-derived suppressive cells and tumor-associated macrophages) of highly immunosuppressive capacities within the TME not only affect oncolysis but also actively impair the functioning of reovirus-driven antitumor T cell immunity. Thus, myeloid cells within the TME play a critical role during the virotherapy, which, if properly understood, can identify novel therapeutic combination strategies potentiating the therapeutic efficacy of reovirus-based cancer therapy.
Collapse
|
|
19
|
Valdivia G, Alonso-Diez Á, Pérez-Alenza D, Peña L. From Conventional to Precision Therapy in Canine Mammary Cancer: A Comprehensive Review. Front Vet Sci 2021; 8:623800. [PMID: 33681329 PMCID: PMC7925635 DOI: 10.3389/fvets.2021.623800] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/11/2021] [Indexed: 12/16/2022] Open
Abstract
Canine mammary tumors (CMTs) are the most common neoplasm in intact female dogs. Canine mammary cancer (CMC) represents 50% of CMTs, and besides surgery, which is the elective treatment, additional targeted and non-targeted therapies could offer benefits in terms of survival to these patients. Also, CMC is considered a good spontaneous intermediate animal model for the research of human breast cancer (HBC), and therefore, the study of new treatments for CMC is a promising field in comparative oncology. Dogs with CMC have a comparable disease, an intact immune system, and a much shorter life span, which allows the achievement of results in a relatively short time. Besides conventional chemotherapy, innovative therapies have a large niche of opportunities. In this article, a comprehensive review of the current research in adjuvant therapies for CMC is conducted to gather available information and evaluate the perspectives. Firstly, updates are provided on the clinical-pathological approach and the use of conventional therapies, to delve later into precision therapies against therapeutic targets such as hormone receptors, tyrosine kinase receptors, p53 tumor suppressor gene, cyclooxygenases, the signaling pathways involved in epithelial-mesenchymal transition, and immunotherapy in different approaches. A comparison of the different investigations on targeted therapies in HBC is also carried out. In the last years, the increasing number of basic research studies of new promising therapeutic agents on CMC cell lines and CMC mouse xenografts is outstanding. As the main conclusion of this review, the lack of effort to bring the in vitro studies into the field of applied clinical research emerges. There is a great need for well-planned large prospective randomized clinical trials in dogs with CMC to obtain valid results for both species, humans and dogs, on the use of new therapies. Following the One Health concept, human and veterinary oncology will have to join forces to take advantage of both the economic and technological resources that are invested in HBC research, together with the innumerable advantages of dogs with CMC as a spontaneous animal model.
Collapse
Affiliation(s)
- Guillermo Valdivia
- Department Animal Medicine, Surgery and Pathology, Veterinary School, Complutense University of Madrid, Madrid, Spain
- Mammary Oncology Unit, Complutense Veterinary Teaching Hospital, Complutense University of Madrid, Madrid, Spain
| | - Ángela Alonso-Diez
- Department Animal Medicine, Surgery and Pathology, Veterinary School, Complutense University of Madrid, Madrid, Spain
- Mammary Oncology Unit, Complutense Veterinary Teaching Hospital, Complutense University of Madrid, Madrid, Spain
| | - Dolores Pérez-Alenza
- Department Animal Medicine, Surgery and Pathology, Veterinary School, Complutense University of Madrid, Madrid, Spain
- Mammary Oncology Unit, Complutense Veterinary Teaching Hospital, Complutense University of Madrid, Madrid, Spain
| | - Laura Peña
- Department Animal Medicine, Surgery and Pathology, Veterinary School, Complutense University of Madrid, Madrid, Spain
- Mammary Oncology Unit, Complutense Veterinary Teaching Hospital, Complutense University of Madrid, Madrid, Spain
| |
Collapse
|
|
20
|
Müller L, Berkeley R, Barr T, Ilett E, Errington-Mais F. Past, Present and Future of Oncolytic Reovirus. Cancers (Basel) 2020; 12:E3219. [PMID: 33142841 PMCID: PMC7693452 DOI: 10.3390/cancers12113219] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/28/2020] [Accepted: 10/30/2020] [Indexed: 12/12/2022] Open
Abstract
Oncolytic virotherapy (OVT) has received significant attention in recent years, especially since the approval of talimogene Laherparepvec (T-VEC) in 2015 by the Food and Drug administration (FDA). Mechanistic studies of oncolytic viruses (OVs) have revealed that most, if not all, OVs induce direct oncolysis and stimulate innate and adaptive anti-tumour immunity. With the advancement of tumour modelling, allowing characterisation of the effects of tumour microenvironment (TME) components and identification of the cellular mechanisms required for cell death (both direct oncolysis and anti-tumour immune responses), it is clear that a "one size fits all" approach is not applicable to all OVs, or indeed the same OV across different tumour types and disease locations. This article will provide an unbiased review of oncolytic reovirus (clinically formulated as pelareorep), including the molecular and cellular requirements for reovirus oncolysis and anti-tumour immunity, reports of pre-clinical efficacy and its overall clinical trajectory. Moreover, as it is now abundantly clear that the true potential of all OVs, including reovirus, will only be reached upon the development of synergistic combination strategies, reovirus combination therapeutics will be discussed, including the limitations and challenges that remain to harness the full potential of this promising therapeutic agent.
Collapse
|
|
21
|
Marotel M, Hasim MS, Hagerman A, Ardolino M. The two-faces of NK cells in oncolytic virotherapy. Cytokine Growth Factor Rev 2020; 56:59-68. [PMID: 32586674 DOI: 10.1016/j.cytogfr.2020.06.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 06/04/2020] [Indexed: 12/17/2022]
Abstract
Oncolytic viruses (OVs) are immunotherapeutics capable of directly killing cancer cells and with potent immunostimulatory properties. OVs exert their antitumor effect, at least partially, by activating the antitumor immune response, of which NK cells are an important component. However, if on the one hand increasing evidence revealed that NK cells are important mediators of oncolytic virotherapy, on the other hand, NK cells have evolved to fight viral infections, and therefore they can have a detrimental effect for the efficacy of OVs. In this review, we will discuss the dichotomy between the antitumor and antiviral functions of NK cells related to oncolytic virotherapy. We will also review NK cell-based and OV-based therapies, engineered OVs aimed at enhancing immune stimulation, and combination therapies involving OVs and NK cells currently used in cancer immunotherapy.
Collapse
Affiliation(s)
- M Marotel
- Ottawa Hospital Research Institute, Cancer Therapeutics Program, Ottawa, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Canada
| | - M S Hasim
- Ottawa Hospital Research Institute, Cancer Therapeutics Program, Ottawa, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Canada
| | - A Hagerman
- Ottawa Hospital Research Institute, Cancer Therapeutics Program, Ottawa, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Canada; University of Ottawa, Department of Biochemistry, Microbiology and Immunology, Ottawa, Canada
| | - M Ardolino
- Ottawa Hospital Research Institute, Cancer Therapeutics Program, Ottawa, Canada; Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Canada; University of Ottawa, Department of Biochemistry, Microbiology and Immunology, Ottawa, Canada.
| |
Collapse
|
|
22
|
Oncolytic measles virus therapy enhances tumor antigen-specific T-cell responses in patients with multiple myeloma. Leukemia 2020; 34:3310-3322. [PMID: 32327728 PMCID: PMC7581629 DOI: 10.1038/s41375-020-0828-7] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 03/13/2020] [Accepted: 03/30/2020] [Indexed: 12/24/2022]
Abstract
Oncolytic virus therapy leads to immunogenic death of virus-infected tumor cells and this has been shown in preclinical models to enhance the cytotoxic T-lymphocyte response against tumor-associated antigens (TAAs), leading to killing of uninfected tumor cells. To investigate whether oncolytic virotherapy can increase immune responses to tumor antigens in human subjects, we studied T-cell responses against a panel of known myeloma TAAs using PBMC samples obtained from ten myeloma patients before and after systemic administration of an oncolytic measles virus encoding sodium iodide symporter (MV-NIS). Despite their prior exposures to multiple immunosuppressive antimyeloma treatment regimens, T-cell responses to some of the TAAs were detectable even before measles virotherapy. Measurable baseline T-cell responses against MAGE-C1 and hTERT were present. Furthermore, MV-NIS treatment significantly (P < 0.05) increased T-cell responses against MAGE-C1 and MAGE-A3. Interestingly, one patient who achieved complete remission after MV-NIS therapy had strong baseline T-cell responses both to measles virus proteins and to eight of the ten tested TAAs. Our data demonstrate that oncolytic virotherapy can function as an antigen agnostic vaccine, increasing cytotoxic T-lymphocyte responses against TAAs in patients with multiple myeloma, providing a basis for continued exploration of this modality in combination with immune checkpoint blockade.
Collapse
|
|
23
|
Oncolytic immunotherapy and bortezomib synergy improves survival of refractory multiple myeloma in a preclinical model. Blood Adv 2020; 3:797-812. [PMID: 30850386 DOI: 10.1182/bloodadvances.2018025593] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 01/14/2019] [Indexed: 02/06/2023] Open
Abstract
The oncolytic reovirus (RV) has demonstrated clinical efficacy and minimal toxicity in a variety of cancers, including multiple myeloma (MM). MM is a malignancy of plasma cells that is considered treatable but incurable because of the 90% relapse rate that is primarily from drug resistance. The systemic nature of MM and the antitumor immunosuppression by its tumor microenvironment presents an ongoing therapeutic challenge. In the present study, we demonstrate that RV synergizes with the standard-of-care MM drug bortezomib (BTZ) and, importantly, enhances its therapeutic potential in therapy-resistant human MM cell lines in vitro. Using the syngeneic Vk*MYC BTZ-resistant immunocompetent transplantable MM murine model, we also demonstrate that mice harboring BTZ-insensitive MM tumors respond to the RV/BTZ combination treatment in terms of decreased tumor burden and improved overall survival (P < .00001). We demonstrate that BTZ augments RV replication in tumor-associated endothelial cells and myeloma cells, leading to enhanced viral delivery and thereby stimulating cytokine release, immune activity, apoptosis, and reduction of the MM-associated immune suppression. We conclude that combined RV/BTZ is an attractive therapeutic strategy with no safety signals for the treatment of MM.
Collapse
|
|
24
|
Jayawardena N, Poirier JT, Burga LN, Bostina M. Virus-Receptor Interactions and Virus Neutralization: Insights for Oncolytic Virus Development. Oncolytic Virother 2020; 9:1-15. [PMID: 32185149 PMCID: PMC7064293 DOI: 10.2147/ov.s186337] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 02/09/2020] [Indexed: 12/24/2022] Open
Abstract
Oncolytic viruses (OVs) are replication competent agents that selectively target cancer cells. After penetrating the tumor cell, viruses replicate and eventually trigger cell lysis, releasing the new viral progeny, which at their turn will attack and kill neighbouring cells. The ability of OVs to self-amplify within the tumor while sparing normal cells can provide several advantages including the capacity to encode and locally produce therapeutic protein payloads, and to prime the host immune system. OVs targeting of cancer cells is mediated by host factors that are differentially expressed between normal tissue and tumors, including viral receptors and internalization factors. In this review article, we will discuss the evolution of oncolytic viruses that have reached the stage of clinical trials, their mechanisms of oncolysis, cellular receptors, strategies for targeting cancers, viral neutralization and developments to bypass virus neutralization.
Collapse
Affiliation(s)
- Nadishka Jayawardena
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - John T Poirier
- Department of Medicine and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Laura N Burga
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - Mihnea Bostina
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
- Otago Micro and Nano Imaging, University of Otago, Dunedin, New Zealand
| |
Collapse
|
|
25
|
Wedekind MF, Cripe TP. Oncolytic Viruses and Their Potential as a Therapeutic Opportunity in Osteosarcoma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1258:77-89. [PMID: 32767235 DOI: 10.1007/978-3-030-43085-6_5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Osteosarcoma remains an unmet medical need. Oncolytic viruses are gaining traction as novel cancer therapeutics. These viruses are either naturally nonpathogenic or engineered to be safe by specific genetic deletions yet retain the ability to infect and kill human cancer cells and elicit anticancer immunity. Some versions are being specifically designed and tested in patients with osteosarcoma, though due to their generalized mechanism of action most are being tested in patients across a broad range of cancer types. The activity of these viruses is impacted not only by the susceptibility of tumor cells to infection but also by the tumor microenvironment (TME) and by tumor immunogenicity. Here we review the field of oncolytic viruses with a particular emphasis on highlighting any available data in preclinical osteosarcoma models or in patients with osteosarcoma. While in general the viruses have been shown safe to administer to patients by a variety of routes, their therapeutic efficacy to date has been limited. Given the low rate of adverse events and the likely absence of long-term side effects, the utility of oncolytic viruses will most likely be realized when used in combination with other agents.
Collapse
Affiliation(s)
| | - Timothy P Cripe
- Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
| |
Collapse
|
|
26
|
Harrington K, Freeman DJ, Kelly B, Harper J, Soria JC. Optimizing oncolytic virotherapy in cancer treatment. Nat Rev Drug Discov 2019; 18:689-706. [PMID: 31292532 DOI: 10.1038/s41573-019-0029-0] [Citation(s) in RCA: 337] [Impact Index Per Article: 56.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2019] [Indexed: 02/07/2023]
Abstract
In the wake of the success of modern immunotherapy, oncolytic viruses (OVs) are currently seen as a potential therapeutic option for patients with cancer who do not respond or fail to achieve durable responses following treatment with immune checkpoint inhibitors. OVs offer a multifaceted therapeutic platform because they preferentially replicate in tumour cells, can be engineered to express transgenes that augment their cytotoxic and immunostimulatory activities, and modulate the tumour microenvironment to optimize immune-mediated tumour eradication, both at locoregional and systemic sites of disease. Lysis of tumour cells releases tumour-specific antigens that trigger both the innate and adaptive immune systems. OVs also represent attractive combination partners with other systemically delivered agents by virtue of their highly favourable safety profiles. Rational combinations of OVs with different immune modifiers and/or antitumour agents, based on mechanisms of tumour resistance to immune-mediated attack, may benefit the large, currently underserved, population of patients who respond poorly to immune checkpoint inhibition.
Collapse
Affiliation(s)
- Kevin Harrington
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
| | | | - Beth Kelly
- Oncology R&D, AstraZeneca, Gaithersburg, MD, USA
| | | | - Jean-Charles Soria
- Oncology R&D, AstraZeneca, Gaithersburg, MD, USA.,Department of Medicine and Medical Oncology, Université Paris-Sud, Orsay, France
| |
Collapse
|
|
27
|
Mast Cells and Natural Killer Cells-A Potentially Critical Interaction. Viruses 2019; 11:v11060514. [PMID: 31167464 PMCID: PMC6631774 DOI: 10.3390/v11060514] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 05/31/2019] [Accepted: 06/02/2019] [Indexed: 12/16/2022] Open
Abstract
Natural killer (NK) cells play critical roles in host defense against infectious agents or neoplastic cells. NK cells provide a rapid innate immune response including the killing of target cells without the need for priming. However, activated NK cells can show improved effector functions. Mast cells are also critical for early host defense against a variety of pathogens and are predominately located at mucosal surfaces and close to blood vessels. Our group has recently shown that virus-infected mast cells selectively recruit NK cells and positively modulate their functions through mechanisms dependent on soluble mediators, such as interferons. Here, we review the possible consequences of this interaction in both host defense and pathologies involving NK cell and mast cell activation.
Collapse
|
|
28
|
Schijven J, Brizee S, Teunis P, de Vos C, Eblé P, Rutjes S. Quantitative Assessment of the Health Risk for Livestock When Animal Viruses Are Applied in Human Oncolytic Therapy: A Case Study for Seneca Valley Virus. RISK ANALYSIS : AN OFFICIAL PUBLICATION OF THE SOCIETY FOR RISK ANALYSIS 2019; 39:982-991. [PMID: 30395685 DOI: 10.1111/risa.13227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 10/01/2018] [Indexed: 06/08/2023]
Abstract
Some viruses cause tumor regression and can be used to treat cancer patients; these viruses are called oncolytic viruses. To assess whether oncolytic viruses from animal origin excreted by patients pose a health risk for livestock, a quantitative risk assessment (QRA) was performed to estimate the risk for the Dutch pig industry after environmental release of Seneca Valley virus (SVV). The QRA assumed SVV excretion in stool by one cancer patient on Day 1 in the Netherlands, discharge of SVV with treated wastewater into the river Meuse, downstream intake of river water for drinking water production, and consumption of this drinking water by pigs. Dose-response curves for SVV infection and clinical disease in pigs were constructed from experimental data. In the worst scenario (four log10 virus reduction by drinking water treatment and a farm with 10,000 pigs), the infection risk is less than 1% with 95% certainty. The risk of clinical disease is almost seven orders of magnitude lower. Risks may increase proportionally with the numbers of treated patients and days of virus excretion. These data indicate that application of wild-type oncolytic animal viruses may infect susceptible livestock. A QRA regarding the use of oncolytic animal virus is, therefore, highly recommended. For this, data on excretion by patients, and dose-response parameters for infection and clinical disease in livestock, should be studied.
Collapse
Affiliation(s)
- Jack Schijven
- Laboratory for Zoonoses and Environmental Microbiology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
- Faculty of Geosciences, Utrecht University, Utrecht, The Netherlands
| | - Sabrina Brizee
- Laboratory for Zoonoses and Environmental Microbiology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
| | - Peter Teunis
- Laboratory for Zoonoses and Environmental Microbiology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
- Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Clazien de Vos
- Wageningen Bioveterinary Research (WBVR), Wageningen University & Research, Lelystad, The Netherlands
| | - Phaedra Eblé
- Wageningen Bioveterinary Research (WBVR), Wageningen University & Research, Lelystad, The Netherlands
| | - Saskia Rutjes
- Laboratory for Zoonoses and Environmental Microbiology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
| |
Collapse
|
|
29
|
Martinez-Quintanilla J, Seah I, Chua M, Shah K. Oncolytic viruses: overcoming translational challenges. J Clin Invest 2019; 129:1407-1418. [PMID: 30829653 DOI: 10.1172/jci122287] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Oncolytic virotherapy (OVT) is a promising approach in which WT or engineered viruses selectively replicate and destroy tumor cells while sparing normal ones. In the last two decades, different oncolytic viruses (OVs) have been modified and tested in a number of preclinical studies, some of which have led to clinical trials in cancer patients. These clinical trials have revealed several critical limitations with regard to viral delivery, spread, resistance, and antiviral immunity. Here, we focus on promising research strategies that have been developed to overcome the aforementioned obstacles. Such strategies include engineering OVs to target a broad spectrum of tumor cells while evading the immune system, developing unique delivery mechanisms, combining other immunotherapeutic agents with OVT, and using clinically translatable mouse tumor models to potentially translate OVT more readily into clinical settings.
Collapse
Affiliation(s)
| | - Ivan Seah
- Center for Stem Cell Therapeutics and Imaging and
| | - Melissa Chua
- Center for Stem Cell Therapeutics and Imaging and.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Khalid Shah
- Center for Stem Cell Therapeutics and Imaging and.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
| |
Collapse
|
|
30
|
Ma W, He H, Wang H. Oncolytic herpes simplex virus and immunotherapy. BMC Immunol 2018; 19:40. [PMID: 30563466 PMCID: PMC6299639 DOI: 10.1186/s12865-018-0281-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 12/06/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Oncolytic viruses have been proposed to be employed as a potential treatment of cancer. Well targeted, they will serve the purpose of cracking tumor cells without causing damage to normal cells. In this category of oncolytic viral drugs human pathogens herpes simplex virus (HSV) is especially suitable for the cause. Although most viral infection causes antiviral reaction in the host, HSV has multiple mechanisms to evade those responses. Powerful anti-tumor effect can thus be achieved via genetic manipulation of the HSV genes involved in this evading mechanism, namely deletions or mutations that adapt its function towards a tumor microenvironment. Currently, oncolytic HSV (oHSV) is widely use in clinical; moreover, there's hope that its curative effect will be further enhanced through the combination of oHSV with both traditional and emerging therapeutics. RESULTS In this review, we provide a summary of the HSV host antiviral response evasion mechanism, HSV expresses immune evasion genes such as ICP34.5, ICP0, Us3, which are involved in inducing and activating host responses, so that the virus can evade the immune system and establish effective long-term latent infection; we outlined details of the oHSV strains generated by removing genes critical to viral replication such as ICP34.5, ICP0, and inserting therapeutic genes such as LacZ, granulocyte macrophage colony-stimulating factor (GM-CSF); security and limitation of some oHSV such G207, 1716, OncoVEX, NV1020, HF10, G47 in clinical application; and the achievements of oHSV combined with immunotherapy and chemotherapy. CONCLUSION We reviewed the immunotherapy mechanism of the oHSV and provided a series of cases. We also pointed out that an in-depth study of the application of oHSV in cancer treatment will potentially benefits cancer patients more.
Collapse
Affiliation(s)
- Wenqing Ma
- Ruminant Diseases Research Center, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China
| | - Hongbin He
- Ruminant Diseases Research Center, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China.
| | - Hongmei Wang
- Ruminant Diseases Research Center, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China.
| |
Collapse
|
|
31
|
Sánchez D, Cesarman-Maus G, Amador-Molina A, Lizano M. Oncolytic Viruses for Canine Cancer Treatment. Cancers (Basel) 2018; 10:cancers10110404. [PMID: 30373251 PMCID: PMC6266482 DOI: 10.3390/cancers10110404] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/16/2018] [Accepted: 10/23/2018] [Indexed: 12/17/2022] Open
Abstract
Oncolytic virotherapy has been investigated for several decades and is emerging as a plausible biological therapy with several ongoing clinical trials and two viruses are now approved for cancer treatment in humans. The direct cytotoxicity and immune-stimulatory effects make oncolytic viruses an interesting strategy for cancer treatment. In this review, we summarize the results of in vitro and in vivo published studies of oncolytic viruses in different phases of evaluation in dogs, using PubMed and Google scholar as search platforms, without time restrictions (to date). Natural and genetically modified oncolytic viruses were evaluated with some encouraging results. The most studied viruses to date are the reovirus, myxoma virus, and vaccinia, tested mostly in solid tumors such as osteosarcomas, mammary gland tumors, soft tissue sarcomas, and mastocytomas. Although the results are promising, there are issues that need addressing such as ensuring tumor specificity, developing optimal dosing, circumventing preexisting antibodies from previous exposure or the development of antibodies during treatment, and assuring a reasonable safety profile, all of which are required in order to make this approach a successful therapy in dogs.
Collapse
Affiliation(s)
- Diana Sánchez
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico.
| | - Gabriela Cesarman-Maus
- Department of Hematology, Instituto Nacional de Cancerología, Mexico City 14080, Mexico.
| | - Alfredo Amador-Molina
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico.
| | - Marcela Lizano
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico.
| |
Collapse
|
|
32
|
Berkeley RA, Steele LP, Mulder AA, van den Wollenberg DJM, Kottke TJ, Thompson J, Coffey M, Hoeben RC, Vile RG, Melcher A, Ilett EJ. Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy. Cancer Immunol Res 2018; 6:1161-1173. [PMID: 30209061 DOI: 10.1158/2326-6066.cir-18-0309] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 08/14/2018] [Accepted: 08/16/2018] [Indexed: 11/16/2022]
Abstract
Immunotherapy is showing promise for otherwise incurable cancers. Oncolytic viruses (OVs), developed as direct cytotoxic agents, mediate their antitumor effects via activation of the immune system. However, OVs also stimulate antiviral immune responses, including the induction of OV-neutralizing antibodies. Current dogma suggests that the presence of preexisting antiviral neutralizing antibodies in patients, or their development during viral therapy, is a barrier to systemic OV delivery, rendering repeat systemic treatments ineffective. However, we have found that human monocytes loaded with preformed reovirus-antibody complexes, in which the reovirus is fully neutralized, deliver functional replicative reovirus to tumor cells, resulting in tumor cell infection and lysis. This delivery mechanism is mediated, at least in part, by antibody receptors (in particular FcγRIII) that mediate uptake and internalization of the reovirus/antibody complexes by the monocytes. This finding has implications for oncolytic virotherapy and for the design of clinical OV treatment strategies. Cancer Immunol Res; 6(10); 1161-73. ©2018 AACR.
Collapse
Affiliation(s)
- Robert A Berkeley
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Lynette P Steele
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Aat A Mulder
- Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands
| | | | | | - Jill Thompson
- Department of Immunology, Mayo Clinic, Rochester, Minnesota
| | - Matthew Coffey
- Oncolytics Biotech Incorporated, Calgary, Alberta, Canada
| | - Rob C Hoeben
- Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands
| | - Richard G Vile
- Department of Immunology, Mayo Clinic, Rochester, Minnesota
| | - Alan Melcher
- Institute of Cancer Research, London, United Kingdom
| | - Elizabeth J Ilett
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
| |
Collapse
|
|
33
|
Bourhill T, Mori Y, Rancourt DE, Shmulevitz M, Johnston RN. Going (Reo)Viral: Factors Promoting Successful Reoviral Oncolytic Infection. Viruses 2018; 10:E421. [PMID: 30103501 PMCID: PMC6116061 DOI: 10.3390/v10080421] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 08/09/2018] [Accepted: 08/09/2018] [Indexed: 02/06/2023] Open
Abstract
Oncolytic viruses show intriguing potential as cancer therapeutic agents. These viruses are capable of selectively targeting and killing cancerous cells while leaving healthy cells largely unaffected. The use of oncolytic viruses for cancer treatments in selected circumstances has recently been approved by the Food and Drug Administration (FDA) of the US and work is progressing on engineering viral vectors for enhanced selectivity, efficacy and safety. However, a better fundamental understanding of tumour and viral biology is essential for the continued advancement of the oncolytic field. This knowledge will not only help to engineer more potent and effective viruses but may also contribute to the identification of biomarkers that can determine which patients will benefit most from this treatment. A mechanistic understanding of the overlapping activity of viral and standard chemotherapeutics will enable the development of better combinational approaches to improve patient outcomes. In this review, we will examine each of the factors that contribute to productive viral infections in cancerous cells versus healthy cells. Special attention will be paid to reovirus as it is a well-studied virus and the only wild-type virus to have received orphan drug designation by the FDA. Although considerable insight into reoviral biology exists, there remain numerous deficiencies in our understanding of the factors regulating its successful oncolytic infection. Here we will discuss what is known to regulate infection as well as speculate about potential new mechanisms that may enhance successful replication. A joint appreciation of both tumour and viral biology will drive innovation for the next generation of reoviral mediated oncolytic therapy.
Collapse
Affiliation(s)
- Tarryn Bourhill
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
| | - Yoshinori Mori
- Department of Gastroenterology, Nagoya City West Medical Center, Kita-Ku, Nagoya 467-8601, Japan.
| | - Derrick E Rancourt
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
| | - Maya Shmulevitz
- Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
| | - Randal N Johnston
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
| |
Collapse
|
|
34
|
Phillips MB, Stuart JD, Rodríguez Stewart RM, Berry JT, Mainou BA, Boehme KW. Current understanding of reovirus oncolysis mechanisms. Oncolytic Virother 2018; 7:53-63. [PMID: 29942799 PMCID: PMC6005300 DOI: 10.2147/ov.s143808] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Mammalian orthoreovirus (reovirus) is under development as a cancer virotherapy. Clinical trials demonstrate that reovirus-based therapies are safe and tolerated in patients with a wide variety of cancers. Although reovirus monotherapy has proven largely ineffective, reovirus sensitizes cancer cells to existing chemotherapeutic agents and radiation. Clinical trials are underway to test the efficacy of reovirus in combination with chemotherapeutic and radiation regimens and to evaluate the effectiveness of reovirus in conjunction with immunotherapies. Central to the use of reovirus to treat cancer is its capacity to directly kill cancer cells and alter the cellular environment to augment other therapies. Apoptotic cell death is a prominent mechanism of reovirus cancer cell killing. However, reoviruses can also kill cancer cells through nonapoptotic mechanisms. Here, we describe mechanisms of reovirus cancer cell killing, highlight how reovirus is used in combination with existing cancer treatments, and discuss what is known as to how reovirus modulates cancer immunotherapy.
Collapse
Affiliation(s)
- Matthew B Phillips
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA
| | - Johnasha D Stuart
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA
| | | | | | | | - Karl W Boehme
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA
| |
Collapse
|
|
35
|
Comins C, Simpson GR, Rogers W, Relph K, Harrington K, Melcher A, Roulstone V, Kyula J, Pandha H. Synergistic antitumour effects of rapamycin and oncolytic reovirus. Cancer Gene Ther 2018; 25:148-160. [PMID: 29720674 DOI: 10.1038/s41417-018-0011-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 08/30/2017] [Accepted: 08/31/2017] [Indexed: 12/24/2022]
Abstract
There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent, Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anticancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an antireovirus-neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin. However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death Annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic antitumour efficacy of reovirus and rapamycin combination.
Collapse
Affiliation(s)
- Charles Comins
- Oncology, Faculty of Health and Medical Sciences, University of Surrey, Leggett Building, Guildford, Surrey, GU2 7WG, UK
| | - Guy Richard Simpson
- Oncology, Faculty of Health and Medical Sciences, University of Surrey, Leggett Building, Guildford, Surrey, GU2 7WG, UK
| | - William Rogers
- Oncology, Faculty of Health and Medical Sciences, University of Surrey, Leggett Building, Guildford, Surrey, GU2 7WG, UK
| | - Kate Relph
- Oncology, Faculty of Health and Medical Sciences, University of Surrey, Leggett Building, Guildford, Surrey, GU2 7WG, UK
| | - Kevin Harrington
- Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK
| | - Alan Melcher
- Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK
| | - Victoria Roulstone
- Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK
| | - Joan Kyula
- Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK
| | - Hardev Pandha
- Oncology, Faculty of Health and Medical Sciences, University of Surrey, Leggett Building, Guildford, Surrey, GU2 7WG, UK.
| |
Collapse
|
|
36
|
Abstract
A group of impressive immunotherapies for cancer treatment, including immune checkpoint-blocking antibodies, gene therapy and immune cell adoptive cellular immunotherapy, have been established, providing new weapons to fight cancer. Natural killer (NK) cells are a component of the first line of defense against tumors and virus infections. Studies have shown dysfunctional NK cells in patients with cancer. Thus, restoring NK cell antitumor functionality could be a promising therapeutic strategy. NK cells that are activated and expanded ex vivo can supplement malfunctional NK cells in tumor patients. Therapeutic antibodies, chimeric antigen receptor (CAR), or bispecific proteins can all retarget NK cells precisely to tumor cells. Therapeutic antibody blockade of the immune checkpoints of NK cells has been suggested to overcome the immunosuppressive signals delivered to NK cells. Oncolytic virotherapy provokes antitumor activity of NK cells by triggering antiviral immune responses. Herein, we review the current immunotherapeutic approaches employed to restore NK cell antitumor functionality for the treatment of cancer.
Collapse
Affiliation(s)
- Yangxi Li
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China
| | - Rui Sun
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China
| |
Collapse
|
|
37
|
Hwang CC, Igase M, Sakurai M, Haraguchi T, Tani K, Itamoto K, Shimokawa T, Nakaichi M, Nemoto Y, Noguchi S, Coffey M, Okuda M, Mizuno T. Oncolytic reovirus therapy: Pilot study in dogs with spontaneously occurring tumours. Vet Comp Oncol 2017; 16:229-238. [PMID: 29076241 DOI: 10.1111/vco.12361] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 09/17/2017] [Accepted: 09/18/2017] [Indexed: 12/26/2022]
Abstract
Oncolytic virotherapy is a novel treatment involving replication-competent virus in the elimination of cancer. We have previously reported the oncolytic effects of reovirus in various canine cancer cell lines. This study aims to establish the safety profile of reovirus in dogs with spontaneously occurring tumours and to determine a recommended dosing regimen. Nineteen dogs with various tumours, mostly of advanced stages, were treated with reovirus, ranging from 1.0 × 108 to 5.0 × 109 TCID50 given as intratumour injection (IT) or intravenous infusion (IV) daily for up to 5 consecutive days in 1 or multiple treatment cycles. Adverse events (AEs) were graded according to the Veterinary Cooperative Oncology Group- Common Terminology Criteria for Adverse Events (VCOG-CTCAE) v1.1 guidelines. Viral shedding, neutralizing anti-reovirus antibody (NARA) production and immunohistochemical (IHC) detection of reovirus protein in the tumours were also assessed. AE was not observed in most dogs and events were limited to Grade I or II fever, vomiting, diarrhoea and inflammation of the injected tumour. No infectious virus was shed and all dogs had elevated NARA levels post-treatment. Although IHC results were only available in 6 dogs, 4 were detected positive for reovirus protein. In conclusion, reovirus is well-tolerated and can be given safely to tumour-bearing dogs according to the dosing regimen used in this study without significant concerns of viral shedding. Reovirus is also potentially effective in various types of canine tumours.
Collapse
Affiliation(s)
- C C Hwang
- Laboratory of Molecular Diagnostics and Therapeutics, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan
| | - M Igase
- Laboratory of Molecular Diagnostics and Therapeutics, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan
| | - M Sakurai
- Laboratory of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - T Haraguchi
- Laboratory of Small Animal Clinical Science (Surgical Division), Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - K Tani
- Laboratory of Veterinary Surgery, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - K Itamoto
- Laboratory of Small Animal Clinical Science (Surgical Division), Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - T Shimokawa
- Laboratory of Veterinary Internal Medicine, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - M Nakaichi
- Laboratory of Veterinary Radiology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Y Nemoto
- Laboratory of Molecular Diagnostics and Therapeutics, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan
| | - S Noguchi
- Laboratory of Molecular Diagnostics and Therapeutics, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan
| | - M Coffey
- Oncolytics Biotech Inc, Calgary, Canada
| | - M Okuda
- Laboratory of Veterinary Internal Medicine, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan.,Biomedical Science Center for Translational Research, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan
| | - T Mizuno
- Laboratory of Molecular Diagnostics and Therapeutics, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan.,Biomedical Science Center for Translational Research, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan
| |
Collapse
|
|
38
|
Zhao X, Ouyang W, Chester C, Long S, Wang N, He Z. Cytokine-induced killer cell delivery enhances the antitumor activity of oncolytic reovirus. PLoS One 2017; 12:e0184816. [PMID: 28922411 PMCID: PMC5602626 DOI: 10.1371/journal.pone.0184816] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 08/31/2017] [Indexed: 02/07/2023] Open
Abstract
Oncolytic viruses (OV) have recently emerged as a promising therapeutic modality in cancer treatment. OV selectively infect and kill tumor cells, while sparing untransformed cells. The direct cytotoxic effects combined with the capacity to trigger an immune response make OV an appealing combination partner in the burgeoning field of cancer immunotherapy. One of the leading OV therapeutic candidates is the double-stranded RNA virus reovirus. In order to improve the oncolytic activity of reovirus and allow for systemic administration despite the prevalence of neutralizing antibodies, cytokine-induced killer (CIK) cells were explored as cell carriers for reovirus delivery. In this study, CIK cells were successfully loaded with reovirus ex vivo, and viral replication was limited in CIK cells. Confocal microscopy and flow cytometry demonstrated that CIK cells retained reovirus on the surface. Moreover, CIK cells could promote reovirus infection of tumor cells in the presence of neutralizing antibodies; meanwhile, cytotoxicity of CIK cells was increased after loading with reovirus. These findings support further investigation of reovirus and CIK combination for antitumor therapy.
Collapse
Affiliation(s)
- Xing Zhao
- Stem Cell and Tissue Engineering Research Center, Guizhou Medical University, Guiyang, Guizhou, China
- Department of Immunology, Guizhou Medical University, Guiyang, Guizhou, China
| | - Weiwei Ouyang
- Department of Thoracic Oncology, Affiliated Hospital of Guizhou Medical University, and Guizhou Cancer Hospital, Guiyang, Guizhou, China
| | - Cariad Chester
- Department of Medicine, Division of Oncology, Stanford University, Stanford, California, United States of America
| | - Shiqi Long
- Department of Immunology, Guizhou Medical University, Guiyang, Guizhou, China
| | - Nianxue Wang
- Department of Immunology, Guizhou Medical University, Guiyang, Guizhou, China
| | - Zhixu He
- Stem Cell and Tissue Engineering Research Center, Guizhou Medical University, Guiyang, Guizhou, China
| |
Collapse
|
|
39
|
Jaime-Ramirez AC, Yu JG, Caserta E, Yoo JY, Zhang J, Lee TJ, Hofmeister C, Lee JH, Kumar B, Pan Q, Kumar P, Baiocchi R, Teknos T, Pichiorri F, Kaur B, Old M. Reolysin and Histone Deacetylase Inhibition in the Treatment of Head and Neck Squamous Cell Carcinoma. Mol Ther Oncolytics 2017; 5:87-96. [PMID: 28812060 PMCID: PMC5440762 DOI: 10.1016/j.omto.2017.05.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 05/03/2017] [Indexed: 02/09/2023] Open
Abstract
Oncolytic viruses (OVs) are emerging as powerful anti-cancer agents and are currently being tested for their safety and efficacy in patients. Reovirus (Reolysin), a naturally occurring non-pathogenic, double-stranded RNA virus, has natural oncolytic activity and is being tested in phase I-III clinical trials in a variety of tumor types. With its recent US Food and Drug Administration (FDA) orphan drug designation for several tumor types, Reolysin is a potential therapeutic agent for various cancers, including head and neck squamous cell carcinomas (HNSCCs), which have a 5-year survival of ∼55%. Histone deacetylase inhibitors (HDACis) comprise a structurally diverse class of compounds with targeted anti-cancer effects. The first FDA-approved HDACi, vorinostat (suberoylanilide hydroxamic acid [SAHA]), is currently being tested in patients with head and neck cancer. Recent findings indicate that HDAC inhibition in myeloma cells results in the upregulation of the Reolysin entry receptor, junctional adhesion molecule 1 (JAM-1), facilitating reovirus infection and tumor cell killing both in vitro and in vivo. In this study, we tested the anti-tumor efficacy of HDAC inhibitors AR-42 or SAHA in conjunction with Reolysin in HNSCCs. While HDAC inhibition increased JAM-1 and reovirus entry, the impact of this combination therapy was tested on the development of anti-tumor immune responses.
Collapse
Affiliation(s)
| | - Jun-Ge Yu
- Department of Otolaryngology-Head and Neck Surgery, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA
| | - Enrico Caserta
- Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Ji Young Yoo
- Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA
| | - Jianying Zhang
- Biomedical Informatics Department, Center for Biostatistics, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Tae Jin Lee
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA
| | - Craig Hofmeister
- Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - John H. Lee
- Department of Otolaryngology/Head and Neck Surgery, Sanford Health, Sioux Falls, SD 57105, USA
| | - Bhavna Kumar
- Department of Otolaryngology-Head and Neck Surgery, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA
| | - Quintin Pan
- Department of Otolaryngology-Head and Neck Surgery, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA
| | - Pawan Kumar
- Department of Otolaryngology-Head and Neck Surgery, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA
| | - Robert Baiocchi
- Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Theodoros Teknos
- Department of Otolaryngology-Head and Neck Surgery, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA
| | - Flavia Pichiorri
- Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Balveen Kaur
- Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA
| | - Matthew Old
- Department of Otolaryngology-Head and Neck Surgery, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA
| |
Collapse
|
|
40
|
African Swine Fever Virus NP868R Capping Enzyme Promotes Reovirus Rescue during Reverse Genetics by Promoting Reovirus Protein Expression, Virion Assembly, and RNA Incorporation into Infectious Virions. J Virol 2017; 91:JVI.02416-16. [PMID: 28298603 DOI: 10.1128/jvi.02416-16] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 03/07/2017] [Indexed: 12/25/2022] Open
Abstract
Reoviruses, like many eukaryotic viruses, contain an inverted 7-methylguanosine (m7G) cap linked to the 5' nucleotide of mRNA. The traditional functions of capping are to promote mRNA stability, protein translation, and concealment from cellular proteins that recognize foreign RNA. To address the role of mRNA capping during reovirus replication, we assessed the benefits of adding the African swine fever virus NP868R capping enzyme during reovirus rescue. C3P3, a fusion protein containing T7 RNA polymerase and NP868R, was found to increase protein expression 5- to 10-fold compared to T7 RNA polymerase alone while enhancing reovirus rescue from the current reverse genetics system by 100-fold. Surprisingly, RNA stability was not increased by C3P3, suggesting a direct effect on protein translation. A time course analysis revealed that C3P3 increased protein synthesis within the first 2 days of a reverse genetics transfection. This analysis also revealed that C3P3 enhanced processing of outer capsid μ1 protein to μ1C, a previously described hallmark of reovirus assembly. Finally, to determine the rate of infectious-RNA incorporation into new virions, we developed a new recombinant reovirus S1 gene that expressed the fluorescent protein UnaG. Following transfection of cells with UnaG and infection with wild-type virus, passage of UnaG through progeny was significantly enhanced by C3P3. These data suggest that capping provides nontraditional functions to reovirus, such as promoting assembly and infectious-RNA incorporation.IMPORTANCE Our findings expand our understanding of how viruses utilize capping, suggesting that capping provides nontraditional functions to reovirus, such as promoting assembly and infectious-RNA incorporation, in addition to enhancing protein translation. Beyond providing mechanistic insight into reovirus replication, our findings also show that reovirus reverse genetics rescue is enhanced 100-fold by the NP868R capping enzyme. Since reovirus shows promise as a cancer therapy, efficient reovirus reverse genetics rescue will accelerate production of recombinant reoviruses as candidates to enhance therapeutic potency. NP868R-assisted reovirus rescue will also expedite production of recombinant reovirus for mechanistic insights into reovirus protein function and structure.
Collapse
|
|
41
|
Mahalingam D, Fountzilas C, Moseley J, Noronha N, Tran H, Chakrabarty R, Selvaggi G, Coffey M, Thompson B, Sarantopoulos J. A phase II study of REOLYSIN® (pelareorep) in combination with carboplatin and paclitaxel for patients with advanced malignant melanoma. Cancer Chemother Pharmacol 2017; 79:697-703. [DOI: 10.1007/s00280-017-3260-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 02/08/2017] [Indexed: 01/31/2023]
|
|
42
|
Alkayyal AA, Tai LH, Kennedy MA, de Souza CT, Zhang J, Lefebvre C, Sahi S, Ananth AA, Mahmoud AB, Makrigiannis AP, Cron GO, Macdonald B, Marginean EC, Stojdl DF, Bell JC, Auer RC. NK-Cell Recruitment Is Necessary for Eradication of Peritoneal Carcinomatosis with an IL12-Expressing Maraba Virus Cellular Vaccine. Cancer Immunol Res 2017; 5:211-221. [PMID: 28159747 DOI: 10.1158/2326-6066.cir-16-0162] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 12/09/2016] [Accepted: 01/11/2017] [Indexed: 11/16/2022]
Abstract
Despite improvements in chemotherapy and radical surgical debulking, peritoneal carcinomatosis (PC) remains among the most common causes of death from abdominal cancers. Immunotherapies have been effective for selected solid malignancies, but their potential in PC has been little explored. Here, we report that intraperitoneal injection of an infected cell vaccine (ICV), consisting of autologous tumor cells infected ex vivo with an oncolytic Maraba MG1 virus expressing IL12, promotes the migration of activated natural killer (NK) cells to the peritoneal cavity in response to the secretion of IFNγ-induced protein-10 (IP-10) from dendritic cells. The recruitment of cytotoxic, IFNγ-secreting NK cells was associated with reduced tumor burden and improved survival in a colon cancer model of PC. Even in mice with bulky PC (tumors > 8 mm), a complete radiologic response was demonstrated within 8 to14 weeks, associated with 100% long-term survival. The impact of MG1-IL12-ICV upon NK-cell recruitment and function observed in the murine system was recapitulated in human lymphocytes exposed to human tumor cell lines infected with MG1-IL12. These findings suggest that an MG1-IL12-ICV is a promising therapy that could provide benefit to the thousands of patients diagnosed with PC each year. Cancer Immunol Res; 5(3); 211-21. ©2017 AACR.
Collapse
Affiliation(s)
- Almohanad A Alkayyal
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute.,Department of Laboratory Medicine, University of Tabuk, Tabuk, Saudi Arabia.,Department of BMI, University of Ottawa, Ottawa, Ontario, Canada
| | - Lee-Hwa Tai
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute
| | - Michael A Kennedy
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute
| | | | - Jiqing Zhang
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute
| | - Charles Lefebvre
- Apoptosis Research Centre, CHEO Research Institute, Ottawa, Ontario, Canada
| | - Shalini Sahi
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute
| | - Abhirami A Ananth
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute.,Department of BMI, University of Ottawa, Ottawa, Ontario, Canada
| | - Ahmad Bakur Mahmoud
- Department of BMI, University of Ottawa, Ottawa, Ontario, Canada.,Department of Medical Technology, Taibah University, Medina, Saudi Arabia
| | | | - Greg O Cron
- Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada.,Department of Radiology, University of Ottawa, Ottawa, Ontario, Canada
| | - Blair Macdonald
- Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada
| | - E Celia Marginean
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - David F Stojdl
- Department of BMI, University of Ottawa, Ottawa, Ontario, Canada.,Apoptosis Research Centre, CHEO Research Institute, Ottawa, Ontario, Canada
| | - John C Bell
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute.,Department of BMI, University of Ottawa, Ottawa, Ontario, Canada
| | - Rebecca C Auer
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute. .,Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada
| |
Collapse
|
|
43
|
Taking a Stab at Cancer; Oncolytic Virus-Mediated Anti-Cancer Vaccination Strategies. Biomedicines 2017; 5:biomedicines5010003. [PMID: 28536346 PMCID: PMC5423491 DOI: 10.3390/biomedicines5010003] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Revised: 12/20/2016] [Accepted: 12/22/2016] [Indexed: 12/14/2022] Open
Abstract
Vaccines have classically been used for disease prevention. Modern clinical vaccines are continuously being developed for both traditional use as well as for new applications. Typically thought of in terms of infectious disease control, vaccination approaches can alternatively be adapted as a cancer therapy. Vaccines targeting cancer antigens can be used to induce anti-tumour immunity and have demonstrated therapeutic efficacy both pre-clinically and clinically. Various approaches now exist and further establish the tremendous potential and adaptability of anti-cancer vaccination. Classical strategies include ex vivo-loaded immune cells, RNA- or DNA-based vaccines and tumour cell lysates. Recent oncolytic virus development has resulted in a surge of novel viruses engineered to induce powerful tumour-specific immune responses. In addition to their use as cancer vaccines, oncolytic viruses have the added benefit of being directly cytolytic to cancer cells and thus promote antigen recognition within a highly immune-stimulating tumour microenvironment. While oncolytic viruses are perfectly equipped for efficient immunization, this complicates their use upon previous exposure. Indeed, the host's anti-viral counter-attacks often impair multiple-dosing regimens. In this review we will focus on the use of oncolytic viruses for anti-tumour vaccination. We will explore different strategies as well as ways to circumvent some of their limitations.
Collapse
|
|
44
|
Berkey SE, Thorne SH, Bartlett DL. Oncolytic Virotherapy and the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1036:157-172. [PMID: 29275471 DOI: 10.1007/978-3-319-67577-0_11] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Oncolytic viral therapy is a promising approach to treat many malignancies, including breast, colorectal, hepatocellular, and melanoma. The best results are seen when using "targeted and armed" viruses. These are viruses that have been genetically modified to selectively replicate within cancer cells and express specific transgenes that alter the tumor microenvironment to inhibit tumor progression. The products of these transgenes induce cell death, make the virus less virulent, compromise tumor vascularity, and are capable of modulating or enhancing the immune system-such as cytokines and chemokines. In addition, oncolytic viruses can induce anti-vascular effects and disrupt the extracellular matrix to improve viral spread within the tumor. Oncolytic viruses also improve crosstalk between fibroblasts, cytokine-induced killer cells, and cancer cells within the microenvironment, leading to enhanced tumor cell death.
Collapse
Affiliation(s)
- Sara E Berkey
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Steve H Thorne
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - David L Bartlett
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| |
Collapse
|
|
45
|
Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: A new era of cancer treatment at dawn. Cancer Sci 2016; 107:1373-1379. [PMID: 27486853 PMCID: PMC5084676 DOI: 10.1111/cas.13027] [Citation(s) in RCA: 503] [Impact Index Per Article: 55.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 07/31/2016] [Accepted: 08/01/2016] [Indexed: 12/12/2022] Open
Abstract
Oncolytic virus therapy is perhaps the next major breakthrough in cancer treatment following the success in immunotherapy using immune checkpoint inhibitors. Oncolytic viruses are defined as genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming the normal tissues. T‐Vec (talimogene laherparepvec), a second‐generation oncolytic herpes simplex virus type 1 (HSV‐1) armed with GM‐CSF, was recently approved as the first oncolytic virus drug in the USA and Europe. The phase III trial proved that local intralesional injections with T‐Vec in advanced malignant melanoma patients can not only suppress the growth of injected tumors but also act systemically and prolong overall survival. Other oncolytic viruses that are closing in on drug approval in North America and Europe include vaccinia virus JX‐594 (pexastimogene devacirepvec) for hepatocellular carcinoma, GM‐CSF‐expressing adenovirus CG0070 for bladder cancer, and Reolysin (pelareorep), a wild‐type variant of reovirus, for head and neck cancer. In Japan, a phase II clinical trial of G47∆, a third‐generation oncolytic HSV‐1, is ongoing in glioblastoma patients. G47∆ was recently designated as a “Sakigake” breakthrough therapy drug in Japan. This new system by the Japanese government should provide G47∆ with priority reviews and a fast‐track drug approval by the regulatory authorities. Whereas numerous oncolytic viruses have been subjected to clinical trials, the common feature that is expected to play a major role in prolonging the survival of cancer patients is an induction of specific antitumor immunity in the course of tumor‐specific viral replication. It appears that it will not be long before oncolytic virus therapy becomes a standard therapeutic option for all cancer patients.
Collapse
Affiliation(s)
- Hiroshi Fukuhara
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yasushi Ino
- Division of Innovative Cancer Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tomoki Todo
- Division of Innovative Cancer Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| |
Collapse
|
|
46
|
Sun CW, Willmon C, Wu LC, Knopick P, Thoerner J, Vile R, Townes TM, Terman DS. Sickle Cells Abolish Melanoma Tumorigenesis in Hemoglobin SS Knockin Mice and Augment the Tumoricidal Effect of Oncolytic Virus In Vivo. Front Oncol 2016; 6:166. [PMID: 27458571 PMCID: PMC4937018 DOI: 10.3389/fonc.2016.00166] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Accepted: 06/20/2016] [Indexed: 01/19/2023] Open
Abstract
Insights from the study of cancer resistance in animals have led to the discovery of novel anticancer pathways and opened new venues for cancer prevention and treatment. Sickle cells (SSRBCs) from subjects with homozygous sickle cell anemia (SCA) have been shown to target hypoxic tumor niches, induce diffuse vaso-occlusion, and potentiate a tumoricidal response in a heme- and oxidant-dependent manner. These findings spawned the hypothesis that SSRBCs and the vasculopathic microenvironment of subjects with SCA might be inimical to tumor outgrowth and thereby constitute a natural antitumor defense. We therefore implanted the B16F10 melanoma into humanized hemoglobin SS knockin mice which exhibit the hematologic and vasculopathic sequelae of human SCA. Over the 31-day observation period, hemoglobin SS mice showed no significant melanoma outgrowth. By contrast, 68-100% of melanomas implanted in background and hemoglobin AA knockin control mice reached the tumor growth end point (p < 0.0001). SS knockin mice also exhibited established markers of underlying vasculopathy, e.g., chronic hemolysis (anemia, reticulocytosis) and vascular inflammation (leukocytosis) that differed significantly from all control groups. Genetic differences or normal AA gene knockin do not explain the impaired tumor outgrowth in SS knockin mice. These data point instead to the chronic pro-oxidative vasculopathic network in these mice as the predominant cause. In related studies, we demonstrate the ability of the sickle cell component of this system to function as a therapeutic vehicle in potentiating the oncolytic/vasculopathic effect of RNA reovirus. Sickle cells were shown to efficiently adsorb and transfer the virus to melanoma cells where it induced apoptosis even in the presence of anti-reovirus neutralizing antibodies. In vivo, SSRBCs along with their viral cargo rapidly targeted the tumor and initiated a tumoricidal response exceeding that of free virus and similarly loaded normal RBCs without toxicity. Collectively, these data unveil two hitherto unrecognized findings: hemoglobin SS knockin mice appear to present a natural barrier to melanoma tumorigenesis while SSRBCs demonstrate therapeutic function as a vehicle for enhancing the oncolytic effect of free reovirus against established melanoma.
Collapse
Affiliation(s)
- Chiang Wang Sun
- Department of Biochemistry and Molecular Genetics, University of Alabama Medical School at Birmingham, Birmingham, AL, USA
| | - Candice Willmon
- Department of Molecular Medicine, Mayo Clinic Foundation, Rochester, MN, USA
| | - Li-Chen Wu
- Department of Biochemistry and Molecular Genetics, University of Alabama Medical School at Birmingham, Birmingham, AL, USA
| | - Peter Knopick
- Department of Immunology, University of North Dakota Medical School, Grand Forks, ND, USA
| | - Jutta Thoerner
- Hisotpathology Section, Hospital of the Monterey Peninsula, Monterey, CA, USA
| | - Richard Vile
- Department of Molecular Medicine, Mayo Clinic Foundation, Rochester, MN, USA
| | - Tim M. Townes
- Department of Biochemistry and Molecular Genetics, University of Alabama Medical School at Birmingham, Birmingham, AL, USA
| | - David S. Terman
- Department of Biochemistry and Molecular Genetics, University of Alabama Medical School at Birmingham, Birmingham, AL, USA
| |
Collapse
|
|
47
|
Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma. Mol Ther 2016; 24:1150-1158. [PMID: 27039845 PMCID: PMC4923331 DOI: 10.1038/mt.2016.66] [Citation(s) in RCA: 110] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 03/24/2016] [Indexed: 12/13/2022] Open
Abstract
Pelareorep causes oncolysis in tumor cells with activated Ras. We hypothesized that pelareorep would have efficacy and immunomodulatory activity in metastatic pancreatic adenocarcinoma (MPA) when combined with carboplatin and paclitaxel. A randomized phase 2 study (NCT01280058) was conducted in treatment-naive patients with MPA randomized to two treatment arms: paclitaxel/carboplatin + pelareorep (Arm A, n = 36 evaluable patients) versus paclitaxel/carboplatin (Arm B, n = 37 evaluable patients). There was no difference in progression-free survival (PFS) between the arms (Arm A PFS = 4.9 months, Arm B PFS = 5.2 months, P = 0.6), and Kirsten rat sarcoma viral oncogene (KRAS) status did not impact outcome. Quality-adjusted Time without Symptoms or Toxicity analysis revealed that the majority of PFS time was without toxicity or progression (4.3 months). Patient immunophenotype appeared important, as soluble immune biomarkers were associated with treatment outcome (fractalkine, interleukin (IL)-6, IL-8, regulated on activation, normal T cell expressed and secreted (RANTES), and vascular endothelial growth factor (VEGF)). Increased circulating T and natural killer (NK)-cell subsets were also significantly associated with treatment outcome. Addition of pelareorep was associated with higher levels of 14 proinflammatory plasma cytokines/chemokines and cells with an immunosuppressive phenotype (Tregs, cytotoxic T lymphocyte associated protein 4 (CTLA4)(+) T cells). Overall, pelareorep was safe but does not improve PFS when administered with carboplatin/paclitaxel, regardless of KRAS mutational status. Immunologic studies suggest that chemotherapy backbone improves immune reconstitution and that targeting remaining immunosuppressive mediators may improve oncolytic virotherapy.
Collapse
|
|
48
|
Lawson KA, Mostafa AA, Shi ZQ, Spurrell J, Chen W, Kawakami J, Gratton K, Thakur S, Morris DG. Repurposing Sunitinib with Oncolytic Reovirus as a Novel Immunotherapeutic Strategy for Renal Cell Carcinoma. Clin Cancer Res 2016; 22:5839-5850. [PMID: 27220962 DOI: 10.1158/1078-0432.ccr-16-0143] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 04/11/2016] [Accepted: 04/18/2016] [Indexed: 11/16/2022]
Abstract
PURPOSE In addition to their direct cytopathic effects, oncolytic viruses are capable of priming antitumor immune responses. However, strategies to enhance the immunotherapeutic potential of these agents are lacking. Here, we investigated the ability of the multi-tyrosine kinase inhibitor and first-line metastatic renal cell carcinoma (RCC) agent, sunitinib, to augment the antitumor immune response generated by oncolytic reovirus. EXPERIMENTAL DESIGN In vitro, oncolysis and chemokine production were assessed in a panel of human and murine RCC cell lines after exposure to reovirus, sunitinib, or their combination. In vivo, the RENCA syngeneic murine model of RCC was employed to determine therapeutic and tumor-specific immune responses after treatment with reovirus (intratumoral), sunitinib, or their combination. Parallel investigations employing the KLN205 syngeneic murine model of lung squamous cell carcinoma (NSCLC) were conducted for further validation. RESULTS Reovirus-mediated oncolysis and chemokine production was observed following RCC infection. Reovirus monotherapy reduced tumor burden and was capable of generating a systemic adaptive antitumor immune response evidenced by increased numbers of tumor-specific CD8+ IFNγ-producing cells. Coadministration of sunitinib with reovirus further reduced tumor burden resulting in improved survival, decreased accumulation of immune suppressor cells, and the establishment of protective immunity upon tumor rechallenge. Similar results were observed for KLN205 tumor-bearing mice, highlighting the potential broad applicability of this approach. CONCLUSIONS The ability to repurpose sunitinib for augmentation of reovirus' immunotherapeutic efficacy positions this novel combination therapy as an attractive strategy ready for clinical testing against a range of histologies, including RCC and NSCLC. Clin Cancer Res; 22(23); 5839-50. ©2016 AACR.
Collapse
Affiliation(s)
- Keith A Lawson
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada.,Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Ahmed A Mostafa
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada.,Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Zhong Qiao Shi
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada.,Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Jason Spurrell
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada.,Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Wenqian Chen
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada.,Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Jun Kawakami
- Southern Alberta Institute of Urology, University of Calgary, Calgary, Alberta, Canada
| | - Kathy Gratton
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada.,Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Satbir Thakur
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada.,Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Donald G Morris
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada. .,Tom Baker Cancer Centre, Calgary, Alberta, Canada
| |
Collapse
|
|
49
|
Zamarin D, Pesonen S. Replication-Competent Viruses as Cancer Immunotherapeutics: Emerging Clinical Data. Hum Gene Ther 2016; 26:538-49. [PMID: 26176173 PMCID: PMC4968310 DOI: 10.1089/hum.2015.055] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Replication-competent (oncolytic) viruses (OV) as cancer immunotherapeutics have gained an increasing level of attention over the last few years while the clinical evidence of virus-mediated antitumor immune responses is still anecdotal. Multiple clinical studies are currently ongoing and more immunomonitoring results are expected within the next five years. All viruses can be recognized by the immune system and are therefore potential candidates for immune therapeutics. However, each virus activates innate immune system by using different combination of recognition receptors/pathways which leads to qualitatively different adaptive immune responses. This review summarizes immunological findings in cancer patients following treatment with replication-competent viruses.
Collapse
Affiliation(s)
- Dmitriy Zamarin
- 1 Memorial Sloan Kettering Cancer Center , New York, New York
| | | |
Collapse
|
|
50
|
Engineering Recombinant Reoviruses To Display gp41 Membrane-Proximal External-Region Epitopes from HIV-1. mSphere 2016; 1:mSphere00086-16. [PMID: 27303748 PMCID: PMC4888892 DOI: 10.1128/msphere.00086-16] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 04/25/2016] [Indexed: 12/30/2022] Open
Abstract
Vaccines to protect against HIV-1, the causative agent of AIDS, are not approved for use. Antibodies that neutralize genetically diverse strains of HIV-1 bind to discrete regions of the envelope glycoproteins, including the gp41 MPER. We engineered recombinant reoviruses that displayed MPER epitopes in attachment protein σ1 (REO-MPER vectors). The REO-MPER vectors replicated with wild-type efficiency, were genetically stable, and retained native antigenicity. However, we did not detect HIV-1-specific immune responses following inoculation of the REO-MPER vectors into small animals. This work provides proof of principle for engineering reovirus to express antigenic epitopes and illustrates the difficulty in eliciting MPER-specific immune responses. The gp41 membrane-proximal external region (MPER) is a target for broadly neutralizing antibody responses against human immunodeficiency virus type 1 (HIV-1). However, replication-defective virus vaccines currently under evaluation in clinical trials do not efficiently elicit MPER-specific antibodies. Structural modeling suggests that the MPER forms an α-helical coiled coil that is required for function and immunogenicity. To maintain the native MPER conformation, we used reverse genetics to engineer replication-competent reovirus vectors that displayed MPER sequences in the α-helical coiled-coil tail domain of viral attachment protein σ1. Sequences in reovirus strain type 1 Lang (T1L) σ1 were exchanged with sequences encoding HIV-1 strain Ba-L MPER epitope 2F5 or the entire MPER. Individual 2F5 or MPER substitutions were introduced at virion-proximal or virion-distal sites in the σ1 tail. Recombinant reoviruses containing heterologous HIV-1 sequences were viable and produced progeny yields comparable to those with wild-type virus. HIV-1 sequences were retained following 10 serial passages in cell culture, indicating that the substitutions were genetically stable. Recombinant viruses engineered to display the 2F5 epitope or full-length MPER in σ1 were recognized by purified 2F5 antibody. Inoculation of mice with 2F5-containing vectors or rabbits with 2F5- or MPER-containing vectors elicited anti-reovirus antibodies, but HIV-1-specific antibodies were not detected. Together, these findings indicate that heterologous sequences that form α-helices can functionally replace native sequences in the α-helical tail domain of reovirus attachment protein σ1. However, although these vectors retain native antigenicity, they were not immunogenic, illustrating the difficulty of experimentally inducing immune responses to this essential region of HIV-1. IMPORTANCE Vaccines to protect against HIV-1, the causative agent of AIDS, are not approved for use. Antibodies that neutralize genetically diverse strains of HIV-1 bind to discrete regions of the envelope glycoproteins, including the gp41 MPER. We engineered recombinant reoviruses that displayed MPER epitopes in attachment protein σ1 (REO-MPER vectors). The REO-MPER vectors replicated with wild-type efficiency, were genetically stable, and retained native antigenicity. However, we did not detect HIV-1-specific immune responses following inoculation of the REO-MPER vectors into small animals. This work provides proof of principle for engineering reovirus to express antigenic epitopes and illustrates the difficulty in eliciting MPER-specific immune responses.
Collapse
|