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El-Shemi AG, Alqurashi A, Abdulrahman JA, Alzahrani HD, Almwalad KS, Felfilan HH, Alomiri WS, Aloufi JA, Madkhali GH, Maqliyah SA, Alshahrani JB, Kamal HT, Daghistani SH, Refaat B, Minshawi F. IL-10-Directed Cancer Immunotherapy: Preclinical Advances, Clinical Insights, and Future Perspectives. Cancers (Basel) 2025; 17:1012. [PMID: 40149345 PMCID: PMC11940594 DOI: 10.3390/cancers17061012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 03/12/2025] [Accepted: 03/14/2025] [Indexed: 03/29/2025] Open
Abstract
Interleukin-10 (IL-10) is a dimeric cytokine encoded by the IL-10 gene on chromosome 1 [...].
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Affiliation(s)
- Adel G. El-Shemi
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | | | - Jihan Abdullah Abdulrahman
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Hanin Dhaifallah Alzahrani
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Khawlah Saad Almwalad
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Hadeel Hisham Felfilan
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Wahaj Saud Alomiri
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Jana Ahmed Aloufi
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Ghadeer Hassn Madkhali
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
- Department of Hematology, Dr. Sulaiman Al-Habib Medical Diagnostic Laboratory, Olaya District, Riyadh 12234-3785, Saudi Arabia
| | - Sarah Adel Maqliyah
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
- Department of Blood Bank and Laboratory, Saudi German Hospital, Makkah 24242, Saudi Arabia
| | - Jood Bandar Alshahrani
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Huda Taj Kamal
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Sawsan Hazim Daghistani
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Bassem Refaat
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Faisal Minshawi
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
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Nabi R, Chouljenko VN, Musarrat F, Davis ME, Mohan H, Ghavimi R, Stanfield B, Dutta O, Kousoulas KG. The Novel Oncolytic Herpes Simplex Virus Type-1 (HSV-1) Vaccine Strain VC2 Constitutively Expressing GM-CSF Causes Increased Intratumoral T Cell Infiltration and Inhibition of Tumor Metastasis in the 4T1/Balb/c Mouse Model of Stage Four Breast Cancer. J Med Virol 2025; 97:e70220. [PMID: 39930884 DOI: 10.1002/jmv.70220] [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: 09/17/2024] [Revised: 01/24/2025] [Accepted: 01/26/2025] [Indexed: 05/08/2025]
Abstract
Oncolytic virotherapy (OVT) aims to disrupt the tumor microenvironment and provide a unique therapeutic approach against solid tumors. Herpes simplex virus type-1 (HSV-1) has shown strong promise for treating various solid tumors and has been approved to treat melanoma and glioma in human patients. Previously, we reported the generation of an engineered HSV-1 vaccine strain VC2, which has shown exceptional promise as an oncolytic and immunotherapeutic virus. In the present work, we engineered VC2 to constitutively express the murine granulocyte-macrophage colony-stimulating factor (GM-CSF) gene inserted in place of HSV-1 Glycoprotein C (gC). We tested the efficacy of VC2-GMCSF for its ability to generate antitumor response in the 4T1 stage four metastatic breast cancer mouse model. GM-CSF expression enhanced VC2 viral replication and infectious virus production. Tumors formed after 7 days of engraftment in the mammary fat pad of Balb/CJ mice were treated by injecting ~5 × 104 plaque forming units (PFU) of VC2/VC2-GMCSF once. Intratumor treatment did not appreciably reduce average primary tumor sizes. However, metastatic foci were significantly reduced in mice lungs treated with VC2-GMCSF compared to VC2 or mock treatment. VC2-GMCSF intratumoral treatment induced a stronger intratumor T cell infiltration but not an increased cytotoxic activity. A significant T cell infiltration was observed in the metastatic areas in VC2-GMCSF treated animals, which was associated with reduced pro-tumor marker PDL1 and VEGF gene expression. These results show that constitutive expression of GM-CSF enhanced the overall efficacy of VC2 for OVT. VC2-GMCSF holds promise as oncolytic and immunotherapeutic virotherapy for breast and other cancers.
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Affiliation(s)
- Rafiq Nabi
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Vladimir N Chouljenko
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Farhana Musarrat
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Megan E Davis
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Harikrishnan Mohan
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Reza Ghavimi
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Brent Stanfield
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Ojasvi Dutta
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Konstantin G Kousoulas
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
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Kar S, Mehrotra S, Prajapati VK. From infection to remedy: Harnessing oncolytic viruses in cancer treatment. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2025; 144:213-257. [PMID: 39978967 DOI: 10.1016/bs.apcsb.2024.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Oncolytic virus (OV) mediated immunotherapy is one of the recent techniques used to treat higher grade cancers where conventional therapies like chemotherapy, radiation fail. OVs as a therapeutic tool show high efficacy and fewer side effects than conventional methods as supported by multiple preclinical and clinical studies since they are engineered to target tumours. In this chapter, we discuss the modifications in viruses to make them oncolytic, types of strains commonly administered, mechanisms employed by viruses to specifically target and eradicate malignancy and progress achieved as reported in case studies (preclinical and clinical trials). OVs also face some unique challenges with respect to the malignancy being treated and the varied pathogen exposure of the patients, which is also highlighted here. Since pathogen exposure varies according to population dynamics worldwide, chances of generating a non-specific recall response to an OV cannot be negated. Lastly, the future perspectives and ongoing practises of combination therapies are discussed as they provide a leading edge over monotherapies in terms of tumour clearance, blocking metastasis and enhancing patient survival. Efforts undertaken to overcome current challenges are also highlighted.
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Affiliation(s)
- Sramona Kar
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Sanjana Mehrotra
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India.
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Glaschke S, Dobrovolny HM. Spatiotemporal spread of oncolytic virus in a heterogeneous cell population. Comput Biol Med 2024; 183:109235. [PMID: 39369544 DOI: 10.1016/j.compbiomed.2024.109235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 09/27/2024] [Accepted: 09/30/2024] [Indexed: 10/08/2024]
Abstract
Oncolytic (cancer-killing) virus treatment is a promising new therapy for cancer, with many viruses currently being tested for their ability to eradicate tumors. One of the major stumbling blocks to the development of this treatment modality has been preventing spread of the virus to non-cancerous cells. Our recent ability to manipulate RNA and DNA now allows for the possibility of creating designer viruses specifically targeted to cancer cells, thereby significantly reducing unwanted side effects in patients. In this study, we use a partial differential equation model to determine the characteristics of a virus needed to contain spread of an oncolytic virus within a spherical tumor and prevent it from spreading to non-cancerous cells outside the tumor. We find that oncolytic viruses that have different infection rates or different cell death rates in cancer and non-cancerous cells can be made to stay within the tumor. We find that there is a minimum difference in infection rates or cell death rates that will contain the virus and that this threshold value depends on the growth rate of the cancer. Identification of these types of thresholds can help researchers develop safer strains of oncolytic viruses allowing further development of this promising treatment.
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Affiliation(s)
- Sabrina Glaschke
- Institute of Physics, Universitat Kassel, Kassel, Germany; Department of Physics & Astronomy, Texas Christian University, Fort Worth, TX, USA
| | - Hana M Dobrovolny
- Department of Physics & Astronomy, Texas Christian University, Fort Worth, TX, USA.
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Liu X, Chen H, Tan G, Zhong L, Jiang H, Smith SM, Wang HZ. A comprehensive neuroimaging review of the primary and metastatic brain tumors treated with immunotherapy: current status, and the application of advanced imaging approaches and artificial intelligence. Front Immunol 2024; 15:1496627. [PMID: 39669560 PMCID: PMC11634813 DOI: 10.3389/fimmu.2024.1496627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 10/28/2024] [Indexed: 12/14/2024] Open
Abstract
Cancer immunotherapy has emerged as a novel clinical therapeutic option for a variety of solid tumors over the past decades. The application of immunotherapy in primary and metastatic brain tumors continues to grow despite limitations due to the physiological characteristics of the immune system within the central nervous system (CNS) and distinct pathological barriers of malignant brain tumors. The post-immunotherapy treatment imaging is more complex. In this review, we summarize the clinical application of immunotherapies in solid tumors beyond the CNS. We provide an overview of current immunotherapies used in brain tumors, including immune checkpoint inhibitors (ICIs), oncolytic viruses, vaccines, and CAR T-cell therapies. We focus on the imaging criteria for the assessment of treatment response to immunotherapy, and post-immunotherapy treatment imaging patterns. We discuss advanced imaging techniques in the evaluation of treatment response to immunotherapy in brain tumors. The imaging characteristics of immunotherapy treatment-related complications in CNS are described. Lastly, future imaging challenges in this field are explored.
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Affiliation(s)
- Xiang Liu
- Department of Radiology, The Affiliated Yuebei People’s Hospital of Shantou University Medical College, Shaoguan, Guangdong, China
- Advanced Neuroimaging Laboratory, The Affiliated Yuebei People’s Hospital of Shantou University Medical College, Shaoguan, Guangdong, China
| | - Hongyan Chen
- Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Guirong Tan
- Department of Radiology, The Affiliated Yuebei People’s Hospital of Shantou University Medical College, Shaoguan, Guangdong, China
- Advanced Neuroimaging Laboratory, The Affiliated Yuebei People’s Hospital of Shantou University Medical College, Shaoguan, Guangdong, China
| | - Lijuan Zhong
- Department of Pathology, The Affiliated Yuebei People’s Hospital of Shantou University Medical College, Shaoguan, Guangdong, China
| | - Haihui Jiang
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Stephen M. Smith
- Department of Imaging Sciences, University of Rochester Medical Center, Rochester, NY, United States
| | - Henry Z. Wang
- Department of Imaging Sciences, University of Rochester Medical Center, Rochester, NY, United States
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Wu X, Fang S. Comparison of differences in immune cells and immune microenvironment among different kinds of oncolytic virus treatments. Front Immunol 2024; 15:1494887. [PMID: 39588373 PMCID: PMC11586384 DOI: 10.3389/fimmu.2024.1494887] [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: 09/11/2024] [Accepted: 10/24/2024] [Indexed: 11/27/2024] Open
Abstract
Oncolytic viruses are either naturally occurring or genetically engineered viruses that can activate immune cells and selectively replicate in and destroy cancer cells without damaging healthy tissues. Oncolytic virus therapy (OVT) represents an emerging treatment approach for cancer. In this review, we outline the properties of oncolytic viruses and then offer an overview of the immune cells and tumor microenvironment (TME) across various OVTs. A thorough understanding of the immunological mechanisms involved in OVTs could lead to the identification of novel and more effective therapeutic targets for cancer treatment.
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Affiliation(s)
| | - Shaokuan Fang
- Department of Neurology, Neuroscience Centre, The First Hospital of Jilin University, Changchun, China
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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: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [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.
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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.
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Webb MJ, Sangsuwannukul T, van Vloten J, Evgin L, Kendall B, Tonne J, Thompson J, Metko M, Moore M, Chiriboga Yerovi MP, Olin M, Borgatti A, McNiven M, Monga SPS, Borad MJ, Melcher A, Roberts LR, Vile R. Expression of tumor antigens within an oncolytic virus enhances the anti-tumor T cell response. Nat Commun 2024; 15:5442. [PMID: 38937436 PMCID: PMC11211353 DOI: 10.1038/s41467-024-49286-x] [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: 11/07/2023] [Accepted: 05/29/2024] [Indexed: 06/29/2024] Open
Abstract
Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.
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Affiliation(s)
- Mason J Webb
- Department of Hematology/Medical Oncology, Mayo Clinic, Rochester, MN, 55905, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | | | - Jacob van Vloten
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Laura Evgin
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, V5Z1L3, Canada
- Michael Smith Genome Sciences Department, BC Cancer Research Institute, Vancouver, BC, V5Z1L3, Canada
| | - Benjamin Kendall
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Jason Tonne
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Jill Thompson
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Muriel Metko
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Madelyn Moore
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA
| | | | - Michael Olin
- Division of Pediatric Hematology and Oncology, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Antonella Borgatti
- Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN, 55108, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA
- Clinical Investigation Center, University of Minnesota, St. Paul, MN, 55108, USA
| | - Mark McNiven
- Mayo Center for Biomedical Discovery, Mayo Clinic, Rochester, MN, 55905, USA
| | - Satdarshan P S Monga
- Pittsburgh Liver Institute, University of Pittsburgh and UPMC, Pittsburgh, PA, 15261, USA
| | - Mitesh J Borad
- Department of Hematology/Medical Oncology, Mayo Clinic, Phoenix, AZ, 85054, USA
| | - Alan Melcher
- Division of Radiotherapy and Imaging, Institute of Cancer Research, Chester Beatty Laboratories, London, SW3 6JB, UK
| | - Lewis R Roberts
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Richard Vile
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
- Department of Immunology, Mayo Clinic, Rochester, MN, 55905, USA.
- Joan Reece Department of Immuno-oncology, King's College London, London, UK.
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Mirbahari SN, Da Silva M, Zúñiga AIM, Kooshki Zamani N, St-Laurent G, Totonchi M, Azad T. Recent progress in combination therapy of oncolytic vaccinia virus. Front Immunol 2024; 15:1272351. [PMID: 38558795 PMCID: PMC10979700 DOI: 10.3389/fimmu.2024.1272351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 02/29/2024] [Indexed: 04/04/2024] Open
Abstract
In recent years, oncolytic viruses have emerged as promising agents for treating various cancers. An oncolytic virus is a non-pathogenic virus that, due to genetic manipulation, tends to replicate in and cause lysis of cancerous cells while leaving healthy cells unaffected. Among these viruses, vaccinia virus is an attractive platform for use as an oncolytic platform due to its 190 Kb genome with a high capacity for encoding therapeutic payloads. Combining oncolytic VV therapy with other conventional cancer treatments has been shown to be synergistic and more effective than monotherapies. Additionally, OVV can be used as a vector to deliver therapeutic payloads, alone or in combination with other treatments, to increase overall efficacy. Here, we present a comprehensive analysis of preclinical and clinical studies that have evaluated the efficacy of oncolytic vaccinia viruses in cancer immunotherapy. We discuss the outcomes of these studies, including tumor regression rates, overall survival benefits, and long-term responses. Moreover, we provide insights into the challenges and limitations associated with oncolytic vaccinia virus- based therapies, including immune evasion mechanisms, potential toxicities, and the development of resistance.
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Affiliation(s)
- Seyedeh Nasim Mirbahari
- Faculty of Sciences and Advanced Technologies in Biology, University of Science and Culture, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Miles Da Silva
- Department of Microbiology and Immunology, University of British Colombia, Vancouver, BC, Canada
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Abril Ixchel Muñoz Zúñiga
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC, Canada
| | - Nika Kooshki Zamani
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC, Canada
| | - Gabriel St-Laurent
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC, Canada
| | - Mehdi Totonchi
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Taha Azad
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC, Canada
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Zarezadeh Mehrabadi A, Tat M, Ghorbani Alvanegh A, Roozbahani F, Esmaeili Gouvarchin Ghaleh H. Revolutionizing cancer treatment: the power of bi- and tri-specific T-cell engagers in oncolytic virotherapy. Front Immunol 2024; 15:1343378. [PMID: 38464532 PMCID: PMC10921556 DOI: 10.3389/fimmu.2024.1343378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 02/09/2024] [Indexed: 03/12/2024] Open
Abstract
Bi- or tri-specific T cell engagers (BiTE or TriTE) are recombinant bispecific proteins designed to stimulate T-cell immunity directly, bypassing antigen presentation by antigen-presenting cells (APCs). However, these molecules suffer from limitations such as short biological half-life and poor residence time in the tumor microenvironment (TME). Fortunately, these challenges can be overcome when combined with OVs. Various strategies have been developed, such as encoding secretory BiTEs within OV vectors, resulting in improved targeting and activation of T cells, secretion of key cytokines, and bystander killing of tumor cells. Additionally, oncolytic viruses armed with BiTEs have shown promising outcomes in enhancing major histocompatibility complex I antigen (MHC-I) presentation, T-cell proliferation, activation, and cytotoxicity against tumor cells. These combined approaches address tumor heterogeneity, drug delivery, and T-cell infiltration, offering a comprehensive and effective solution. This review article aims to provide a comprehensive overview of Bi- or TriTEs and OVs as promising therapeutic approaches in the field of cancer treatment. We summarize the cutting-edge advancements in oncolytic virotherapy immune-related genetic engineering, focusing on the innovative combination of BiTE or TriTE with OVs.
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Affiliation(s)
| | - Mahdi Tat
- Applied Virology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | | - Fatemeh Roozbahani
- Department of Microbiology and Virology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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11
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Park JS, Lee ME, Kim J, Oh K, Lee N, Jung M, Jang WS, Ham WS. PD-1 inhibitor plus oncolytic vaccinia virus is a safe and effective treatment option for metastatic renal cell carcinoma. Cancer Cell Int 2024; 24:50. [PMID: 38291394 PMCID: PMC10829278 DOI: 10.1186/s12935-024-03238-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 01/21/2024] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Although a combination of immune checkpoint inhibitors (ICIs) is recommended as the first line treatment option for metastatic renal cell carcinoma (mRCC), several immune-related adverse events (irAEs) occur, especially hepatitis. We explored the therapeutic benefits and safety profile of combining oncolytic vaccinia virus, JX-594, with a programmed cell death protein-1 (PD-1) inhibitor. METHODS We used early-stage and advanced-stage orthotopic murine mRCC models developed by our group. PD-1 inhibitor monotherapy or a PD-1 inhibitor combined with either JX-594 or a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor were systemically injected through the peritoneum. An immunofluorescence analysis was performed to analyze the tumor immune microenvironment (TIME). irAEs were assessed in terms of hepatitis. RESULTS In the early-stage mRCC model mice, the combination of JX-594 and a PD-1 inhibitor significantly decreased the primary tumor size and number of lung nodules, compared with the ICI combination, but the JX-594 and PD-1 inhibitor combination and ICI combination did not differ significantly in the advanced-stage mRCC model mice. The JX-594 and PD-1 inhibitor combination induced tumor-suppressing TIME changes in both the early- and advanced-stage mRCC models. Furthermore, mice treated with the ICI combination had significantly greater hepatic injuries than those treated with the JX-594 and PD-1 inhibitor combination which was evaluated in early-stage mRCC model. CONCLUSIONS The JX-594 and PD-1 inhibitor combination effectively reduced primary tumors and the metastatic burden, similar to ICI combination therapy, through dynamic remodeling of the TIME. Furthermore, hepatitis was significantly decreased in the JX-594 and PD-1 inhibitor combination group, suggesting the potential benefit of that combination for reducing ICI-induced toxicity.
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Affiliation(s)
- Jee Soo Park
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Myung Eun Lee
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jongchan Kim
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Urology, Yongin Severance Hospital, Yonsei University Health System, Yongin, Republic of Korea
| | - Keunhee Oh
- Research Center, SillaJen, Inc., Yongin-si, Gyeonggi-do, Republic of Korea
| | - Namhee Lee
- Research Center, SillaJen, Inc., Yongin-si, Gyeonggi-do, Republic of Korea
| | - Minsun Jung
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Won Sik Jang
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Won Sik Ham
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
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12
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E VB, Ranganath Pai KS. Stem Cells and Tumor-Killing Virus to Target Brain Tumor: In Pursuit to Bring a Potential Delivery Vehicle for the Central Nervous System Tumors. Curr Drug Deliv 2024; 21:2-15. [PMID: 36825709 DOI: 10.2174/1567201820666230220101052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 12/08/2022] [Accepted: 12/28/2022] [Indexed: 02/22/2023]
Abstract
To target brain cancer, various therapeutic options are present to fight against cancer cells. But the existing therapies are not showing a proper curation of cancer patients. Henceforth, activating the immune cells and targeting oncogenes/proteins might be an emerging therapeutic approach to target and destroy malignant brain tumor. Stem cells (SCs) are considered potential immunomodulators that trigger the highly suppressed immune system in the tumor microenvironment. Also, engineered SCs can repress the aberrantly expressed oncoproteins that cause tumor cell proliferation and growth. SCs have an excellent migration capability to reach the infected site and support the regeneration of damaged blood vessels and tissues. Likewise, oncolytic virotherapy (OVT) is a promising novel therapeutic molecule in which genetically modified viruses can selectively replicate and destroy cancer cells without harming healthy cells. Same as SCs, oncolytic viruses (OVs) tend to stimulate the host's innate and adaptive immune response to battle against the advanced brain tumor. In clinical studies, various OVs have shown good immunogenic responses with a high safety profile and tolerability against cancer patients with reduced morbidity and mortality rate. SCs act as an attractive cargo for OVs which helps to influence the tumor site and destroy the tumor volume. SCs protect the OVs from systemic degradation and promote therapeutic efficacy against cancer cells. SCs carried OVs might be a potential therapeutic way to bring an effective treatment option for brain tumors.
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Affiliation(s)
- Vignesh Balaji E
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - K Sreedhara Ranganath Pai
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
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13
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Zhang L, Guo S, Chang S, Jiang G. Revolutionizing Cancer Treatment: Unleashing the Power of Combining Oncolytic Viruses with CAR-T Cells. Anticancer Agents Med Chem 2024; 24:1407-1418. [PMID: 39051583 DOI: 10.2174/0118715206308253240723055019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 06/07/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024]
Abstract
Oncolytic Viruses (OVs) have emerged as a promising treatment option for cancer thanks to their significant research potential and encouraging results. These viruses exert a profound impact on the tumor microenvironment, making them effective against various types of cancer. In contrast, the efficacy of Chimeric antigen receptor (CAR)-T cell therapy in treating solid tumors is relatively low. The combination of OVs and CAR-T cell therapy, however, is a promising area of research. OVs play a crucial role in enhancing the tumor-suppressive microenvironment, which in turn enables CAR-T cells to function efficiently in the context of solid malignancies. This review aims to provide a comprehensive analysis of the benefits and drawbacks of OV therapy and CAR-T cell therapy, with a focus on the potential of combining these two treatment approaches.
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Affiliation(s)
- Lin Zhang
- Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - ShuXian Guo
- Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - ShuYing Chang
- Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Guan Jiang
- Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
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14
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Das S, Acharya D. Immunological Assessment of Recent Immunotherapy for Colorectal Cancer. Immunol Invest 2023; 52:1065-1095. [PMID: 37812224 DOI: 10.1080/08820139.2023.2264906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Colorectal cancer (CRC) is the third most prevalent malignancy with increased incidence and mortality rates worldwide. Traditional treatment approaches have attempted to efficiently target CRC; however, they have failed in most cases, owing to the cytotoxicity and non-specificity of these therapies. Therefore, it is essential to develop an effective alternative therapy to improve the clinical outcomes in heterogeneous CRC cases. Immunotherapy has transformed cancer treatment with remarkable efficacy and overcomes the limitations of traditional treatments. With an understanding of the cancer-immunity cycle and tumor microenvironment evolution, current immunotherapy approaches have elicited enhanced antitumor immune responses. In this comprehensive review, we outline the latest advances in immunotherapy targeting CRC and provide insights into antitumor immune responses reported in landmark clinical studies. We focused on highlighting the combination approaches that synergistically induce immune responses and eliminate immunosuppression. This review aimed to understand the limitations and potential of recent immunotherapy clinical studies conducted in the last five years (2019-2023) and to transform this knowledge into a rational design of clinical trials intended for effective antitumor immune responses in CRC.
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Affiliation(s)
- Subhadeep Das
- Department of Biotechnology, GIET University, Gunupur, India
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15
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Pawar VA, Tyagi A, Verma C, Sharma KP, Ansari S, Mani I, Srivastva SK, Shukla PK, Kumar A, Kumar V. Unlocking therapeutic potential: integration of drug repurposing and immunotherapy for various disease targeting. Am J Transl Res 2023; 15:4984-5006. [PMID: 37692967 PMCID: PMC10492070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/31/2023] [Indexed: 09/12/2023]
Abstract
Drug repurposing, also known as drug repositioning, entails the application of pre-approved or formerly assessed drugs having potentially functional therapeutic amalgams for curing various disorders or disease conditions distinctive from their original remedial indication. It has surfaced as a substitute for the development of drugs for treating cancer, cardiovascular diseases, neurodegenerative disorders, and various infectious diseases like Covid-19. Although the earlier lines of findings in this area were serendipitous, recent advancements are based on patient centered approaches following systematic, translational, drug targeting practices that explore pathophysiological ailment mechanisms. The presence of definite information and numerous records with respect to beneficial properties, harmfulness, and pharmacologic characteristics of repurposed drugs increase the chances of approval in the clinical trial stages. The last few years have showcased the successful emergence of repurposed drug immunotherapy in treating various diseases. In this light, the present review emphasises on incorporation of drug repositioning with Immunotherapy targeted for several disorders.
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Affiliation(s)
| | - Anuradha Tyagi
- Department of cBRN, Institute of Nuclear Medicine and Allied ScienceDelhi 110054, India
| | - Chaitenya Verma
- Department of Pathology, Wexner Medical Center, Ohio State UniversityColumbus, Ohio 43201, USA
| | - Kanti Prakash Sharma
- Department of Nutrition Biology, Central University of HaryanaMahendragarh 123029, India
| | - Sekhu Ansari
- Division of Pathology, Cincinnati Children’s Hospital Medical CenterCincinnati, Ohio 45229, USA
| | - Indra Mani
- Department of Microbiology, Gargi College, University of DelhiNew Delhi 110049, India
| | | | - Pradeep Kumar Shukla
- Department of Biological Sciences, Faculty of Science, Sam Higginbottom University of Agriculture, Technology of SciencePrayagraj 211007, UP, India
| | - Antresh Kumar
- Department of Biochemistry, Central University of HaryanaMahendergarh 123031, Haryana, India
| | - Vinay Kumar
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical CenterColumbus, Ohio 43210, USA
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Muthukutty P, Yoo SY. Oncolytic Virus Engineering and Utilizations: Cancer Immunotherapy Perspective. Viruses 2023; 15:1645. [PMID: 37631987 PMCID: PMC10459766 DOI: 10.3390/v15081645] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
Oncolytic viruses have positively impacted cancer immunotherapy over the past 20 years. Both natural and genetically modified viruses have shown promising results in treating various cancers. Various regulatory authorities worldwide have approved four commercial oncolytic viruses, and more are being developed to overcome this limitation and obtain better anti-tumor responses in clinical trials at various stages. Faster advancements in translating research into the commercialization of cancer immunotherapy and a comprehensive understanding of the modification strategies will widen the current knowledge of future technologies related to the development of oncolytic viruses. In this review, we discuss the strategies of virus engineering and the progress of clinical trials to achieve virotherapeutics.
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Affiliation(s)
| | - So Young Yoo
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
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17
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Luo YZ, Zhu H. Immunotherapy for advanced or recurrent hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:405-424. [PMID: 37009314 PMCID: PMC10052663 DOI: 10.4251/wjgo.v15.i3.405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 02/11/2023] [Accepted: 02/28/2023] [Indexed: 03/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is associated with high morbidity and mortality, and is prone to intra- and extrahepatic metastasis due to the anatomical and functional characteristics of the liver. Due to the complexity and high relapse rate associated with radical surgery or radiofrequency ablation, immune checkpoint inhibitors (ICIs) are increasingly being used to treat HCC. Several immunotherapeutic agents, along with their combinations, have been clinically approved to treat advanced or recurrent HCC. This review discusses the leading ICIs in practice and those currently undergoing randomized phase 1–3 trials as monotherapy or combination therapy. Furthermore, we summarize the rapidly developing alternative strategies such as chimeric antigen receptor-engineered T cell therapy and tumor vaccines. Combination therapy is a promising potential treatment option. These immunotherapies are also summarized in this review, which provides insights into the advantages, limitations, and novel angles for future research in establishing viable and alternative therapies against HCC.
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Affiliation(s)
- Ying-Zhe Luo
- Department of Medical Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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18
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Treatment of HPV-Related Uterine Cervical Cancer with a Third-Generation Oncolytic Herpes Simplex Virus in Combination with an Immune Checkpoint Inhibitor. Int J Mol Sci 2023; 24:ijms24031988. [PMID: 36768352 PMCID: PMC9916424 DOI: 10.3390/ijms24031988] [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: 12/04/2022] [Revised: 01/11/2023] [Accepted: 01/16/2023] [Indexed: 01/22/2023] Open
Abstract
Cervical cancer is one of the most common cancers in women. The development of new therapies with immune checkpoint inhibitors (ICIs) is being investigated for cervical cancer; however, their efficacy is not currently sufficient. Oncolytic virus therapy can increase tumor immunogenicity and enhance the antitumor effect of ICIs. In this report, the therapeutic potential of a triple-mutated oncolytic herpes virus (T-01) with an ICI for human papillomavirus (HPV)-related cervical cancer was evaluated using a bilateral syngeneic murine model. The efficacy of intratumoral (i.t.) administration with T-01 and subcutaneous (s.c.) administration of anti-programmed cell death ligand 1 (PD-L1) antibody (Ab) was equivalent to that of anti-PD-L1 Ab alone on the T-01-injected side. Moreover, combination therapy had no significant antitumor effect compared to monotherapy on the T-01-non-injected side. Combination therapy significantly increased the number of tumor specific T cells in the tumor. While T-01 could not be isolated from tumors receiving combination therapy, it could be isolated following T-01 monotherapy. Furthermore, T-01 had a cytotoxic effect on stimulated T cells. These results suggest that T-01 and anti-PD-L1 Ab partially counteract and therefore concomitant administration should be considered with caution.
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19
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Liu X, Xu J, Yao T, Ding J, Li S, Su R, Zhang H, Li H, Yue Q, Gao X. Cryo-Shocked Cancer Cells as an Oncolytic Adenovirus Reservoir for Glioblastoma Immunotherapy. ACS APPLIED MATERIALS & INTERFACES 2023; 15:67-76. [PMID: 36508395 DOI: 10.1021/acsami.2c16806] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Glioblastoma is the most common type of primary brain tumor, which has a high recurrence rate and a high mortality rate. Immunotherapy shows promise in cancer therapy due to its capacity to manipulate the immune system to attack tumor cells with less toxic and durable immune responses. However, the low immunogenicity and limited immune cell infiltration in a glioblastoma lead to a weakened antitumor immune response, resulting in suboptimal therapeutic efficacy. A compelling solution is provided by oncolytic adenovirus (OAs), which can selectively replicate within tumor cells while simultaneously promoting antitumor immunity. Herein, we constructed an oncolytic adenovirus reservoir (OAR) by shocking OA-loaded tumor cells in liquid nitrogen to eliminate proliferation and pathogenicity. OARs showed sustained OAs release and effectively lysed tumor cells in vitro and in vivo. In a mouse intracranial glioblastoma model, OARs could efficiently induce dendritic cells' maturation, facilitate the tumor recruitment, and promote the infiltration of cytotoxic effector T lymphocytes via a single treatment, resulting in specific antitumor immune responses and long-term animal survival. Taken together, these results demonstrated that OAR is a promising synergistic therapeutic strategy for treating glioblastoma.
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Affiliation(s)
- Xiaoxiao Liu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Department of Neurosurgery, Huashan Hospital, Fudan University, 131 Dong An Road, Shanghai 200032, China
| | - Jinliang Xu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Department of Neurosurgery, Huashan Hospital, Fudan University, 131 Dong An Road, Shanghai 200032, China
| | - Tingting Yao
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Department of Neurosurgery, Huashan Hospital, Fudan University, 131 Dong An Road, Shanghai 200032, China
| | - Junqiang Ding
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Department of Neurosurgery, Huashan Hospital, Fudan University, 131 Dong An Road, Shanghai 200032, China
- Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
| | - Sha Li
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Department of Neurosurgery, Huashan Hospital, Fudan University, 131 Dong An Road, Shanghai 200032, China
| | - Runping Su
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Department of Neurosurgery, Huashan Hospital, Fudan University, 131 Dong An Road, Shanghai 200032, China
| | - Hanchang Zhang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Department of Neurosurgery, Huashan Hospital, Fudan University, 131 Dong An Road, Shanghai 200032, China
| | - Hui Li
- Department of Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China
| | - Qi Yue
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Department of Neurosurgery, Huashan Hospital, Fudan University, 131 Dong An Road, Shanghai 200032, China
| | - Xihui Gao
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Department of Neurosurgery, Huashan Hospital, Fudan University, 131 Dong An Road, Shanghai 200032, China
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20
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Popa Ilie IR, Georgescu CE. Immunotherapy in Gastroenteropancreatic Neuroendocrine Neoplasia. Neuroendocrinology 2023; 113:262-278. [PMID: 34348340 DOI: 10.1159/000518106] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/25/2021] [Indexed: 11/19/2022]
Abstract
The worldwide prevalence and incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) and of NENs, in general, have been increasing recently. While valuing the considerable progress made in the treatment strategies for GEP-NEN in recent years, patients with advanced, metastasized disease still have a poor prognosis, which calls for urgent novel therapies. The immune system plays a dual role: both host-protecting and "tumor-promoting." Hence, immunotherapy is potentially a powerful weapon to help NEN patients. However, although recent successes with checkpoint inhibitors have shown that enhancing antitumor immunity can be effective, the dynamic nature of the immunosuppressive tumor microenvironment presents significant hurdles to the broader application of these therapies. Studies led to their approval in NEN of the lung and Merkel cell carcinoma, whereas results in other settings have not been so encouraging. Oncolytic viruses can selectively infect and destroy cancer cells, acting as an in situ cancer vaccine. Moreover, they can remodel the tumor microenvironment toward a T cell-inflamed phenotype. Oncolytic virotherapy has been proposed as an ablative and immunostimulatory treatment strategy for solid tumors that are resistant to checkpoint inhibitors alone. Future efforts should focus on finding the best way to include immunotherapy in the GEP-NEN treatment scenario. In this context, this study aims at providing a comprehensive generalized review of the immune checkpoint blockade and the oncolytic virotherapy use in GEP-NENs that might improve GEP-NEN treatment strategies.
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Affiliation(s)
- Ioana Rada Popa Ilie
- Department of Endocrinology, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Carmen Emanuela Georgescu
- Department of Endocrinology, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
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21
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Abdelmoneim M, Eissa IR, Aboalela MA, Naoe Y, Matsumura S, Sibal PA, Bustos-Villalobos I, Tanaka M, Kodera Y, Kasuya H. Metformin enhances the antitumor activity of oncolytic herpes simplex virus HF10 (canerpaturev) in a pancreatic cell cancer subcutaneous model. Sci Rep 2022; 12:21570. [PMID: 36513720 PMCID: PMC9747797 DOI: 10.1038/s41598-022-25065-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 11/24/2022] [Indexed: 12/15/2022] Open
Abstract
Oncolytic virus (OV) therapy is a promising cancer immunotherapy, especially for cold tumors by inducing the direct lysis of cancer cells and initiation of potent antitumor response. Canerpaturev (C-REV) is an attenuated oncolytic herpes simplex virus-1, which demonstrated a potent antitumor effect in various preclinical models when used either alone or combined. Metformin is a commonly prescribed antidiabetic drug that demonstrated a potent immune modulator effect and antitumor response. We combined C-REV with metformin in a low immunogenic bilateral murine tumor model to enhance C-REV's antitumor efficacy. In vitro, metformin does not enhance the C-REV cell cytotoxic effect. However, in in vivo model, intratumoral administration of C-REV with the systemic administration of metformin led to synergistic antitumor effect on both sides of tumor and prolonged survival. Moreover, combination therapy increased the effector CD44+ CD8+ PD1- subset and decreased the proportion of terminally-differentiated CD103+ KLRG-1+ T-regulatory cells on both sides of tumor. Interestingly, combination therapy efficiently modulates conventional dendritic cells type-1 (cDC1) on tumors, and tumor-drained lymph nodes. Our findings suggest that combination of C-REV and metformin enhances systemic antitumor immunity. This study may provide insights into the mechanism of action of OV therapy plus metformin combination against various tumor models.
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Affiliation(s)
- Mohamed Abdelmoneim
- grid.27476.300000 0001 0943 978XGraduate School of Medicine, Cancer Immune Therapy Research Center, Nagoya University, Nagoya, Japan ,grid.27476.300000 0001 0943 978XDepartment of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan ,grid.31451.320000 0001 2158 2757Department of Microbiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Ibrahim Ragab Eissa
- grid.27476.300000 0001 0943 978XGraduate School of Medicine, Cancer Immune Therapy Research Center, Nagoya University, Nagoya, Japan ,grid.27476.300000 0001 0943 978XDepartment of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan ,grid.412258.80000 0000 9477 7793Faculty of Science, Tanta University, Tanta, Egypt
| | - Mona Alhussein Aboalela
- grid.27476.300000 0001 0943 978XGraduate School of Medicine, Cancer Immune Therapy Research Center, Nagoya University, Nagoya, Japan ,grid.27476.300000 0001 0943 978XDepartment of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan ,grid.31451.320000 0001 2158 2757Medical Microbiology and Immunology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Yoshinori Naoe
- grid.27476.300000 0001 0943 978XGraduate School of Medicine, Cancer Immune Therapy Research Center, Nagoya University, Nagoya, Japan
| | - Shigeru Matsumura
- grid.27476.300000 0001 0943 978XGraduate School of Medicine, Cancer Immune Therapy Research Center, Nagoya University, Nagoya, Japan
| | - Patricia Angela Sibal
- grid.27476.300000 0001 0943 978XGraduate School of Medicine, Cancer Immune Therapy Research Center, Nagoya University, Nagoya, Japan
| | - Itzel Bustos-Villalobos
- grid.27476.300000 0001 0943 978XGraduate School of Medicine, Cancer Immune Therapy Research Center, Nagoya University, Nagoya, Japan
| | - Maki Tanaka
- grid.410820.fTakara Bio Inc., Kusatsu, Shiga Japan
| | - Yasuhiro Kodera
- grid.27476.300000 0001 0943 978XDepartment of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Hideki Kasuya
- grid.27476.300000 0001 0943 978XGraduate School of Medicine, Cancer Immune Therapy Research Center, Nagoya University, Nagoya, Japan
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22
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Da BL, Suchman KI, Lau L, Rabiee A, He AR, Shetty K, Yu H, Wong LL, Amdur RL, Crawford JM, Fox SS, Grimaldi GM, Shah PK, Weinstein J, Bernstein D, Satapathy SK, Chambwe N, Xiang X, Mishra L. Pathogenesis to management of hepatocellular carcinoma. Genes Cancer 2022; 13:72-87. [PMID: 36533190 PMCID: PMC9746873 DOI: 10.18632/genesandcancer.226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/17/2022] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer whose incidence continues to rise in many parts of the world due to a concomitant rise in many associated risk factors, such as alcohol use and obesity. Although early-stage HCC can be potentially curable through liver resection, liver-directed therapies, or transplantation, patients usually present with intermediate to advanced disease, which continues to be associated with a poor prognosis. This is because HCC is a cancer with significant complexities, including substantial clinical, histopathologic, and genomic heterogeneity. However, the scientific community has made a major effort to better characterize HCC in those aspects via utilizing tissue sampling and histological classification, whole genome sequencing, and developing viable animal models. These efforts ultimately aim to develop clinically relevant biomarkers and discover molecular targets for new therapies. For example, until recently, there was only one approved systemic therapy for advanced or metastatic HCC in the form of sorafenib. Through these efforts, several additional targeted therapies have gained approval in the United States, although much progress remains to be desired. This review will focus on the link between characterizing the pathogenesis of HCC with current and future HCC management.
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Affiliation(s)
- Ben L. Da
- Department of Internal Medicine, Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY 11030, USA
| | - Kelly I. Suchman
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY 11030, USA
| | - Lawrence Lau
- Department of Surgery, North Shore University Hospital, Northwell Health, Manhasset, NY 11030, USA
| | - Atoosa Rabiee
- Department of Gastroenterology and Hepatology, VA Medical Center, Washington, DC 20422, USA
| | - Aiwu Ruth He
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
| | - Kirti Shetty
- Division of Gastroenterology and Hepatology, University of Maryland, Baltimore, MD 21201, USA
| | - Herbert Yu
- Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI 96813-5516, USA
| | - Linda L. Wong
- Department of Surgery, University of Hawaii, Honolulu, HI 96813-5516, USA
| | - Richard L. Amdur
- Quantitative Intelligence, The Institutes for Health Systems Science and Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 10022, USA
| | - James M. Crawford
- Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Sharon S. Fox
- Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Gregory M. Grimaldi
- Department of Radiology, Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
| | - Priya K. Shah
- Department of Radiology, Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
| | - Jonathan Weinstein
- Division of Vascular and Interventional Radiology, Department of Radiology, Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
| | - David Bernstein
- Department of Internal Medicine, Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY 11030, USA
| | - Sanjaya K. Satapathy
- Department of Internal Medicine, Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY 11030, USA
| | - Nyasha Chambwe
- The Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA
| | - Xiyan Xiang
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
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23
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Shayan S, Arashkia A, Azadmanesh K. Modifying oncolytic virotherapy to overcome the barrier of the hypoxic tumor microenvironment. Where do we stand? Cancer Cell Int 2022; 22:370. [PMID: 36424577 PMCID: PMC9686061 DOI: 10.1186/s12935-022-02774-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 11/01/2022] [Indexed: 11/25/2022] Open
Abstract
Viruses are completely dependent on host cell machinery for their reproduction. As a result, factors that influence the state of cells, such as signaling pathways and gene expression, could determine the outcome of viral pathogenicity. One of the important factors influencing cells or the outcome of viral infection is the level of oxygen. Recently, oncolytic virotherapy has attracted attention as a promising approach to improving cancer treatment. However, it was shown that tumor cells are mostly less oxygenated compared with their normal counterparts, which might affect the outcome of oncolytic virotherapy. Therefore, knowing how oncolytic viruses could cope with stressful environments, particularly hypoxic environments, might be essential for improving oncolytic virotherapy.
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Affiliation(s)
- Sara Shayan
- grid.420169.80000 0000 9562 2611Department of Molecular Virology, Pasteur Institute of Iran, No. 69, Pasteur Ave, Tehran, Iran
| | - Arash Arashkia
- grid.420169.80000 0000 9562 2611Department of Molecular Virology, Pasteur Institute of Iran, No. 69, Pasteur Ave, Tehran, Iran
| | - Kayhan Azadmanesh
- grid.420169.80000 0000 9562 2611Department of Molecular Virology, Pasteur Institute of Iran, No. 69, Pasteur Ave, Tehran, Iran
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24
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Jafari M, Kadkhodazadeh M, Shapourabadi MB, Goradel NH, Shokrgozar MA, Arashkia A, Abdoli S, Sharifzadeh Z. Immunovirotherapy: The role of antibody based therapeutics combination with oncolytic viruses. Front Immunol 2022; 13:1012806. [PMID: 36311790 PMCID: PMC9608759 DOI: 10.3389/fimmu.2022.1012806] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022] Open
Abstract
Despite the fact that the new drugs and targeted therapies have been approved for cancer therapy during the past 30 years, the majority of cancer types are still remain challenging to be treated. Due to the tumor heterogeneity, immune system evasion and the complex interaction between the tumor microenvironment and immune cells, the great majority of malignancies need multimodal therapy. Unfortunately, tumors frequently develop treatment resistance, so it is important to have a variety of therapeutic choices available for the treatment of neoplastic diseases. Immunotherapy has lately shown clinical responses in malignancies with unfavorable outcomes. Oncolytic virus (OV) immunotherapy is a cancer treatment strategy that employs naturally occurring or genetically-modified viruses that multiply preferentially within cancer cells. OVs have the ability to not only induce oncolysis but also activate cells of the immune system, which in turn activates innate and adaptive anticancer responses. Despite the fact that OVs were translated into clinical trials, with T-VECs receiving FDA approval for melanoma, their use in fighting cancer faced some challenges, including off-target side effects, immune system clearance, non-specific uptake, and intratumoral spread of OVs in solid tumors. Although various strategies have been used to overcome the challenges, these strategies have not provided promising outcomes in monotherapy with OVs. In this situation, it is increasingly common to use rational combinations of immunotherapies to improve patient benefit. With the development of other aspects of cancer immunotherapy strategies, combinational therapy has been proposed to improve the anti-tumor activities of OVs. In this regard, OVs were combined with other biotherapeutic platforms, including various forms of antibodies, nanobodies, chimeric antigen receptor (CAR) T cells, and dendritic cells, to reduce the side effects of OVs and enhance their efficacy. This article reviews the promising outcomes of OVs in cancer therapy, the challenges OVs face and solutions, and their combination with other biotherapeutic agents.
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Affiliation(s)
- Mahdie Jafari
- Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
| | | | | | - Nasser Hashemi Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Arash Arashkia
- Department of Molecular Virology, Pasture Institute of Iran, Tehran, Iran
| | - Shahriyar Abdoli
- School of Advanced Medical Technologies, Golestan University of Medical Sciences, Gorgan, Iran
- *Correspondence: Zahra Sharifzadeh, ; Shahriyar Abdoli,
| | - Zahra Sharifzadeh
- Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
- *Correspondence: Zahra Sharifzadeh, ; Shahriyar Abdoli,
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25
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Therapeutic Efficacy of Oncolytic Viruses in Fighting Cancer: Recent Advances and Perspective. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3142306. [PMID: 35910836 PMCID: PMC9337963 DOI: 10.1155/2022/3142306] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 04/20/2022] [Accepted: 05/26/2022] [Indexed: 12/22/2022]
Abstract
Immunotherapy is at the cutting edge of modern cancer treatment. Innovative medicines have been developed with varying degrees of success that target all aspects of tumor biology: tumors, niches, and the immune system. Oncolytic viruses (OVs) are a novel and potentially immunotherapeutic approach for cancer treatment. OVs reproduce exclusively in cancer cells, causing the tumor mass to lyse. OVs can also activate the immune system in addition to their primary activity. Tumors create an immunosuppressive environment by suppressing the immune system’s ability to respond to tumor cells. By injecting OVs into the tumor, the immune system is stimulated, allowing it to generate a robust and long-lasting response against the tumor. The essential biological properties of oncolytic viruses, as well as the underlying mechanisms that enable their usage as prospective anticancer medicines, are outlined in this review. We also discuss the increased efficacy of virotherapy when combined with other cancer medications.
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26
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Lauer UM, Beil J. Oncolytic viruses: challenges and considerations in an evolving clinical landscape. Future Oncol 2022; 18:2713-2732. [PMID: 35818970 DOI: 10.2217/fon-2022-0440] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Despite advances in treatment, cancer remains a leading cause of death worldwide. Although treatment strategies are continually progressing, cancers have evolved many mechanisms for evading therapies and the host immune system. Oncolytic viruses (OVs) could provide a much-needed option for cancers that are resistant to existing treatments. OVs can be engineered to specifically target and kill cancer cells, while simultaneously triggering an immune response at the site of infection. This review will focus on the challenges of developing a successful OV and translation to clinical practice, discussing the innovative strategies that are being used to optimize the potential of OVs. Here, we will also explore the current clinical landscape and the prospects of OVs in early clinical development.
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Affiliation(s)
- Ulrich M Lauer
- Department of Internal Medicine VIII, Virotherapy Center Tübingen, Medical Oncology & Pneumology, Medical University Hospital Tübingen, Otfried-Mueller-Str. 10, Tübingen, 72076, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Tübingen, Otfried-Mueller-Str. 10, Tübingen, 72076, Germany
| | - Julia Beil
- Department of Internal Medicine VIII, Virotherapy Center Tübingen, Medical Oncology & Pneumology, Medical University Hospital Tübingen, Otfried-Mueller-Str. 10, Tübingen, 72076, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Tübingen, Otfried-Mueller-Str. 10, Tübingen, 72076, Germany
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27
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Zhou P, Wang X, Xing M, Yang X, Wu M, Shi H, Zhu C, Wang X, Guo Y, Tang S, Huang Z, Zhou D. Intratumoral delivery of a novel oncolytic adenovirus encoding human antibody against PD-1 elicits enhanced antitumor efficacy. Mol Ther Oncolytics 2022; 25:236-248. [PMID: 35615266 PMCID: PMC9118129 DOI: 10.1016/j.omto.2022.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 04/21/2022] [Indexed: 11/21/2022] Open
Abstract
To date, diverse combination therapies with immune checkpoint inhibitors (ICIs), particularly oncolytic virotherapy, have demonstrated enhanced therapeutic outcomes in cancer treatment. However, high pre-existing immunity against the widely used adenovirus human serotype 5 (AdHu5) limits its extensive clinical application. In this study, we constructed an innovative oncolytic virus (OV) based on a chimpanzee adenoviral vector with low seropositivity in the human population, named AdC68-spE1A-αPD-1, which endows the parental OV (AdC68-spE1A-ΔE3) with the ability to express full-length anti-human programmed cell death-1 monoclonal antibody (αPD-1). In vitro studies indicated that the AdC68-spE1A-αPD-1 retained parental oncolytic capacity, and αPD-1 was efficiently secreted from the infected tumor cells and bound exclusively to human PD-1 (hPD-1) protein. In vivo, intratumoral treatment with AdC68-spE1A-αPD-1 resulted in significant tumor suppression, prolonged overall survival, and enhanced systemic antitumor memory response in an hPD-1 knockin mouse tumor model. This strategy outperformed the unarmed OV and was comparable with combination therapy with intratumoral injection of AdC68-spE1A-ΔE3 and systemic administration of commercial αPD-1. In summary, AdC68-spE1A-αPD-1 is a cost-effective approach with potential clinical applications. .
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Affiliation(s)
- Ping Zhou
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xuchen Wang
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Man Xing
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Xi Yang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Mangteng Wu
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hongyang Shi
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Caihong Zhu
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Xiang Wang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Yingying Guo
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Shubing Tang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Zhong Huang
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
| | - Dongming Zhou
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China
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28
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Lee WS, Kim DS, Kim JH, Heo Y, Yang H, Go EJ, Kim JH, Lee SJ, Ahn BC, Yum JS, Chon HJ, Kim C. Intratumoral immunotherapy using a TLR2/3 agonist, L-pampo, induces robust antitumor immune responses and enhances immune checkpoint blockade. J Immunother Cancer 2022; 10:jitc-2022-004799. [PMID: 35764365 PMCID: PMC9240943 DOI: 10.1136/jitc-2022-004799] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Toll-like receptors (TLRs) are critical innate immune sensors that elicit antitumor immune responses in cancer immunotherapy. Although a few TLR agonists have been approved for the treatment of patients with early-stage superficial cancers, their therapeutic efficacy is limited in patient with advanced invasive cancers. Here, we identified the therapeutic role of a TLR2/3 agonist, L-pampo (LP), which promotes antitumor immunity and enhances the immune checkpoint blockade. METHODS We generated LP by combining a TLR2 agonist, Pam3CSK4, with a TLR3 agonist, Poly (I:C). Immune responses to stimulation with various TLR agonists were compared. Tumor-bearing mice were intratumorally treated with LP, and their tumor sizes were measured. The antitumor effects of LP treatment were determined using flow cytometry, multiplexed imaging, and NanoString nCounter immune profiling. The immunotherapeutic potential of LP in combination with α-programmed cell death protein-1 (PD-1) or α-cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) was evaluated in syngeneic MC38 colon cancer and B16F10 melanoma. RESULTS The LP treatment induced a potent activation of T helper 1 (Th1) and 2 (Th2)-mediated immunity, tumor cell apoptosis, and immunogenic tumor cell death. Intratumoral LP treatment effectively inhibited tumor progression by activating tumor-specific T cell immunity. LP-induced immune responses were mediated by CD8+ T cells and interferon-γ, but not by CD4+ T cells and CD25+ T cells. LP simultaneously activated TLR2 and TLR3 signaling, thereby extensively changing the immune-related gene signatures within the tumor microenvironment (TME). Moreover, intratumoral LP treatment led to systemic abscopal antitumor effects in non-injected distant tumors. Notably, LP treatment combined with ɑPD-1 and ɑCTLA-4 further enhanced the efficacy of monotherapy, resulting in complete tumor regression and prolonged overall survival. Furthermore, LP-based combination immunotherapy elicited durable antitumor immunity with tumor-specific immune memory in colon cancer and melanoma. CONCLUSIONS Our study demonstrated that intratumoral LP treatment improves the innate and adaptive antitumor immunity within the TME and enhances the efficacy of αPD-1 and αCTLA-4 immune checkpoint blockade.
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Affiliation(s)
- Won Suk Lee
- Laboratory of Translational Immuno-Oncology, Seongnam, Gyeonggi-do, Korea (the Republic of).,Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Dong Sung Kim
- Laboratory of Translational Immuno-Oncology, Seongnam, Gyeonggi-do, Korea (the Republic of).,Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Jeong Hun Kim
- Laboratory of Translational Immuno-Oncology, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Yoonki Heo
- CHA Vaccine Institute, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Hannah Yang
- Laboratory of Translational Immuno-Oncology, Seongnam, Gyeonggi-do, Korea (the Republic of).,Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Eun-Jin Go
- Laboratory of Translational Immuno-Oncology, Seongnam, Gyeonggi-do, Korea (the Republic of).,Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Jin Hyoung Kim
- Laboratory of Translational Immuno-Oncology, Seongnam, Gyeonggi-do, Korea (the Republic of).,Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Seung Joon Lee
- Laboratory of Translational Immuno-Oncology, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Byung Cheol Ahn
- CHA Vaccine Institute, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Jung Sun Yum
- CHA Vaccine Institute, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Hong Jae Chon
- Laboratory of Translational Immuno-Oncology, Seongnam, Gyeonggi-do, Korea (the Republic of) .,Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of).,Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, Korea (the Republic of)
| | - Chan Kim
- Laboratory of Translational Immuno-Oncology, Seongnam, Gyeonggi-do, Korea (the Republic of) .,Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of).,Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, Korea (the Republic of)
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29
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Liu JKH, Irvine AF, Jones RL, Samson A. Immunotherapies for hepatocellular carcinoma. Cancer Med 2022; 11:571-591. [PMID: 34953051 PMCID: PMC8817091 DOI: 10.1002/cam4.4468] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/21/2022] Open
Abstract
Cases of hepatocellular carcinoma (HCC) are rapidly rising. This is particularly the case in the Western world, as a result of increasing rates of chronic liver disease, secondary to lifestyle-associated risk factors and the lack of an established screening programme for the general population. Traditionally, radical/curative treatment options for HCC, including liver transplantation and surgical resection are reserved for the minority of patients, presenting with an early stage cancer. For patients with advanced disease, Sorafenib and Lenvatinib were, until recently, the only licensed systemic treatments, and provided only limited survival benefits at the cost of a multitude of potential side effects. Recent scientific advances in the field of cancer immunotherapy have renewed significant interest in advanced HCC, in order to fulfil this apparent area of unmet clinical need. This has led to the success and recent regulatory approval of an Atezolizumab/Bevacizumab combination for the first-line treatment of advanced HCC following results from the IMbrave150 clinical trial in 2019, with further immune checkpoint inhibitors currently undergoing testing in advanced clinical trials. Furthermore, other cancer immunotherapies, including chimeric antigen receptor T-cells, dendritic cell vaccines and oncolytic viruses are also in early stage clinical trials, for the treatment of advanced HCC. This review will summarise the major approaches that have been and are currently in development for the systemic treatment of advanced HCC, their advantages, drawbacks, and predictions of where this revolutionary treatment field will continue to travel for the foreseeable future.
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Affiliation(s)
- Justin K. H. Liu
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
| | - Andrew F. Irvine
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
| | - Rebecca L. Jones
- Leeds Liver UnitSt James's University HospitalLeeds Teaching Hospitals NHS TrustLeedsUK
| | - Adel Samson
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
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30
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Park JS, Lee ME, Jang WS, Kim J, Park SM, Oh K, Lee N, Ham WS. Systemic Injection of Oncolytic Vaccinia Virus Suppresses Primary Tumor Growth and Lung Metastasis in Metastatic Renal Cell Carcinoma by Remodeling Tumor Microenvironment. Biomedicines 2022; 10:173. [PMID: 35052851 PMCID: PMC8773601 DOI: 10.3390/biomedicines10010173] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/20/2021] [Accepted: 01/11/2022] [Indexed: 02/04/2023] Open
Abstract
Immune checkpoint inhibitors and tyrosine kinase inhibitors are the first-line treatment for metastatic renal cell carcinoma (mRCC), but their benefits are limited to specific patient subsets. Here, we aimed to evaluate the therapeutic efficacy of JX-594 (pexastimogene devacirepvec, Pexa-vec) monotherapy by systemic injection in comparison with sunitinib monotherapy in metastatic orthotopic RCC murine models. Two highly metastatic orthotopic RCC models were developed to compare the treatment efficacy in the International Metastatic RCC Database Consortium favorable-risk and intermediate- or poor-risk groups. JX-594 was systemically injected through the peritoneum, whereas sunitinib was orally administered. Post-treatment, tumor microenvironment (TME) remodeling was determined using immunofluorescence analysis. Systemic JX-594 monotherapy injection demonstrated therapeutic benefit in both early- and advanced-stage mRCC models. Sunitinib monotherapy significantly reduced the primary tumor burden and number of lung metastases in the early-stage, but not in the advanced-stage mRCC model. Systemic JX-594 delivery remodeled the primary TME and lung metastatic sites by increasing tumor-infiltrating CD4/8+ T cells and dendritic cells. Systemic JX-594 monotherapy demonstrated significantly better therapeutic outcomes compared with sunitinib monotherapy in both early- and advanced-stage mRCCs by converting cold tumors into hot tumors. Sunitinib monotherapy effectively suppressed primary tumor growth and lung metastasis in early-stage mRCC.
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Affiliation(s)
- Jee Soo Park
- Department of Urology, Urological Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (J.K.); (S.M.P.)
- Department of Urology, Sorokdo National Hospital, Goheung 59562, Korea
| | - Myung Eun Lee
- Department of Urology, Urological Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (J.K.); (S.M.P.)
| | - Won Sik Jang
- Department of Urology, Urological Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (J.K.); (S.M.P.)
| | - Jongchan Kim
- Department of Urology, Urological Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (J.K.); (S.M.P.)
- Department of Urology, Yongin Severance Hospital, Yonsei University Health System, Seoul 03722, Korea
| | - Se Mi Park
- Department of Urology, Urological Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (J.K.); (S.M.P.)
| | - Keunhee Oh
- Research Center, SillaJen, Inc., Seoul 07325, Korea; (K.O.); (N.L.)
| | - Namhee Lee
- Research Center, SillaJen, Inc., Seoul 07325, Korea; (K.O.); (N.L.)
| | - Won Sik Ham
- Department of Urology, Urological Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (J.K.); (S.M.P.)
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Kim JH, Lee WS, Lee HJ, Yang H, Lee SJ, Kong SJ, Je S, Yang HJ, Jung J, Cheon J, Kang B, Chon HJ, Kim C. Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway. Oncoimmunology 2021; 10:2005280. [PMID: 34858729 PMCID: PMC8632076 DOI: 10.1080/2162402x.2021.2005280] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Kynurenine (Kyn) is a key inducer of an immunosuppressive tumor microenvironment (TME). Although indoleamine 2,3-dioxygenase (IDO)-selective inhibitors have been developed to suppress the Kyn pathway, the results were not satisfactory due to the presence of various opposing mechanisms. Here, we employed an orally administered novel Kyn pathway regulator to overcome the limitation of anti-tumor immune response. We identified a novel core structure that inhibited both IDO and TDO. An orally available lead compound, STB-C017 (designated hereafter as STB), effectively inhibited the enzymatic and cellular activity of IDO and TDO in vitro. Moreover, it potently suppressed Kyn levels in both the plasma and tumor in vivo. STB monotherapy increased the infiltration of CD8+ T cells into TME. In addition, STB reprogrammed the TME with widespread changes in immune-mediated gene signatures. Notably, STB-based combination immunotherapy elicited the most potent anti-tumor efficacy through concurrent treatment with immune checkpoint inhibitors, leading to complete tumor regression and long-term overall survival. Our study demonstrated that a novel Kyn pathway regulator derived using deep learning technology can activate T cell immunity and potentiate immune checkpoint blockade by overcoming an immunosuppressive TME.
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Affiliation(s)
- Jeong Hun Kim
- Laboratory of Translational Immuno-Oncology, Seongnam, Korea.,Medical Oncology, Department of Internal Medicine,CHA Bundang Medical Center, Cha University, Seongnam, Korea.,Graduate School of Department of Biomedical Science, Cha University, Seongnam, Korea
| | - Won Suk Lee
- Laboratory of Translational Immuno-Oncology, Seongnam, Korea.,Medical Oncology, Department of Internal Medicine,CHA Bundang Medical Center, Cha University, Seongnam, Korea
| | - Hye Jin Lee
- Laboratory of Translational Immuno-Oncology, Seongnam, Korea.,Medical Oncology, Department of Internal Medicine,CHA Bundang Medical Center, Cha University, Seongnam, Korea.,Graduate School of Department of Biomedical Science, Cha University, Seongnam, Korea
| | - Hannah Yang
- Laboratory of Translational Immuno-Oncology, Seongnam, Korea.,Medical Oncology, Department of Internal Medicine,CHA Bundang Medical Center, Cha University, Seongnam, Korea
| | - Seung Joon Lee
- Laboratory of Translational Immuno-Oncology, Seongnam, Korea.,Graduate School of Department of Biomedical Science, Cha University, Seongnam, Korea
| | - So Jung Kong
- Laboratory of Translational Immuno-Oncology, Seongnam, Korea.,Medical Oncology, Department of Internal Medicine,CHA Bundang Medical Center, Cha University, Seongnam, Korea
| | - Soyeon Je
- Medical Science Study Centre, Syntekabio Inc, Seoul, South Korea
| | - Hyun-Jin Yang
- Medical Science Study Centre, Syntekabio Inc, Seoul, South Korea
| | - Jongsun Jung
- Insilico Clinical Trial Research Center, Syntekabio Inc, Daejeon, South Korea
| | - Jaekyung Cheon
- Laboratory of Translational Immuno-Oncology, Seongnam, Korea.,Medical Oncology, Department of Internal Medicine,CHA Bundang Medical Center, Cha University, Seongnam, Korea.,Graduate School of Department of Biomedical Science, Cha University, Seongnam, Korea
| | - Beodeul Kang
- Laboratory of Translational Immuno-Oncology, Seongnam, Korea.,Medical Oncology, Department of Internal Medicine,CHA Bundang Medical Center, Cha University, Seongnam, Korea.,Graduate School of Department of Biomedical Science, Cha University, Seongnam, Korea
| | - Hong Jae Chon
- Laboratory of Translational Immuno-Oncology, Seongnam, Korea.,Medical Oncology, Department of Internal Medicine,CHA Bundang Medical Center, Cha University, Seongnam, Korea.,Graduate School of Department of Biomedical Science, Cha University, Seongnam, Korea
| | - Chan Kim
- Laboratory of Translational Immuno-Oncology, Seongnam, Korea.,Medical Oncology, Department of Internal Medicine,CHA Bundang Medical Center, Cha University, Seongnam, Korea.,Graduate School of Department of Biomedical Science, Cha University, Seongnam, Korea
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Rahman MM, McFadden G. Oncolytic Viruses: Newest Frontier for Cancer Immunotherapy. Cancers (Basel) 2021; 13:5452. [PMID: 34771615 PMCID: PMC8582515 DOI: 10.3390/cancers13215452] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer remains a leading cause of death worldwide. Despite many signs of progress, currently available cancer treatments often do not provide desired outcomes for too many cancers. Therefore, newer and more effective therapeutic approaches are needed. Oncolytic viruses (OVs) have emerged as a novel cancer treatment modality, which selectively targets and kills cancer cells while sparing normal ones. In the past several decades, many different OV candidates have been developed and tested in both laboratory settings as well as in cancer patient clinical trials. Many approaches have been taken to overcome the limitations of OVs, including engineering OVs to selectively activate anti-tumor immune responses. However, newer approaches like the combination of OVs with current immunotherapies to convert "immune-cold" tumors to "immune-hot" will almost certainly improve the potency of OVs. Here, we discuss strategies that are explored to further improve oncolytic virotherapy.
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Affiliation(s)
- Masmudur M. Rahman
- Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA;
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Kim CW, Chon HJ, Kim C. Combination Immunotherapies to Overcome Intrinsic Resistance to Checkpoint Blockade in Microsatellite Stable Colorectal Cancer. Cancers (Basel) 2021; 13:4906. [PMID: 34638390 PMCID: PMC8507875 DOI: 10.3390/cancers13194906] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 09/18/2021] [Accepted: 09/26/2021] [Indexed: 12/19/2022] Open
Abstract
Although immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of treating various malignancies, progress has been severely limited in metastatic colorectal cancer (mCRC). ICIs are effective in a fraction of patients with microsatellite instability-high mCRC but have little clinical efficacy in patients with microsatellite stable (MSS) mCRC, which accounts for 95% of mCRC cases. MSS mCRCs are considered to have intrinsic resistance to ICI monotherapy through multiple mechanisms. (1) They are poorly immunogenic because of their low tumor mutation burden; (2) frequent activation of the WNT/β-catenin signaling pathway excludes intratumoral CD8+ T cell immunity; (3) the tumor microenvironment is immunosuppressive because of the presence of various immunosuppressive cells, including tumor-associated macrophages and regulatory T cells; and (4) frequent liver metastasis in MSS mCRC may reduce the efficacy of ICIs. To overcome these resistance mechanisms, combination approaches using various agents, including STING agonists, MEK inhibitors, VEGF/R inhibitors, WNT/β-catenin inhibitors, oncolytic viruses, and chemo/radiotherapy, are actively ongoing. Preliminary evidence of the efficacy of some has been shown in early clinical trials. This review summarizes novel combination immunotherapy strategies described in recent preclinical and clinical studies to overcome the limitations of ICI monotherapy in MSS mCRC.
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Affiliation(s)
- Chang Woo Kim
- Department of Surgery, Ajou University School of Medicine, 164 World Cup-ro, Yeongtong-gu, Suwon 16499, Korea;
| | - Hong Jae Chon
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Korea
| | - Chan Kim
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Korea
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Santos Apolonio J, Lima de Souza Gonçalves V, Cordeiro Santos ML, Silva Luz M, Silva Souza JV, Rocha Pinheiro SL, de Souza WR, Sande Loureiro M, de Melo FF. Oncolytic virus therapy in cancer: A current review. World J Virol 2021; 10:229-255. [PMID: 34631474 PMCID: PMC8474975 DOI: 10.5501/wjv.v10.i5.229] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/19/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
In view of the advancement in the understanding about the most diverse types of cancer and consequently a relentless search for a cure and increased survival rates of cancer patients, finding a therapy that is able to combat the mechanism of aggression of this disease is extremely important. Thus, oncolytic viruses (OVs) have demonstrated great benefits in the treatment of cancer because it mediates antitumor effects in several ways. Viruses can be used to infect cancer cells, especially over normal cells, to present tumor-associated antigens, to activate "danger signals" that generate a less immune-tolerant tumor microenvironment, and to serve transduction vehicles for expression of inflammatory and immunomodulatory cytokines. The success of therapies using OVs was initially demonstrated by the use of the genetically modified herpes virus, talimogene laherparepvec, for the treatment of melanoma. At this time, several OVs are being studied as a potential treatment for cancer in clinical trials. However, it is necessary to be aware of the safety and possible adverse effects of this therapy; after all, an effective treatment for cancer should promote regression, attack the tumor, and in the meantime induce minimal systemic repercussions. In this manuscript, we will present a current review of the mechanism of action of OVs, main clinical uses, updates, and future perspectives on this treatment.
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Affiliation(s)
- Jonathan Santos Apolonio
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Maria Luísa Cordeiro Santos
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - João Victor Silva Souza
- Universidade Estadual do Sudoeste da Bahia, Campus Vitória da Conquista, Vitória da Conquista 45083-900, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Wedja Rafaela de Souza
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Matheus Sande Loureiro
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
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Liu J, Yi J, Zhang Z, Cao D, Li L, Yao Y. Deoxyribonuclease 1-like 3 may be a potential prognostic biomarker associated with immune infiltration in colon cancer. Aging (Albany NY) 2021; 13:16513-16526. [PMID: 34157681 PMCID: PMC8266351 DOI: 10.18632/aging.203173] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 05/24/2021] [Indexed: 01/11/2023]
Abstract
Colon adenocarcinoma (COAD) is a common cancer of the digestive system. It’s high morbidity and mortality make it one of the leading causes of cancer deaths. In this study, we studied the microenvironment of colon cancer to find new diagnostic markers and immunotherapy targets for colon cancer. Tumor purity of colon cancer samples in TCGA database were obtained by ESTIMATE algorithm. Then, we analyzed the association of Immune, Stromal, and Estimate scores with tumor prognosis and clinicopathological features. By comparing the gene expression profiles between tumor and normal samples, the high and low immune score groups, 117 intersecting differentially expressed genes (DEGs) were obtained. The function, molecular pathway, and prognostic value of these 117 DEGs pointed toward the importance of deoxyribonuclease 1-like 3 (DNASE1L3). Validation results from multiple databases showed low expression of DNASE1L3 in colon cancer. A single GSEA and correlation analysis of immune cells indicated that DNASE1L3 was closely related to immunity. The low expression of DNASE1L3 in colon cancer samples was measured with qRT-PCR. The scratch and cell proliferation experiments suggested that DNASE1L3 may affect cell migration. Therefore, we concluded that DNASE1L3 might be a biomarker associated with prognosis and immune infiltration in colon cancer.
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Affiliation(s)
- Jing Liu
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou 510317, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510317, China
| | - Jingya Yi
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou 510317, China
| | - Zhihong Zhang
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou 510317, China
| | - Donglin Cao
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou 510317, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510317, China
| | - Lei Li
- Center for Reproductive Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.,Key Laboratory for Reproductive Medicine of Guangdong Province, Guangzhou 510150, China
| | - Yachao Yao
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou 510317, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510317, China
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Guo ZS. Oncolytic Virus Immunotherapy: Showcasing Impressive Progress in Special Issue II. Biomedicines 2021; 9:biomedicines9060663. [PMID: 34200560 PMCID: PMC8226691 DOI: 10.3390/biomedicines9060663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 06/09/2021] [Indexed: 12/19/2022] Open
Affiliation(s)
- Zong-Sheng Guo
- UPMC Hillman Cancer Center and Departments of Surgery, Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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37
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Chen Z, Dong R. Advances in the conventional clinical treatment for hepatoblastoma and therapeutic innovation. WORLD JOURNAL OF PEDIATRIC SURGERY 2021; 4:e000220. [DOI: 10.1136/wjps-2020-000220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 05/21/2021] [Indexed: 11/03/2022] Open
Abstract
BackgroundHepatoblastoma (HB) is a rare malignancy usually occurring in children under 3 years old. With advancements in surgical techniques and molecular biology, new treatments have been developed.Data resourcesThe recent literatures on new treatments, molecular mechanisms and clinical trials for HB were searched and reviewed.ResultsSurgical resection remains the main option for treatment of HB. Although complete resection is recommended, a resection with microscopical positive margins (R1) may have similar 5-year overall survival and 5-year event-free survival (EFS) rates after cisplatin chemotherapy and the control of metastasis, as only once described so far. Indocyanine green-guided surgery can help achieve precise resection. Additionally, associating liver partition and portal vein ligation for staged hepatectomy can rapidly increase future liver remnant volume compared with portal vein ligation or embolization. Cisplatin-containing chemotherapies slightly differ among the guidelines from the International Childhood Liver Tumors Strategy Group (SIOPEL), Children’s Oncology Group (COG) and Chinese Anti-Cancer Association Pediatric Committee (CCCG), and the 3-year EFS rate of patients in SIOPEL and CCCG studies was recently shown to be higher than that in COG studies. Liver transplantation is an option for patients with unresectable HB, and successful cases of autologous liver transplantation have been reported. In addition, effective inhibitors of important targets, such as the mTOR (mammalian target of rapamycin) inhibitor rapamycin, β-catenin inhibitor celecoxib and EpCAM (epithelial cell adhesion molecule) inhibitor catumaxomab, have been demonstrated to reduce the activity of HB cells and to control metastasis in experimental research and clinical trials.ConclusionThese advances in surgical and medical treatment provide better outcomes for children with HB, and identifying novel targets may lead to the development of future targeted therapies and immunotherapies.
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Heidbuechel JPW, Engeland CE. Oncolytic viruses encoding bispecific T cell engagers: a blueprint for emerging immunovirotherapies. J Hematol Oncol 2021; 14:63. [PMID: 33863363 PMCID: PMC8052795 DOI: 10.1186/s13045-021-01075-5] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 03/30/2021] [Indexed: 02/08/2023] Open
Abstract
Bispecific T cell engagers (BiTEs) are an innovative class of immunotherapeutics that redirect T cells to tumor surface antigens. While efficacious against certain hematological malignancies, limited bioavailability and severe toxicities have so far hampered broader clinical application, especially against solid tumors. Another emerging cancer immunotherapy are oncolytic viruses (OVs) which selectively infect and replicate in malignant cells, thereby mediating tumor vaccination effects. These oncotropic viruses can serve as vectors for tumor-targeted immunomodulation and synergize with other immunotherapies. In this article, we discuss the use of OVs to overcome challenges in BiTE therapy. We review the current state of the field, covering published preclinical studies as well as ongoing clinical investigations. We systematically introduce OV-BiTE vector design and characteristics as well as evidence for immune-stimulating and anti-tumor effects. Moreover, we address additional combination regimens, including CAR T cells and immune checkpoint inhibitors, and further strategies to modulate the tumor microenvironment using OV-BiTEs. The inherent complexity of these novel therapeutics highlights the importance of translational research including correlative studies in early-phase clinical trials. More broadly, OV-BiTEs can serve as a blueprint for diverse OV-based cancer immunotherapies.
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Affiliation(s)
- Johannes P W Heidbuechel
- Research Group Mechanisms of Oncolytic Immunotherapy, Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Christine E Engeland
- Research Group Mechanisms of Oncolytic Immunotherapy, Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
- Department of Medical Oncology, University Hospital Heidelberg, Heidelberg, Germany.
- Center for Biomedical Research and Education (ZBAF), School of Medicine, Institute of Virology and Microbiology, Faculty of Health, Witten/Herdecke University, Witten, Germany.
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Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model. Pharmaceutics 2021; 13:pharmaceutics13040547. [PMID: 33919827 PMCID: PMC8070801 DOI: 10.3390/pharmaceutics13040547] [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: 03/26/2021] [Revised: 04/10/2021] [Accepted: 04/11/2021] [Indexed: 12/24/2022] Open
Abstract
Malignant melanoma, an aggressive form of skin cancer, has a low five-year survival rate in patients with advanced disease. Immunotherapy represents a promising approach to improve survival rates among patients at advanced stage. Herein, the aim of the study was to design and produce, by using engineering tools, a novel oncolytic adenovirus AdV-D24- inducible co-stimulator ligand (ICOSL)-CD40L expressing potent co-stimulatory molecules enhancing clinical efficacy through the modulation of anti-cancer immune responses. Firstly, we demonstrated the vector's identity and genetic stability by restriction enzyme assay and sequencing, then, by performing in vitro and in vivo pre-clinical studies we explored the anti-cancer efficacy of the virus alone or in combination with anti PD-1 inhibitor in human melanoma cell lines, i.e., MUG Mel-1 and MUG Mel-2, and in immunocompetent C57BL/6 melanoma B16V mouse model. We showed that both monotherapy and combination approaches exhibit enhanced anti-cancer ability and immunogenic cell death in in vitro settings. Furthermore, AdV-D24-ICOSL-CD40L combined with anti PD-1 revealed a fall in tumor volume and 100% survival in in vivo context, thus suggesting enhanced efficacy and survival via complementary anti-cancer properties of those agents in melanoma therapy. Collectively, the novel oncolytic vector AdV-D24-ICOSL-CD40L alone or in combination with anticancer drugs, such as check point inhibitors, may open novel therapeutic perspectives for the treatment of melanoma.
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40
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Wang X, Zhao X, He Z. Mesenchymal stem cell carriers enhance anti-tumor efficacy of oncolytic virotherapy. Oncol Lett 2021; 21:238. [PMID: 33664802 PMCID: PMC7882891 DOI: 10.3892/ol.2021.12499] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 12/09/2020] [Indexed: 12/21/2022] Open
Abstract
Oncolytic viruses (OVs) specifically infect, replicate and eventually destroy tumor cells, with no concomitant toxicity to adjacent normal cells. Furthermore, OVs can regulate tumor microenvironments and stimulate anti-tumor immune responses. Mesenchymal stem cells (MSCs) have inherent tumor tropisms and immunosuppressive functions. MSCs carrying OVs not only protect viruses from clearing by the immune system, but they also deliver the virus to tumor lesions. Equally, cytokines released by MSCs enhance anti-tumor immune responses, suggesting that MSCs carrying OVs may be considered as a promising strategy in enhancing the anti-tumor efficacies of virotherapy. In the present review, preclinical and clinical studies were evaluated and discussed, as well as the effectiveness of MSCs carrying OVs for tumor treatment.
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Affiliation(s)
- Xianyao Wang
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
- Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, Guizhou 550004, P.R. China
- Department of Immunology, Guizhou Medical University, Guiyang, Guizhou 550025, P.R. China
| | - Xing Zhao
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
- Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, Guizhou 550004, P.R. China
- Department of Immunology, Guizhou Medical University, Guiyang, Guizhou 550025, P.R. China
| | - Zhixu He
- Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, Guizhou 550004, P.R. China
- Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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41
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Zhang Z, Zeng P, Gao W, Zhou Q, Feng T, Tian X. Circadian clock: a regulator of the immunity in cancer. Cell Commun Signal 2021; 19:37. [PMID: 33752691 PMCID: PMC7986390 DOI: 10.1186/s12964-021-00721-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/10/2021] [Indexed: 02/06/2023] Open
Abstract
The circadian clock is an endogenous timekeeper system that controls and optimizes biological processes, which are consistent with a master circadian clock and peripheral clocks and are controlled by various genes. Notably, the disruption of circadian clock genes has been identified to affect a wide range of ailments, including cancers. The cancer-immunity cycle is composed of seven major steps, namely cancer cell antigen release and presentation, priming and activation of effector immunity cells, trafficking, and infiltration of immunity to tumors, and elimination of cancer cells. Existing evidence indicates that the circadian clock functions as a gate that govern many aspects of the cancer-immunity cycle. In this review, we highlight the importance of the circadian clock during tumorigenesis, and discuss the potential role of the circadian clock in the cancer-immunity cycle. A comprehensive understanding of the regulatory function of the circadian clock in the cancer-immunity cycle holds promise in developing new strategies for the treatment of cancer.
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