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Omole AO, Zhao Z, Chang-Liao S, de Oliveira JFA, Boone CE, Sutorus L, Sack M, Varner J, Fiering SN, Steinmetz NF. Virus nanotechnology for intratumoural immunotherapy. NATURE REVIEWS BIOENGINEERING 2024; 2:916-929. [PMID: 39698315 PMCID: PMC11655125 DOI: 10.1038/s44222-024-00231-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/22/2024] [Indexed: 12/20/2024]
Abstract
Viruses can be designed to be tools and carrier vehicles for intratumoural immunotherapy. Their nanometre-scale size and shape allow for functionalization with or encapsulation of medical cargoes and tissue-specific ligands. Importantly, immunotherapies may particularly benefit from the inherent immunomodulatory properties of viruses. For example, mammalian viruses have already been tested for oncolytic virotherapy, and bacteriophages and plant viruses can be engineered for immunotherapeutic treatment approaches. In this Review, we discuss how viruses - including oncolytic viruses, immunomodulatory plant viruses and bacteriophages - and virus-like particles can be designed for intratumoural immunotherapy to elicit anti-tumour immunity and induce systemic anti-tumour responses at distant non-injected sites. We further highlight the engineering of viruses and virus-like particles as drug-delivery systems, and outline key translational challenges and clinical opportunities.
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Affiliation(s)
- Anthony O. Omole
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Zhongchao Zhao
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Sabrina Chang-Liao
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Jessica Fernanda Affonso de Oliveira
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Christine E. Boone
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
| | - Lucas Sutorus
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | | | - Judith Varner
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Center for Engineering in Cancer, Institute of Engineering Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Pathology, University of California, San Diego, La Jolla, CA, USA
| | - Steven N. Fiering
- Department of Microbiology and Immunology, Dartmouth Cancer Center, Dartmouth Geisel School of Medicine and Dartmouth-Hitchock Health, Lebanon, NH, USA
| | - Nicole F. Steinmetz
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
- Center for Engineering in Cancer, Institute of Engineering Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Radiology, University of California, San Diego, La Jolla, CA, USA
- Institute for Materials Discovery and Design, University of California, San Diego, La Jolla, CA, USA
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Naing C, Ni H, Aung HH, Htet NH, Nikolova D. Gene therapy for people with hepatocellular carcinoma. Cochrane Database Syst Rev 2024; 6:CD013731. [PMID: 38837373 PMCID: PMC11152182 DOI: 10.1002/14651858.cd013731.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/07/2024]
Abstract
BACKGROUND Hepatocellular carcinoma is the most common type of liver cancer, accounting for 70% to 85% of individuals with primary liver cancer. Gene therapy, which uses genes to treat or prevent diseases, holds potential for treatment, especially for tumours. Trials on the effects of gene therapy in people with hepatocellular carcinoma have been published or are ongoing. OBJECTIVES To evaluate the benefits and harms of gene therapy in people with hepatocellular carcinoma, irrespective of sex, administered dose, and type of formulation. SEARCH METHODS We identified randomised clinical trials through electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We searched five online clinical trial registries to identify unpublished or ongoing trials. We checked reference lists of the retrieved studies for further trials. The date of last search was 20 January 2023. SELECTION CRITERIA We aimed to include randomised clinical trials assessing any type of gene therapy in people diagnosed with hepatocellular carcinoma, irrespective of year, language of publication, format, or outcomes reported. DATA COLLECTION AND ANALYSIS We followed Cochrane methodology and used Review Manager to prepare the review. The primary outcomes were all-cause mortality/overall survival (whatever data were provided), serious adverse events during treatment, and health-related quality of life. The secondary outcomes were proportion of people with disease progression, adverse events considered non-serious, and proportion of people without improvement in liver function tests. We assessed risk of bias of the included trials using RoB 2 and the certainty of evidence using GRADE. We presented the results of time-to-event outcomes as hazard ratios (HR), dichotomous outcomes as risk ratios (RR), and continuous outcomes as mean difference (MD) with their 95% confidence intervals (CI). Our primary analyses were based on intention-to-treat and outcome data at the longest follow-up. MAIN RESULTS We included six randomised clinical trials with 364 participants. The participants had unresectable (i.e. advanced inoperable) hepatocellular carcinoma. We found no trials assessing the effects of gene therapy in people with operable hepatocellular carcinoma. Four trials were conducted in China, one in several countries (from North America, Asia, and Europe), and one in Egypt. The number of participants in the six trials ranged from 10 to 129 (median 47), median age was 55.2 years, and the mean proportion of males was 72.7%. The follow-up duration ranged from six months to five years. As the trials compared different types of gene therapy and had different controls, we could not perform meta-analyses. Five of the six trials administered co-interventions equally to the experimental and control groups. All trials assessed one or more outcomes of interest in this review. The certainty of evidence was very low in five of the six comparisons and low in the double-dose gene therapy comparison. Below, we reported the results of the primary outcomes only. Pexastimogene devacirepvec (Pexa-Vec) plus best supportive care versus best supportive care alone There is uncertainty about whether there may be little to no difference between the effect of Pexa-Vec plus best supportive care compared with best supportive care alone on overall survival (HR 1.19, 95% CI 0.78 to 1.82; 1 trial (censored observation at 20-month follow-up), 129 participants; very low-certainty evidence) and on serious adverse events (RR 1.42, 95% CI 0.60 to 3.33; 1 trial at 20 months after treatment, 129 participants; very low-certainty evidence). The trial reported quality of life narratively as "assessment of quality of life and time to symptomatic progression was confounded by the high patient dropout rate." Adenovirus-thymidine kinase with ganciclovir (ADV-TK/GCV) plus liver transplantation versus liver transplantation alone There is uncertainty about whether ADV-TK/GCV plus liver transplantation may benefit all-cause mortality at the two-year follow-up (RR 0.39, 95% CI 0.20 to 0.76; 1 trial, 45 participants; very low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life. Double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation alone There is uncertainty about whether double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation may benefit all-cause mortality at five-year follow-up (RR 0.40, 95% CI 0.22 to 0.73; 1 trial, 86 participants; low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life. Recombinant human adenovirus-p53 with hydroxycamptothecin (rAd-p53/HCT) versus hydroxycamptothecin alone There is uncertainty about whether there may be little to no difference between the effect of rAd-p53/HCT versus hydroxycamptothecin alone on the overall survival at 12-month follow-up (RR 3.06, 95% CI 0.16 to 60.47; 1 trial, 48 participants; very low-certainty evidence). The trial did not report serious adverse events or quality of life. rAd-p53/5-Fu (5-fluorouracil) plus transarterial chemoembolisation versus transarterial chemoembolisation alone The trial included 46 participants. We had insufficient data to assess overall survival. The trial did not report serious adverse events or quality of life. E1B-deleted (dl1520) adenovirus versus percutaneous ethanol injection The trial included 10 participants. It did not report data on overall survival, serious adverse events, or health-related quality of life. One trial did not provide any information on sponsorship; one trial received a national research grant, one trial by the Pedersen foundation, and three were industry-funded trials. We found five ongoing randomised clinical trials. AUTHORS' CONCLUSIONS The evidence is very uncertain about the effects of gene therapy on the studied outcomes because of high risk of bias and imprecision of outcome results. The trials were underpowered and lacked trial data on clinically important outcomes. There was only one trial per comparison, and we could not perform meta-analyses. Therefore, we do not know if gene therapy may reduce, increase, or have little to no effect on all-cause mortality or overall survival, or serious adverse events in adults with unresectable hepatocellular carcinoma. The impact of gene therapy on adverse events needs to be investigated further. Evidence on the effect of gene therapy on health-related quality of life is lacking.
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Affiliation(s)
- Cho Naing
- Division of Tropical Health and Medicine, James Cook University, Queensland, Australia
| | - Han Ni
- Department of Medicine, Newcastle University Medicine Malaysia, Johor, Malaysia
| | - Htar Htar Aung
- School of Medicine, IMU University, Kuala Lumpur, Malaysia
| | | | - Dimitrinka Nikolova
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital ─ Rigshospitalet, Copenhagen, Denmark
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Kim IW, Yoon AR, Hong J, Kasala D, Yun CO. Synergistic antitumor immune response mediated by paclitaxel-conjugated nanohybrid oncolytic adenovirus with dendritic cell therapy. Front Immunol 2024; 15:1355566. [PMID: 38835775 PMCID: PMC11148213 DOI: 10.3389/fimmu.2024.1355566] [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: 12/14/2023] [Accepted: 05/06/2024] [Indexed: 06/06/2024] Open
Abstract
Dendritic cell (DC)-based vaccines have emerged as a promising strategy in cancer immunotherapy due to low toxicity. However, the therapeutic efficacy of DC as a monotherapy is insufficient due to highly immunosuppressive tumor environment. To address these limitations of DC as immunotherapeutic agent, we have developed a polymeric nanocomplex incorporating (1) oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) and (2) arginine-grafted bioreducible polymer with PEGylated paclitaxel (APP) to restore antitumor immune surveillance function in tumor milieu and potentiate immunostimulatory attributes of DC vaccine. Nanohybrid complex (oAd/APP) in combination with DC (oAd/APP+DC) induced superior expression level of antitumor cytokines (IL-12, GM-CSF, and interferon gamma) than either oAd/APP or DC monotherapy in tumor tissues, thus resulting in superior intratumoral infiltration of both endogenous and exogenous DCs. Furthermore, oAd/APP+DC treatment led superior migration of DC to secondary lymphoid organs, such as draining lymph nodes and spleen, in comparison with either monotherapy. Superior migration profile of DCs in oAd/APP+DC treatment group resulted in more prolific activation of tumor-specific T cells in these lymphoid organs and greater intratumoral infiltration of T cells. Additionally, oAd/APP+DC treatment led to lower subset of tumor infiltrating lymphocytes and splenocytes being immunosuppressive regulatory T cells than any other treatment groups. Collectively, oAd/APP+DC led to superior induction of antitumor immune response and amelioration of immunosuppressive tumor microenvironment to elicit potent tumor growth inhibition than either monotherapy.
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Affiliation(s)
- In-Wook Kim
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, Republic of Korea
- Institute of Nano Science and Technology (INST), Hanyang University, Seoul, Republic of Korea
| | - A-Rum Yoon
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, Republic of Korea
- Institute of Nano Science and Technology (INST), Hanyang University, Seoul, Republic of Korea
| | - JinWoo Hong
- GeneMedicine CO., Ltd., Seoul, Republic of Korea
| | - Dayananda Kasala
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
| | - Chae-Ok Yun
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, Republic of Korea
- Institute of Nano Science and Technology (INST), Hanyang University, Seoul, Republic of Korea
- GeneMedicine CO., Ltd., Seoul, Republic of Korea
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Wei H, Dong C, Li X. Treatment Options for Hepatocellular Carcinoma Using Immunotherapy: Present and Future. J Clin Transl Hepatol 2024; 12:389-405. [PMID: 38638377 PMCID: PMC11022065 DOI: 10.14218/jcth.2023.00462] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 04/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cancer, and the body's immune responses greatly affect its progression and the prognosis of patients. Immunological suppression and the maintenance of self-tolerance in the tumor microenvironment are essential responses, and these form part of the theoretical foundations of immunotherapy. In this review, we first discuss the tumor microenvironment of HCC, describe immunosuppression in HCC, and review the major biomarkers used to track HCC progression and response to treatment. We then examine antibody-based therapies, with a focus on immune checkpoint inhibitors (ICIs), monoclonal antibodies that target key proteins in the immune response (programmed cell death protein 1, anti-cytotoxic T-lymphocyte associated protein 4, and programmed death-ligand 1) which have transformed the treatment of HCC and other cancers. ICIs may be used alone or in conjunction with various targeted therapies for patients with advanced HCC who are receiving first-line treatments or subsequent treatments. We also discuss the use of different cellular immunotherapies, including T cell receptor (TCR) T cell therapy and chimeric antigen receptor (CAR) T cell therapy. We then review the use of HCC vaccines, adjuvant immunotherapy, and oncolytic virotherapy, and describe the goals of future research in the development of treatments for HCC.
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Affiliation(s)
- Hongbin Wei
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, Gansu, China
- Cancer Prevention and Treatment Center of Lanzhou University School of Medicine, Lanzhou, Gansu, China
- Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou, Gansu, China
- Clinical Research Center for General Surgery of Gansu Province, Lanzhou, Gansu, China
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Yarahmadi A, Zare M, Aghayari M, Afkhami H, Jafari GA. Therapeutic bacteria and viruses to combat cancer: double-edged sword in cancer therapy: new insights for future. Cell Commun Signal 2024; 22:239. [PMID: 38654309 PMCID: PMC11040964 DOI: 10.1186/s12964-024-01622-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 04/17/2024] [Indexed: 04/25/2024] Open
Abstract
Cancer, ranked as the second leading cause of mortality worldwide, leads to the death of approximately seven million people annually, establishing itself as one of the most significant health challenges globally. The discovery and identification of new anti-cancer drugs that kill or inactivate cancer cells without harming normal and healthy cells and reduce adverse effects on the immune system is a potential challenge in medicine and a fundamental goal in Many studies. Therapeutic bacteria and viruses have become a dual-faceted instrument in cancer therapy. They provide a promising avenue for cancer treatment, but at the same time, they also create significant obstacles and complications that contribute to cancer growth and development. This review article explores the role of bacteria and viruses in cancer treatment, examining their potential benefits and drawbacks. By amalgamating established knowledge and perspectives, this review offers an in-depth examination of the present research landscape within this domain and identifies avenues for future investigation.
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Affiliation(s)
- Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Mitra Zare
- Department of Microbiology, Faculty of Sciences, Kerman Branch, Islamic Azad University, Kerman, Iran
| | - Masoomeh Aghayari
- Department of Microbiology, Faculty of Sciences, Urmia Branch, Islamic Azad University, Urmia, Iran
| | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran.
| | - Gholam Ali Jafari
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
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Zhang Z, Yang A, Chaurasiya S, Park AK, Kim SI, Lu J, Valencia H, Fong Y, Woo Y. Anti-Tumor Immunogenicity of the Oncolytic Virus CF33-hNIS-antiPDL1 against Ex Vivo Peritoneal Cells from Gastric Cancer Patients. Int J Mol Sci 2023; 24:14189. [PMID: 37762490 PMCID: PMC10532045 DOI: 10.3390/ijms241814189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/13/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
We studied the immunotherapeutic potential of CF33-hNIS-antiPDL1 oncolytic virus (OV) against gastric cancer with peritoneal metastasis (GCPM). We collected fresh malignant ascites (MA) or peritoneal washings (PW) during routine paracenteses and diagnostic laparoscopies from GC patients (n = 27). Cells were analyzed for cancer cell markers and T cells, or treated with PBS, CF33-GFP, or CF33-hNIS-antiPDL1 (MOI = 3). We analyzed infectivity, replication, cytotoxicity, CD107α upregulation of CD8+ and CD4+ T cells, CD274 (PD-L1) blockade of cancer cells by virus-encoded anti-PD-L1 scFv, and the release of growth factors and cytokines. We observed higher CD45-/large-size cells and lower CD8+ T cell percentages in MA than PW. CD45-/large-size cells were morphologically malignant and expressed CD274 (PD-L1), CD252 (OX40L), and EGFR. CD4+ and CD8+ T cells did not express cell surface exhaustion markers. Virus infection and replication increased cancer cell death at 15 h and 48 h. CF33-hNIS-antiPDL1 treatment produced functional anti-PD-L1 scFv, which blocked surface PD-L1 binding of live cancer cells and increased CD8+CD107α+ and CD4+CD107α+ T cell percentages while decreasing EGF, PDGF, soluble anti-PD-L1, and IL-10. CF33-OVs infect, replicate in, express functional proteins, and kill ex vivo GCPM cells with immune-activating effects. CF33-hNIS-antiPDL1 displays real potential for intraperitoneal GCPM therapy.
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Affiliation(s)
- Zhifang Zhang
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA; (Z.Z.); (A.Y.); (S.C.); (S.-I.K.); (J.L.); (H.V.); (Y.F.)
| | - Annie Yang
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA; (Z.Z.); (A.Y.); (S.C.); (S.-I.K.); (J.L.); (H.V.); (Y.F.)
| | - Shyambabu Chaurasiya
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA; (Z.Z.); (A.Y.); (S.C.); (S.-I.K.); (J.L.); (H.V.); (Y.F.)
| | - Anthony K. Park
- Cancer Immunotherapeutics Program, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA 91010, USA;
| | - Sang-In Kim
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA; (Z.Z.); (A.Y.); (S.C.); (S.-I.K.); (J.L.); (H.V.); (Y.F.)
| | - Jianming Lu
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA; (Z.Z.); (A.Y.); (S.C.); (S.-I.K.); (J.L.); (H.V.); (Y.F.)
| | - Hannah Valencia
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA; (Z.Z.); (A.Y.); (S.C.); (S.-I.K.); (J.L.); (H.V.); (Y.F.)
| | - Yuman Fong
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA; (Z.Z.); (A.Y.); (S.C.); (S.-I.K.); (J.L.); (H.V.); (Y.F.)
| | - Yanghee Woo
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA; (Z.Z.); (A.Y.); (S.C.); (S.-I.K.); (J.L.); (H.V.); (Y.F.)
- Cancer Immunotherapeutics Program, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA 91010, USA;
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Wang X, Shen Y, Wan X, Hu X, Cai WQ, Wu Z, Xin Q, Liu X, Gui J, Xin HY, Xin HW. Oncolytic virotherapy evolved into the fourth generation as tumor immunotherapy. J Transl Med 2023; 21:500. [PMID: 37491263 PMCID: PMC10369732 DOI: 10.1186/s12967-023-04360-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 07/16/2023] [Indexed: 07/27/2023] Open
Abstract
BACKGROUND Oncolytic virotherapy (OVT) is a promising anti-tumor modality that utilizes oncolytic viruses (OVs) to preferentially attack cancers rather than normal tissues. With the understanding particularly in the characteristics of viruses and tumor cells, numerous innovative OVs have been engineered to conquer cancers, such as Talimogene Laherparepvec (T-VEC) and tasadenoturev (DNX-2401). However, the therapeutic safety and efficacy must be further optimized and balanced to ensure the superior safe and efficient OVT in clinics, and reasonable combination therapy strategies are also important challenges worthy to be explored. MAIN BODY Here we provided a critical review of the development history and status of OVT, emphasizing the mechanisms of enhancing both safety and efficacy. We propose that oncolytic virotherapy has evolved into the fourth generation as tumor immunotherapy. Particularly, to arouse T cells by designing OVs expressing bi-specific T cell activator (BiTA) is a promising strategy of killing two birds with one stone. Amazing combination of therapeutic strategies of OVs and immune cells confers immense potential for managing cancers. Moreover, the attractive preclinical OVT addressed recently, and the OVT in clinical trials were systematically reviewed. CONCLUSION OVs, which are advancing into clinical trials, are being envisioned as the frontier clinical anti-tumor agents coming soon.
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Affiliation(s)
- Xianwang Wang
- Department of Biochemistry and Molecular Biology, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China.
| | - Yihua Shen
- The Second School of Clinical Medicine, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Xingxia Wan
- College of Arts and Sciences, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Xiaoqing Hu
- The Second School of Clinical Medicine, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Wen-Qi Cai
- Xinzhou Traditional Chinese Medicine Hospital, Zhongnan Hospital of Wuhan University (Xinzhou), Wuhan, 430000, Hubei, China
| | - Zijun Wu
- The Second School of Clinical Medicine, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Qiang Xin
- School of Graduate Students, Inner Mongolia Medical University, Inner Mongolian Autonomous Region, Hohhot, 010110, China
| | - Xiaoqing Liu
- College of Arts and Sciences, Yangtze University, Jingzhou, 434023, Hubei, China
| | - Jingang Gui
- Laboratory of Tumor Immunology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Hong-Yi Xin
- The Doctoral Scientific Research Center, People's Hospital of Lianjiang, Guangdong, 524400, China.
- The Doctoral Scientific Research Center, Affiliated People's Hospital of Lianjiang, Guangdong Medical University, Guangdong, 524400, China.
| | - Hong-Wu Xin
- Department of Biochemistry and Molecular Biology, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China.
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Saito A, Kitayama J, Nagai R, Aizawa K. Anatomical Targeting of Anticancer Drugs to Solid Tumors Using Specific Administration Routes: Review. Pharmaceutics 2023; 15:1664. [PMID: 37376112 DOI: 10.3390/pharmaceutics15061664] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/02/2023] [Accepted: 06/04/2023] [Indexed: 06/29/2023] Open
Abstract
Despite remarkable recent progress in developing anti-cancer agents, outcomes of patients with solid tumors remain unsatisfactory. In general, anti-cancer drugs are systemically administered through peripheral veins and delivered throughout the body. The major problem with systemic chemotherapy is insufficient uptake of intravenous (IV) drugs by targeted tumor tissue. Although dose escalation and treatment intensification have been attempted in order to increase regional concentrations of anti-tumor drugs, these approaches have produced only marginal benefits in terms of patient outcomes, while often damaging healthy organs. To overcome this problem, local administration of anti-cancer agents can yield markedly higher drug concentrations in tumor tissue with less systemic toxicity. This strategy is most commonly used for liver and brain tumors, as well as pleural or peritoneal malignancies. Although the concept is theoretically reasonable, survival benefits are still limited. This review summarizes clinical results and problems and discusses future directions of regional cancer therapy with local administration of chemotherapeutants.
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Affiliation(s)
- Akira Saito
- Department of Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0431, Japan
| | - Joji Kitayama
- Department of Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0431, Japan
- Division of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Tochigi, Tochigi 329-0498, Japan
| | - Ryozo Nagai
- Department of Medicine, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| | - Kenichi Aizawa
- Division of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Tochigi, Tochigi 329-0498, Japan
- Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
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9
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Zolaly MA, Mahallawi W, Khawaji ZY, Alahmadi MA. The Clinical Advances of Oncolytic Viruses in Cancer Immunotherapy. Cureus 2023; 15:e40742. [PMID: 37485097 PMCID: PMC10361339 DOI: 10.7759/cureus.40742] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
A promising future for oncology treatment has been brought about by the emergence of a novel approach utilizing oncolytic viruses in cancer immunotherapy. Oncolytic viruses are viruses that have been exploited genetically to assault malignant cells and activate a robust immune response. Several techniques have been developed to endow viruses with an oncolytic activity through genetic engineering. For instance, redirection capsid modification, stimulation of anti-neoplastic immune response, and genetically arming viruses with cytokines such as IL-12. Oncolytic viral clinical outcomes are sought after, particularly in more advanced cancers. The effectiveness and safety profile of the oncolytic virus in clinical studies with or without the combination of standard treatment (chemotherapy, radiotherapy, or primary excision) has been assessed using response evaluation criteria in solid tumors (RECIST). This review will comprehensively outline the most recent clinical applications and provide the results from various phases of clinical trials in a variety of cancers in the latest published literature.
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Affiliation(s)
- Mohammed A Zolaly
- Pediatric Hematology Oncology, Taibah University, Al-Madinah al-Munawwarah, SAU
| | - Waleed Mahallawi
- Medical Laboratory Technology Department, College of Applied Medical Sciences, Taibah University, Al-Madinah al-Munawwarah, SAU
| | - Zakaria Y Khawaji
- Medicine and Surgery, Taibah University, Al-Madinah al-Munawwarah, SAU
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10
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Meng L, Wei Y, Xiao Y. Chemo-immunoablation of solid tumors: A new concept in tumor ablation. Front Immunol 2023; 13:1057535. [PMID: 36713427 PMCID: PMC9878389 DOI: 10.3389/fimmu.2022.1057535] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/09/2022] [Indexed: 01/13/2023] Open
Abstract
Chemical ablation was designed to inject chemical agents directly into solid tumors to kill cells and is currently only used clinically for the palliative treatment of tumors. The application and combination of different drugs, from anhydrous ethanol, and glacial acetic acid to epi-amycin, have been clinically tested for a long time. The effectiveness is unsatisfactory due to chemical agents' poor diffusion and concentration. Immunotherapy is considered a prospective oncologic therapeutic. Still, the clinical applications were limited by the low response rate of patients to immune drugs and the immune-related adverse effects caused by high doses. The advent of intratumoral immunotherapy has well addressed these issues. However, the efficacy of intratumoral immunotherapy alone is uncertain, as suggested by the results of preclinical and clinical studies. In this study, we will focus on the research of immunosuppressive tumor microenvironment with chemoablation and intratumoral immunotherapy, the synergistic effect between chemotherapeutic drugs and immunotherapy. We propose a new concept of intratumoral chemo-immunoablation. The concept opens a new perspective for tumor treatment from direct killing of tumor cells while, enhancing systemic anti-tumor immune response, and significantly reducing adverse effects of drugs.
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Affiliation(s)
- Liangliang Meng
- Department of Radiology, the First Medical Center, Chinese PLA General Hospital, Beijing, China,Department of Radiology, Chinese PAP Hospital of Beijing, Beijing, China
| | - Yingtian Wei
- Department of Radiology, the First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yueyong Xiao
- Department of Radiology, the First Medical Center, Chinese PLA General Hospital, Beijing, China,*Correspondence: Yueyong Xiao,
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11
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Li X, Sun X, Wang B, Li Y, Tong J. Oncolytic virus-based hepatocellular carcinoma treatment: Current status, intravenous delivery strategies, and emerging combination therapeutic solutions. Asian J Pharm Sci 2023; 18:100771. [PMID: 36896445 PMCID: PMC9989663 DOI: 10.1016/j.ajps.2022.100771] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 10/24/2022] [Accepted: 12/04/2022] [Indexed: 12/30/2022] Open
Abstract
Current treatments for advanced hepatocellular carcinoma (HCC) have limited success in improving patients' quality of life and prolonging life expectancy. The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies. Recently, there has been increased interest in oncolytic viruses (OVs) as a therapeutic modality for HCC. OVs undergo selective replication in cancerous tissues and kill tumor cells. Strikingly, pexastimogene devacirepvec (Pexa-Vec) was granted an orphan drug status in HCC by the U.S. Food and Drug Administration (FDA) in 2013. Meanwhile, dozens of OVs are being tested in HCC-directed clinical and preclinical trials. In this review, the pathogenesis and current therapies of HCC are outlined. Next, we summarize multiple OVs as single therapeutic agents for the treatment of HCC, which have demonstrated certain efficacy and low toxicity. Emerging carrier cell-, bioengineered cell mimetic- or nonbiological vehicle-mediated OV intravenous delivery systems in HCC therapy are described. In addition, we highlight the combination treatments between oncolytic virotherapy and other modalities. Finally, the clinical challenges and prospects of OV-based biotherapy are discussed, with the aim of continuing to develop a fascinating approach in HCC patients.
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Affiliation(s)
- Xinguo Li
- The First Hospital of China Medical University, Shenyang 110001, China
| | - Xiaonan Sun
- The 4th People's Hospital of Shenyang, Shenyang 110031, China
| | - Bingyuan Wang
- The First Hospital of China Medical University, Shenyang 110001, China
| | - Yiling Li
- The First Hospital of China Medical University, Shenyang 110001, China
| | - Jing Tong
- The First Hospital of China Medical University, Shenyang 110001, China
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12
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Li SJ, Sun ZJ. Fueling immune checkpoint blockade with oncolytic viruses: Current paradigms and challenges ahead. Cancer Lett 2022; 550:215937. [DOI: 10.1016/j.canlet.2022.215937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 09/20/2022] [Accepted: 09/29/2022] [Indexed: 11/29/2022]
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13
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Valery M, Cervantes B, Samaha R, Gelli M, Smolenschi C, Fuerea A, Tselikas L, Klotz-Prieux C, Hollebecque A, Boige V, Ducreux M. Immunotherapy and Hepatocellular Cancer: Where Are We Now? Cancers (Basel) 2022; 14:cancers14184523. [PMID: 36139683 PMCID: PMC9497386 DOI: 10.3390/cancers14184523] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/09/2022] [Accepted: 09/14/2022] [Indexed: 02/05/2023] Open
Abstract
Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as "adjuvants" to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner.
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Affiliation(s)
- Marine Valery
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
- Correspondence:
| | - Baptiste Cervantes
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
| | - Ramy Samaha
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
| | - Maximiliano Gelli
- Département d’Anesthésie, Chirurgie et Interventionnel, Gustave Roussy, F-94805 Villejuif, France
| | - Cristina Smolenschi
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
- Département d’Innovation Thérapeutique, Gustave Roussy, F-94805 Villejuif, France
| | - Alina Fuerea
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
| | - Lambros Tselikas
- Département d’Anesthésie, Chirurgie et Interventionnel, Gustave Roussy, F-94805 Villejuif, France
| | | | - Antoine Hollebecque
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
- Département d’Innovation Thérapeutique, Gustave Roussy, F-94805 Villejuif, France
| | - Valérie Boige
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
| | - Michel Ducreux
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
- Inserm Unité Dynamique des Cellules Tumorales, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France
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14
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Lee S, Yang W, Kim DK, Kim H, Shin M, Choi KU, Suh DS, Kim YH, Hwang TH, Kim JH. Inhibition of MEK-ERK pathway enhances oncolytic vaccinia virus replication in doxorubicin-resistant ovarian cancer. Mol Ther Oncolytics 2022; 25:211-224. [PMID: 35592390 PMCID: PMC9096472 DOI: 10.1016/j.omto.2022.04.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 04/15/2022] [Indexed: 12/24/2022] Open
Abstract
Oncolytic vaccinia virus (OVV) has been reported to induce cell death in various types of cancer; however, the oncolytic activity of OVV in drug-resistant ovarian cancer remains limited. In the present study, we established doxorubicin-resistant ovarian cancer cells (A2780-R) from the A2780 human ovarian cancer cell line. Both A2780 and A2780-R cells were infected with OVV to explore its anticancer effects. Interestingly, OVV-infected A2780-R cells showed reduced viral replication and cell death compared with A2780 cells, suggesting their resistance against OVV-induced oncolysis; to understand the mechanism underlying this resistance, we explored the involvement of protein kinases. Among protein kinase inhibitors, PD0325901, an MEK inhibitor, significantly augmented OVV replication and cell death in A2780-R cells. PD0325901 treatment increased the phosphorylation of STAT3 in A2780-R cells. Moreover, cryptotanshinone, a STAT3 inhibitor, abrogated PD0325901-stimulated OVV replication. Furthermore, trametinib, a clinically approved MEK inhibitor, increased OVV replication in A2780-R cells. Transcriptomic analysis showed that the MEK inhibitor promoted OVV replication via increasing STAT3 activation and downregulating the cytosolic DNA-sensing pathway. Combined treatment with OVV and trametinib attenuated A2780-R xenograft tumor growth. These results suggest that pharmacological inhibition of MEK reinforces the oncolytic efficacy of OVV in drug-resistant ovarian cancer.
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Affiliation(s)
- Seoyul Lee
- Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Wookyeom Yang
- Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Dae Kyoung Kim
- Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Hojun Kim
- Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Minjoo Shin
- Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Kyung Un Choi
- Department of Pathology, Pusan National University Hospital, Busan 49241, Republic of Korea
| | - Dong Soo Suh
- Department of Obstetrics and Gynecology, Pusan National University Hospital, Busan 49241, Republic of Korea
| | - Yun Hak Kim
- Department of Anatomy and Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Tae-Ho Hwang
- Gene and Cell Therapy Research Center for Vessel-associated Diseases, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Jae Ho Kim
- Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea.,Biomedical Research Institute, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
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15
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Combination therapy with CAR T cells and oncolytic viruses: a new era in cancer immunotherapy. Cancer Gene Ther 2022; 29:647-660. [PMID: 34158626 DOI: 10.1038/s41417-021-00359-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/16/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy is an encouraging and fast-growing platform used for the treatment of various types of tumors in human body. Despite the recent success of CAR T-cell therapy in hematologic malignancies, especially in B-cell lymphoma and acute lymphoblastic leukemia, the application of this treatment approach in solid tumors faced several obstacles resulted from the heterogeneous expression of antigens as well as the induction of immunosuppressive tumor microenvironment. Oncolytic virotherapy (OV) is a new cancer treatment modality by the use of competent or genetically engineered viruses to replicate in tumor cells selectively. OVs represent potential candidates to synergize the current setbacks of CAR T-cell application in solid tumors and then and overcome them. As well, the application of OVs gives researches the ability to engineer the virus with payloads in the way that it selectively deliver a specific therapeutic agents in tumor milieu to reinforce the cytotoxic activity of CAR T cells. Herein, we made a comprehensive review on the outcomes resulted from the combination of CAR T-cell immunotherapy and oncolytic virotherapy for the treatment of solid cancers. In the current study, we also provided brief details on some challenges that remained in this field and attempted to shed a little light on the future perspectives.
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16
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Carroll HK, Duffy AG, O'Farrelly C. Liver Immunology, Immunotherapy, and Liver Cancers: Time for a Rethink? Semin Liver Dis 2022; 42:212-224. [PMID: 35263795 DOI: 10.1055/s-0042-1744143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The complex immune system of the liver has a major role in tumor surveillance, but also partly explains why current immune therapies are poorly effective against liver cancers. Known primarily for its tolerogenic capacity, the hepatic immune repertoire also comprises diverse populations of armored immune cells with tumor surveillant roles. In healthy people, these work together to successfully identify malignant cells and prevent their proliferation, thus halting tumor formation. When frontline hepatic immune surveillance systems fail, compromised hepatic immunity, driven by obesity, infection, or other pathological factors, allows primary or secondary liver cancers to develop. Tumor growth promotes the normal tolerogenic immunological milieu of the liver, perhaps explaining why current immunotherapies fail to work. This review explores the complex local liver immune system with the hope of identifying potential therapeutic targets needed to best overcome immunological barriers in the liver to create an environment no longer hostile to immunotherapy for the treatment of liver cancer.
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Affiliation(s)
- Hailey K Carroll
- Department of Medical Oncology, The Mater Hospital, Dublin, Ireland
| | - Austin G Duffy
- Department of Medical Oncology, The Mater Hospital, Dublin, Ireland
| | - Cliona O'Farrelly
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland.,School of Medicine, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
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17
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Huang W, Chang W. Newcastle Disease Virus/HK84: Next Potential Star for Targeted Immunotherapy of Hepatocellular Carcinoma? J Clin Transl Hepatol 2022; 10:179-180. [PMID: 35528986 PMCID: PMC9039706 DOI: 10.14218/jcth.2021.00553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/30/2022] [Accepted: 02/12/2022] [Indexed: 02/05/2023] Open
Affiliation(s)
- Weiyi Huang
- Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China
| | - Wenjun Chang
- Department of Navy Environmental and Occupational Health, Naval Medical University, Shanghai, China
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18
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Cerqueira OLD, Antunes F, Assis NG, Cardoso EC, Clavijo-Salomón MA, Domingues AC, Tessarollo NG, Strauss BE. Perspectives for Combining Viral Oncolysis With Additional Immunotherapies for the Treatment of Melanoma. Front Mol Biosci 2022; 9:777775. [PMID: 35495634 PMCID: PMC9048901 DOI: 10.3389/fmolb.2022.777775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 03/22/2022] [Indexed: 12/19/2022] Open
Abstract
Melanoma is the deadliest type of skin cancer with steadily increasing incidence worldwide during the last few decades. In addition to its tumor associated antigens (TAAs), melanoma has a high mutation rate compared to other tumors, which promotes the appearance of tumor specific antigens (TSAs) as well as increased lymphocytic infiltration, inviting the use of therapeutic tools that evoke new or restore pre-existing immune responses. Innovative therapeutic proposals, such as immune checkpoint inhibitors (ICIs), have emerged as effective options for melanoma. However, a significant portion of these patients relapse and become refractory to treatment. Likewise, strategies using viral vectors, replicative or not, have garnered confidence and approval by different regulatory agencies around the world. It is possible that further success of immune therapies against melanoma will come from synergistic combinations of different approaches. In this review we outline molecular features inherent to melanoma and how this supports the use of viral oncolysis and immunotherapies when used as monotherapies or in combination.
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Affiliation(s)
- Otto Luiz Dutra Cerqueira
- Centro de Investigação Translacional em Oncologia (CTO)/LIM, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Fernanda Antunes
- Centro de Investigação Translacional em Oncologia (CTO)/LIM, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Nadine G Assis
- Centro de Investigação Translacional em Oncologia (CTO)/LIM, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Elaine C Cardoso
- Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Maria A Clavijo-Salomón
- Centro de Investigação Translacional em Oncologia (CTO)/LIM, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Ana C Domingues
- Centro de Investigação Translacional em Oncologia (CTO)/LIM, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Nayara G Tessarollo
- Centro de Investigação Translacional em Oncologia (CTO)/LIM, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Bryan E Strauss
- Centro de Investigação Translacional em Oncologia (CTO)/LIM, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
- *Correspondence: Bryan E Strauss,
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19
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Tian Y, Xie D, Yang L. Engineering strategies to enhance oncolytic viruses in cancer immunotherapy. Signal Transduct Target Ther 2022; 7:117. [PMID: 35387984 PMCID: PMC8987060 DOI: 10.1038/s41392-022-00951-x] [Citation(s) in RCA: 136] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 02/07/2023] Open
Abstract
Oncolytic viruses (OVs) are emerging as potentially useful platforms in treatment methods for patients with tumors. They preferentially target and kill tumor cells, leaving healthy cells unharmed. In addition to direct oncolysis, the essential and attractive aspect of oncolytic virotherapy is based on the intrinsic induction of both innate and adaptive immune responses. To further augment this efficacious response, OVs have been genetically engineered to express immune regulators that enhance or restore antitumor immunity. Recently, combinations of OVs with other immunotherapies, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptors (CARs), antigen-specific T-cell receptors (TCRs) and autologous tumor-infiltrating lymphocytes (TILs), have led to promising progress in cancer treatment. This review summarizes the intrinsic mechanisms of OVs, describes the optimization strategies for using armed OVs to enhance the effects of antitumor immunity and highlights rational combinations of OVs with other immunotherapies in recent preclinical and clinical studies.
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Affiliation(s)
- Yaomei Tian
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, No. 17, Section 3, South Renmin Road, 610041, Chengdu, Sichuan, People's Republic of China
- College of Bioengineering, Sichuan University of Science & Engineering, No. 519, Huixing Road, 643000, Zigong, Sichuan, People's Republic of China
| | - Daoyuan Xie
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, No. 17, Section 3, South Renmin Road, 610041, Chengdu, Sichuan, People's Republic of China
| | - Li Yang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, No. 17, Section 3, South Renmin Road, 610041, Chengdu, Sichuan, People's Republic of China.
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20
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Miguel Cejalvo J, Falato C, Villanueva L, Tolosa P, González X, Pascal M, Canes J, Gavilá J, Manso L, Pascual T, Prat A, Salvador F. Oncolytic Viruses: a new immunotherapeutic approach for breast cancer treatment? Cancer Treat Rev 2022; 106:102392. [DOI: 10.1016/j.ctrv.2022.102392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/03/2022] [Accepted: 04/05/2022] [Indexed: 12/22/2022]
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21
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Kerrison WGJ, Lee ATJ, Thway K, Jones RL, Huang PH. Current Status and Future Directions of Immunotherapies in Soft Tissue Sarcomas. Biomedicines 2022; 10:573. [PMID: 35327375 PMCID: PMC8945421 DOI: 10.3390/biomedicines10030573] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/22/2022] [Accepted: 02/24/2022] [Indexed: 12/15/2022] Open
Abstract
Immunotherapy in soft tissue sarcoma (STS) has experienced a surge of interest in the past decade, contributing to an expanding number of therapeutic options for this extremely heterogenous group of rare malignancies. Immune checkpoint inhibitors (CPIs) targeting the PD-1 and CTLA-4 axes have demonstrated promising responses in a select number of STS subtypes, including rarer subtypes, such as alveolar soft part sarcoma, SWI/SNF-deficient sarcomas, clear cell sarcoma, and angiosarcoma. Multiple pan-subtype sarcoma trials have facilitated the study of possible predictive biomarkers of the CPI response. It has also become apparent that certain therapies, when combined with CPIs, can enhance response rates, although the specific mechanisms of this possible synergy remain unconfirmed in STS. In addition to CPIs, several other immune targeting agents, including anti-tumour-associated macrophage and antigen-directed therapies, are now under assessment in STS with promising efficacy in some subtypes. In this article, we review the state of the art in immunotherapy in STS, highlighting the pre-clinical and clinical data available for this promising therapeutic strategy.
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Affiliation(s)
- William G. J. Kerrison
- Division of Molecular Pathology, The Institute of Cancer Research, Sutton SM2 5NG, UK; (W.G.J.K.); (K.T.)
| | | | - Khin Thway
- Division of Molecular Pathology, The Institute of Cancer Research, Sutton SM2 5NG, UK; (W.G.J.K.); (K.T.)
- The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK;
| | - Robin L. Jones
- The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK;
- Division of Clinical Studies, The Institute of Cancer Research, London SW3 6JB, UK
| | - Paul H. Huang
- Division of Molecular Pathology, The Institute of Cancer Research, Sutton SM2 5NG, UK; (W.G.J.K.); (K.T.)
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22
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Rai V, Mukherjee S. Targets of immunotherapy for hepatocellular carcinoma: An update. World J Hepatol 2022; 14:140-157. [PMID: 35126844 PMCID: PMC8790386 DOI: 10.4254/wjh.v14.i1.140] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/20/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma, the most common primary liver cancer, in an immunogenic tumor with a poor prognosis because these tumors are diagnosed at late stages. Although, surgical resection, ablation, liver transplant, and locoregional therapies are available for early stages; however, there are yet no effective treatment for advanced and recurrent tumors. Immune checkpoint inhibitor therapy and adoptive cell transfer therapy has gained the popularity with some positive results because these therapies overcome anergy and systemic immune suppression. However, still there is a lack of an effective treatment and thus there is an unmet need of a novel treatment. At present, the focus of the research is on oncolytic viral therapy and combination therapy where therapies including radiotherapy, immune checkpoint therapy, adoptive cell transfer therapy, and vaccines are combined to get an additive or synergistic effect enhancing the immune response of the liver with a cytotoxic effect on tumor cells. This review discusses the recent key development, the basis of drug resistance, immune evasion, immune tolerance, the available therapies based on stage of the tumor, and the ongoing clinical trials on immune checkpoint inhibitor therapy, adoptive cell transfer therapy, oncolytic viral vaccine therapy, and combination therapy.
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Affiliation(s)
- Vikrant Rai
- Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, United States
| | - Sandeep Mukherjee
- Department of Medicine, Creighton University School of Medicine, Omaha, NE 68124, United States.
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Khan AA, Liu ZK, Xu X. Recent advances in immunotherapy for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2021; 20:511-520. [PMID: 34344612 DOI: 10.1016/j.hbpd.2021.06.010] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 06/22/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Treatment of hepatocellular carcinoma (HCC) is challenging as most patients are diagnosed at advanced stage with underlying chronic liver conditions. Conventional systemic chemotherapy has failed in HCC, and the clinical efficacy of FDA-approved molecular targeted agents such as sorafenib and lenvatinib remains unsatisfactory. DATA SOURCES Literature search was conducted in PubMed for relevant articles published before January 2021. The search aimed to identify recent developments in immune-based treatment approaches for HCC. Information of clinical trials was obtained from https://clinicaltrials.gov/. RESULTS Two immune checkpoint inhibitors (ICIs), nivolumab and pembrolizumab were approved as monotherapies, which has revolutionized HCC treatment. Besides, combination ICIs have also got accelerated FDA approval recently. Immune-based therapies have challenged targeted drugs owing to their safety, tolerability, and survival benefits. In addition to the significant success in ICIs, other immunotherapeutic strategies such as cancer vaccine, chimeric antigen receptor T-cells, natural killer cells, cytokines, and combination therapy, have also shown promising outcomes in clinical trials. Various diagnostic and prognostic biomarkers have been identified which can help in clinical decision making when starting treatment with ICIs. CONCLUSIONS Immunotherapy has emerged as one of the mainstream treatment modalities for advanced HCC in recent years. However, challenges such as low response rate and acquired resistance in previously respondent patients still exist. Further research is needed to understand the unique resistance mechanism to immunotherapy and to discover more predictive biomarkers to guide clinical decision making.
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Affiliation(s)
- Abid Ali Khan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ministry of Public Health, Hangzhou 310003, China
| | - Zhi-Kun Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ministry of Public Health, Hangzhou 310003, China
| | - Xiao Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ministry of Public Health, Hangzhou 310003, China; Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
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24
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Abd-Aziz N, Poh CL. Development of oncolytic viruses for cancer therapy. Transl Res 2021; 237:98-123. [PMID: 33905949 DOI: 10.1016/j.trsl.2021.04.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/15/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023]
Abstract
Oncolytic virotherapy is a therapeutic approach that uses replication-competent viruses to kill cancers. The ability of oncolytic viruses to selectively replicate in cancer cells leads to direct cell lysis and induction of anticancer immune response. Like other anticancer therapies, oncolytic virotherapy has several limitations such as viral delivery to the target, penetration into the tumor mass, and antiviral immune responses. This review provides an insight into the different characteristics of oncolytic viruses (natural and genetically modified) that contribute to effective applications of oncolytic virotherapy in preclinical and clinical trials, and strategies to overcome the limitations. The potential of oncolytic virotherapy combining with other conventional treatments or cancer immunotherapies involving immune checkpoint inhibitors and CAR-T therapy could form part of future multimodality treatment strategies.
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Affiliation(s)
- Noraini Abd-Aziz
- Centre for Virus and Vaccine Research (CVVR), School of Medical and Life Sciences, Sunway University, Subang Jaya, Selangor, Malaysia
| | - Chit Laa Poh
- Centre for Virus and Vaccine Research (CVVR), School of Medical and Life Sciences, Sunway University, Subang Jaya, Selangor, Malaysia.
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25
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Hill C, Grundy M, Bau L, Wallington S, Balkaran J, Ramos V, Fisher K, Seymour L, Coussios C, Carlisle R. Polymer stealthing and mucin-1 retargeting for enhanced pharmacokinetics of an oncolytic vaccinia virus. Mol Ther Oncolytics 2021; 21:47-61. [PMID: 33869742 PMCID: PMC8026752 DOI: 10.1016/j.omto.2021.03.011] [Citation(s) in RCA: 9] [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: 06/19/2020] [Accepted: 03/14/2021] [Indexed: 11/20/2022] Open
Abstract
Vaccinia virus (VV) is a powerful tool for cancer treatment with the potential for tumor tropism, efficient cell-to-cell spread, rapid replication in cancer cells, and stimulation of anti-tumor immunity. It has a well-defined safety profile and is being assessed in late-stage clinical trials. However, VV clinical utility is limited by rapid bloodstream neutralization and poor penetration into tumors. These factors have often restricted its route of delivery to intratumoral or intrahepatic artery injection and may impede repeat dosing. Chemical stealthing improves the pharmacokinetics of non-enveloped viruses, but it has not yet been applied to enveloped viruses such as VV. In the present study, amphiphilic polymer was used to coat VV, leading to reduced binding of a neutralizing anti-VV antibody (81.8% of polymer-coated VV [PCVV] staining positive versus 97.1% of VV [p = 0.0038]). Attachment of anti-mucin-1 (aMUC1) targeting antibody, to give aMUC1-PCVV, enabled binding of the construct to MUC1. In high MUC1 expressing CAPAN-2 cells, infection with PCVV was reduced compared to VV, while infection was restored with aMUC1-PCVV. Pharmacokinetics of aMUC1-PCVV, PCVV, and VV were evaluated. After intravenous (i.v.) injection of 1 × 108 viral genomes (VG) or 5 × 108 VG, circulation time for PCVV and aMUC1-PCVV was increased, with ~5-fold higher circulating dose at 5 min versus VV.
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Affiliation(s)
- Claudia Hill
- Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DQ, UK
| | - Megan Grundy
- Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DQ, UK
| | - Luca Bau
- Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DQ, UK
| | - Sheena Wallington
- Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DQ, UK
| | - Joel Balkaran
- Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DQ, UK
| | - Victor Ramos
- Grup d’Enginyeria de Materials, Institut Quimic de Sarria, Universitat Ramon Llull, Barcelona, Spain
| | - Kerry Fisher
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
| | - Len Seymour
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
| | - Constantin Coussios
- Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DQ, UK
| | - Robert Carlisle
- Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DQ, UK
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26
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Park AK, Fong Y, Kim SI, Yang J, Murad JP, Lu J, Jeang B, Chang WC, Chen NG, Thomas SH, Forman SJ, Priceman SJ. Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors. Sci Transl Med 2021; 12:12/559/eaaz1863. [PMID: 32878978 DOI: 10.1126/scitranslmed.aaz1863] [Citation(s) in RCA: 165] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 06/12/2020] [Accepted: 07/29/2020] [Indexed: 12/16/2022]
Abstract
Chimeric antigen receptor (CAR)-engineered T cell therapy for solid tumors is limited by the lack of both tumor-restricted and homogeneously expressed tumor antigens. Therefore, we engineered an oncolytic virus to express a nonsignaling, truncated CD19 (CD19t) protein for tumor-selective delivery, enabling targeting by CD19-CAR T cells. Infecting tumor cells with an oncolytic vaccinia virus coding for CD19t (OV19t) produced de novo CD19 at the cell surface before virus-mediated tumor lysis. Cocultured CD19-CAR T cells secreted cytokines and exhibited potent cytolytic activity against infected tumors. Using several mouse tumor models, delivery of OV19t promoted tumor control after CD19-CAR T cell administration. OV19t induced local immunity characterized by tumor infiltration of endogenous and adoptively transferred T cells. CAR T cell-mediated tumor killing also induced release of virus from dying tumor cells, which propagated tumor expression of CD19t. Our study features a combination immunotherapy approach using oncolytic viruses to promote de novo CAR T cell targeting of solid tumors.
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Affiliation(s)
- Anthony K Park
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA.,Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA.,Department of Surgery, City of Hope, Duarte, CA 91010, USA
| | - Yuman Fong
- Department of Surgery, City of Hope, Duarte, CA 91010, USA
| | - Sang-In Kim
- Department of Surgery, City of Hope, Duarte, CA 91010, USA
| | - Jason Yang
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA
| | - John P Murad
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA.,Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA
| | - Jianming Lu
- Department of Surgery, City of Hope, Duarte, CA 91010, USA
| | - Brook Jeang
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA
| | - Wen-Chung Chang
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA
| | - Nanhai G Chen
- Department of Surgery, City of Hope, Duarte, CA 91010, USA
| | - Sandra H Thomas
- Department of Clinical and Translational Project Development, City of Hope, Duarte, CA 91010, USA
| | - Stephen J Forman
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA.,Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Saul J Priceman
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA. .,Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
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27
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Abstract
Poxviruses comprise many members that infect both vertebrate and invertebrate animals, including humans. Despite the eradication of the historically notorious smallpox, poxviruses remain significant public health concerns and serious endemic diseases. This short review briefly summarizes the present, historical, and future threats posed by poxviruses to public health, wildlife and domestic animals, the role poxviruses have played in shaping modern medicine and biomedical sciences, the insight poxviruses have provided into complex life processes, and the utility of poxviruses in biotechniques and in fighting other infectious diseases and cancers. It is anticipated that readers will appreciate the great merit and need for continued strong support of poxvirus research; research which benefits not only the expansion of fundamental biological knowledge but also the battle against diverse diseases.
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Affiliation(s)
- Zhilong Yang
- Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, USA. .,Division of Biology, Kansas State University, Manhattan, KS, USA.
| | - Mark Gray
- Division of Biology, Kansas State University, Manhattan, KS, USA
| | - Lake Winter
- Division of Biology, Kansas State University, Manhattan, KS, USA
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28
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Wang X, Zhou N, Liu T, Jia X, Ye T, Chen K, Li G. Oncolytic Vaccinia Virus Expressing White-Spotted Charr Lectin Regulates Antiviral Response in Tumor Cells and Inhibits Tumor Growth In Vitro and In Vivo. Mar Drugs 2021; 19:292. [PMID: 34064193 PMCID: PMC8224321 DOI: 10.3390/md19060292] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 02/07/2023] Open
Abstract
Oncolytic vaccina virus (oncoVV) used for cancer therapy has progressed in recent years. Here, a gene encoding white-spotted charr lectin (WCL) was inserted into an oncoVV vector to form an oncoVV-WCL recombinant virus. OncoVV-WCL induced higher levels of apoptosis and cytotoxicity, and replicated faster than control virus in cancer cells. OncoVV-WCL promoted IRF-3 transcriptional activity to induce higher levels of type I interferons (IFNs) and blocked the IFN-induced antiviral response by inhibiting the activity of IFN-stimulated responsive element (ISRE) and the expression of interferon-stimulated genes (ISGs). The higher levels of viral replication and antitumor activity of oncoVV-WCL were further demonstrated in a mouse xenograft tumor model. Therefore, the engineered oncoVV expressing WCL might provide a new avenue for anticancer gene therapy.
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Affiliation(s)
| | | | | | | | | | | | - Gongchu Li
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China; (X.W.); (N.Z.); (T.L.); (X.J.); (T.Y.); (K.C.)
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29
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Lin W, Zhao Y, Zhong L. Current strategies of virotherapy in clinical trials for cancer treatment. J Med Virol 2021; 93:4668-4692. [PMID: 33738818 DOI: 10.1002/jmv.26947] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 02/12/2021] [Accepted: 03/15/2021] [Indexed: 12/19/2022]
Abstract
As a novel immune-active agent for cancer treatment, viruses have the ability of infecting and replicating in tumor cells. The safety and efficacy of viruses has been tested and confirmed in preclinical and clinical trials. In the last decade, virotherapy has been adopted as a monotherapy or combined therapy with immunotherapy, chemotherapy, or radiotherapy, showing promising outcomes against cancer. In this review, the current strategies of viruses used in clinical trials are classified and described. Besides this, the challenge and future prospects of virotherapy in the management for cancer patients are discussed in this review.
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Affiliation(s)
- Weijian Lin
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, China
| | - Yongxiang Zhao
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, China
| | - Liping Zhong
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, China
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30
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Aitcheson G, Pillai A, Dahman B, John BV. Recent Advances in Systemic Therapies for Advanced Hepatocellular Carcinoma. ACTA ACUST UNITED AC 2021; 20:23-33. [PMID: 33552839 PMCID: PMC7848044 DOI: 10.1007/s11901-021-00560-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2021] [Indexed: 02/06/2023]
Abstract
Purpose of Review This paper aims to summarize the data of recently completed and key ongoing clinical trials of systemic agents for advanced hepatocellular carcinoma (aHCC). In particular, the review focuses on ongoing checkpoint inhibitor combination trials and promising studies combining tyrosine kinase inhibitors with checkpoint inhibitors. Recent Findings The recently approved combination of atezolizumab and bevacizumab based on the IMbrave150 trial has shown the most potential with the highest overall survival of any systemic agent in HCC to date, surpassing sorafenib. Despite COVID-19 delays, other promising trials that involve combining VEGF-directed therapy and checkpoint inhibition, cancer vaccines, phosphatidylserine, YIV-906, and oncolytic and immunotherapeutic vaccinia virus are actively recruiting patients. Summary After almost a 10-year dormancy, the list of potential systemic treatment options for aHCC is growing rapidly. Given the promising data from the IMbrave150 trial, the combination of atezolizumab and bevacizumab is now the new first-line therapy. We discuss the change in landscape, the new second- and third-line systemic treatments in aHCC, and the ongoing clinical trials for newer agents including combination therapies.
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Affiliation(s)
| | - Anjana Pillai
- Division of Gastroenterology, University of Chicago, Chicago, IL USA
| | - Bassam Dahman
- Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, VA USA
| | - Binu V John
- Division of Hepatology, Bruce W Carter VA Medical Center, Miami, FL 33125 USA
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Béguin J, Gantzer M, Farine I, Foloppe J, Klonjkowski B, Maurey C, Quéméneur É, Erbs P. Safety, biodistribution and viral shedding of oncolytic vaccinia virus TG6002 administered intravenously in healthy beagle dogs. Sci Rep 2021; 11:2209. [PMID: 33500518 PMCID: PMC7838210 DOI: 10.1038/s41598-021-81831-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/11/2021] [Indexed: 01/30/2023] Open
Abstract
Oncolytic virotherapy is an emerging strategy that uses replication-competent viruses to kill tumor cells. We have reported the oncolytic effects of TG6002, a recombinant oncolytic vaccinia virus, in preclinical human xenograft models and canine tumor explants. To assess the safety, biodistribution and shedding of TG6002 administered by the intravenous route, we conducted a study in immune-competent healthy dogs. Three dogs each received a single intravenous injection of TG6002 at 105 PFU/kg, 106 PFU/kg or 107 PFU/kg, and one dog received three intravenous injections at 107 PFU/kg. The injections were well tolerated without any clinical, hematological or biochemical adverse events. Viral genomes were only detected in blood at the earliest sampling time point of one-hour post-injection at 107 PFU/kg. Post mortem analyses at day 35 allowed detection of viral DNA in the spleen of the dog which received three injections at 107 PFU/kg. Viral genomes were not detected in the urine, saliva or feces of any dogs. Seven days after the injections, a dose-dependent antibody mediated immune response was identified. In conclusion, intravenous administration of TG6002 shows a good safety profile, supporting the initiation of clinical trials in canine cancer patients as well as further development as a human cancer therapy.
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Affiliation(s)
- Jérémy Béguin
- Transgene, Illkirch-Graffenstaden, France
- UMR Virologie, INRA, Ecole Nationale Vétérinaire d'Alfort, ANSES, Université Paris-Est, Maisons-Alfort, France
- Department of Internal Medicine, Ecole Nationale Vétérinaire d'Alfort, Université Paris-Est, Maisons-Alfort, France
| | | | | | | | - Bernard Klonjkowski
- UMR Virologie, INRA, Ecole Nationale Vétérinaire d'Alfort, ANSES, Université Paris-Est, Maisons-Alfort, France
| | - Christelle Maurey
- Department of Internal Medicine, Ecole Nationale Vétérinaire d'Alfort, Université Paris-Est, Maisons-Alfort, France
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32
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Dai S, Lv Y, Xu W, Yang Y, Liu C, Dong X, Zhang H, Prabhakar BS, Maker AV, Seth P, Wang H. Oncolytic adenovirus encoding LIGHT (TNFSF14) inhibits tumor growth via activating anti-tumor immune responses in 4T1 mouse mammary tumor model in immune competent syngeneic mice. Cancer Gene Ther 2020; 27:923-933. [PMID: 32307442 DOI: 10.1038/s41417-020-0173-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 03/17/2020] [Accepted: 03/26/2020] [Indexed: 12/24/2022]
Abstract
LIGHT, also known as tumor-necrosis factor (TNF) superfamily member 14 (TNFSF14), is predominantly expressed on activated immune cells and some tumor cells. LIGHT is a pivotal regulator both for recruiting and activating immune cells in the tumor lesions. In this study, we armed human telomerase reverse transcriptase (TERT) promoter controlled oncolytic adenovirus with LIGHT to generate rAd.Light. rAd.Light effectively transduced both human and mouse breast tumor cell lines in vitro, and expressed LIGHT protein on the surface of tumor cells. Both rAd.Null, and rAd.Light could replicate in human breast cancer cells, and produced cytotoxicity to human and mouse mammary tumor cells. rAd.Light induced apoptosis resulting in tumor cell death. Using a subcutaneous model of 4T1 cells in BALB/c mice, rAd.Light was delivered intratumorally to evaluate the anti-tumor responses. Both rAd.Light and rAd.Null significantly inhibited the tumor growth, but rAd.Light produced much stronger anti-tumor effects. Histopathological analysis showed the infiltration of T lymphocytes in the tumor tissues. rAd.Light also induced stronger cellular apoptosis than rAd.Null in the tumors. Interestingly, on day 15, compared to rAd.Null, there was a significant reduction of Tregs following rAd.Light treatment. rAd.Light significantly increased Th1 cytokine interleukin (IL)-2 expression, and reduced Th2 cytokines expression, such as transforming growth factor β (TGF-β) and IL-10 in the tumors. These results suggest rAd.Light induced activation of anti-tumor immune responses. In conclusion, rAd.Light produced anti-tumor effect in a subcutaneous model of breast cancer via inducing tumor apoptosis and evoking strong anti-tumor immune responses. Therefore, rAd.Light has great promise to be developed as an effective therapeutic approach for the treatment of breast cancer.
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Affiliation(s)
- Shiyun Dai
- Anhui Medical University, Hefei, 230032, Anhui, PR China
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
| | - Yun Lv
- Anhui Medical University, Hefei, 230032, Anhui, PR China
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
| | - Weidong Xu
- Gene Therapy Program, Department of Medicine, NorthShore Research Institute, Evanston, IL, USA
| | - Yuefeng Yang
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
- Gene Therapy Program, Department of Medicine, NorthShore Research Institute, Evanston, IL, USA
- Department of Experimental Medical Science & Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, 315000, Zhejiang, PR China
| | - Chao Liu
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
- Binzhou Medical University, Yantai, 264003, Shandong, PR China
| | - Xiwen Dong
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
| | - Huan Zhang
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
- The Fifth Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, PR China
| | - Bellur S Prabhakar
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL, USA
| | - Ajay V Maker
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL, USA
- Department of Surgery, Division of Surgical Oncology, University of Illinois, Chicago, IL, USA
| | - Prem Seth
- Gene Therapy Program, Department of Medicine, NorthShore Research Institute, Evanston, IL, USA.
| | - Hua Wang
- Anhui Medical University, Hefei, 230032, Anhui, PR China.
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
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33
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Sasso E, D'Alise AM, Zambrano N, Scarselli E, Folgori A, Nicosia A. New viral vectors for infectious diseases and cancer. Semin Immunol 2020; 50:101430. [PMID: 33262065 DOI: 10.1016/j.smim.2020.101430] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 10/23/2020] [Accepted: 11/16/2020] [Indexed: 12/12/2022]
Abstract
Since the discovery in 1796 by Edward Jenner of vaccinia virus as a way to prevent and finally eradicate smallpox, the concept of using a virus to fight another virus has evolved into the current approaches of viral vectored genetic vaccines. In recent years, key improvements to the vaccinia virus leading to a safer version (Modified Vaccinia Ankara, MVA) and the discovery that some viruses can be used as carriers of heterologous genes encoding for pathological antigens of other infectious agents (the concept of 'viral vectors') has spurred a new wave of clinical research potentially providing for a solution for the long sought after vaccines against major diseases such as HIV, TB, RSV and Malaria, or emerging infectious diseases including those caused by filoviruses and coronaviruses. The unique ability of some of these viral vectors to stimulate the cellular arm of the immune response and, most importantly, T lymphocytes with cell killing activity, has also reawakened the interest toward developing therapeutic vaccines against chronic infectious diseases and cancer. To this end, existing vectors such as those based on Adenoviruses have been improved in immunogenicity and efficacy. Along the same line, new vectors that exploit viruses such as Vesicular Stomatitis Virus (VSV), Measles Virus (MV), Lymphocytic choriomeningitis virus (LCMV), cytomegalovirus (CMV), and Herpes Simplex Virus (HSV), have emerged. Furthermore, technological progress toward modifying their genome to render some of these vectors incompetent for replication has increased confidence toward their use in infant and elderly populations. Lastly, their production process being the same for every product has made viral vectored vaccines the technology of choice for rapid development of vaccines against emerging diseases and for 'personalised' cancer vaccines where there is an absolute need to reduce time to the patient from months to weeks or days. Here we review the recent developments in viral vector technologies, focusing on novel vectors based on primate derived Adenoviruses and Poxviruses, Rhabdoviruses, Paramixoviruses, Arenaviruses and Herpesviruses. We describe the rationale for, immunologic mechanisms involved in, and design of viral vectored gene vaccines under development and discuss the potential utility of these novel genetic vaccine approaches in eliciting protection against infectious diseases and cancer.
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Affiliation(s)
- Emanuele Sasso
- Nouscom srl, Via di Castel Romano 100, 00128 Rome, Italy; Ceinge-Biotecnologie Avanzate S.C. A.R.L., via Gaetano Salvatore 486, 80145 Naples, Italy.
| | | | - Nicola Zambrano
- Ceinge-Biotecnologie Avanzate S.C. A.R.L., via Gaetano Salvatore 486, 80145 Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University Federico II, Via Pansini 5, 80131 Naples, Italy.
| | | | | | - Alfredo Nicosia
- Ceinge-Biotecnologie Avanzate S.C. A.R.L., via Gaetano Salvatore 486, 80145 Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University Federico II, Via Pansini 5, 80131 Naples, Italy.
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Watanabe N, McKenna MK, Rosewell Shaw A, Suzuki M. Clinical CAR-T Cell and Oncolytic Virotherapy for Cancer Treatment. Mol Ther 2020; 29:505-520. [PMID: 33130314 DOI: 10.1016/j.ymthe.2020.10.023] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/30/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023] Open
Abstract
Immunotherapy has recently garnered success with the induction of clinical responses in tumors, which are traditionally associated with poor outcomes. Chimeric antigen receptor T (CAR-T) cells and oncolytic viruses (OVs) have emerged as promising cancer immunotherapy agents. Herein, we provide an overview of the current clinical status of CAR-T cell and OV therapies. While preclinical studies have demonstrated curative potential, the benefit of CAR-T cells and OVs as single-agent treatments remains limited to a subset of patients. Combinations of different targeted therapies may be required to achieve efficient, durable responses against heterogeneous tumors, as well as the microenvironment. Using a combinatorial approach to take advantage of the unique features of CAR-T cells and OVs with other treatments can produce additive therapeutic effects. This review also discusses ongoing clinical evaluations of these combination strategies for improved outcomes in treatment of resistant malignancies.
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Affiliation(s)
- Norihiro Watanabe
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Mary Kathryn McKenna
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Amanda Rosewell Shaw
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Masataka Suzuki
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX 77030, USA.
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Park AK, Fong Y, Kim SI, Yang J, Murad JP, Lu J, Jeang B, Chang WC, Chen NG, Thomas SH, Forman SJ, Priceman SJ. Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors. Sci Transl Med 2020. [DOI: 10.1126/scitranslmed.aaz1863
http://stm.sciencemag.org] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
An effective combination immunotherapy using oncolytic viruses delivers de novo CD19 to promote CD19-CAR T cell therapy against solid tumors in mice.
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Affiliation(s)
- Anthony K. Park
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA
- Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA
- Department of Surgery, City of Hope, Duarte, CA 91010, USA
| | - Yuman Fong
- Department of Surgery, City of Hope, Duarte, CA 91010, USA
| | - Sang-In Kim
- Department of Surgery, City of Hope, Duarte, CA 91010, USA
| | - Jason Yang
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA
| | - John P. Murad
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA
- Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA
| | - Jianming Lu
- Department of Surgery, City of Hope, Duarte, CA 91010, USA
| | - Brook Jeang
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA
| | - Wen-Chung Chang
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA
| | - Nanhai G. Chen
- Department of Surgery, City of Hope, Duarte, CA 91010, USA
| | - Sandra H. Thomas
- Department of Clinical and Translational Project Development, City of Hope, Duarte, CA 91010, USA
| | - Stephen J. Forman
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA
- Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Saul J. Priceman
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA
- Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
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Jo HH, Chun SJ, Yoo JJ, Lee MH, Kim SG, Kim YS. Early Experience of Oncolytic Virus Injection Combined with Sorafenib in a Patient with Advanced Hepatocellular Carcinoma and Portal Vein Thrombosis. JOURNAL OF LIVER CANCER 2020; 20:177-182. [PMID: 37384323 PMCID: PMC10035676 DOI: 10.17998/jlc.20.2.177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 07/22/2020] [Accepted: 07/27/2020] [Indexed: 06/30/2023]
Abstract
JX-594 is a modified oncolytic poxvirus designed to selectively replicate in and destroy cancer cells. In a pilot study, JX-594 injection followed by sorafenib was well-tolerated in three patients and associated with objective tumor responses. In this study, we report a case in which a patient with advanced hepatocellular carcinoma and portal vein thrombosis was treated with a combination of JX-594 and sorafenib.
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Affiliation(s)
- Hyun Ho Jo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Seong Joon Chun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Jeong-Ju Yoo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Min Hee Lee
- Department of Radiology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Sang Gyune Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Young Seok Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
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Ding Y, Fan J, Deng L, Peng Y, Zhou B, Huang B. Evaluation of Tumor Specificity and Immunity of Thymidine Kinase-Deleted Vaccinia Virus Guang9 Strain. Onco Targets Ther 2020; 13:7683-7697. [PMID: 32801778 PMCID: PMC7415446 DOI: 10.2147/ott.s260288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/17/2020] [Indexed: 12/15/2022] Open
Abstract
Purpose Oncolytic viruses are emerging as promising options for clinical cancer treatment due to their inherent ability of tumor tropism and oncolytic property. Aside from tumor lysis, oncolytic viruses can induce host immune responses against tumor cells and may thus be viewed as a form of immunotherapy. Methods The attenuated vaccinia VG9-Luc, which originated from Chinese vaccinia Tian Tan strain, was constructed to express firefly luciferase for bioluminescence imaging and to disrupt the thymidine kinase gene for promoting tumor specificity. An in vivo bioluminescence imaging was performed to observe the virus distribution in live mice. The titers of neutralizing antiviral and antitumor antibodies in plasma were determined by time-resolved fluoroimmunoassay. Results Except BALB/c mice treated with intravenous virus injection, all immunocompromised and immunocompetent mice showed obvious tumor targeting ability of vaccinia VG9-Luc. Besides, host immune response activated by vaccinia VG9-Luc showed the production of antiviral and antitumor antibodies, the process of which was similar between intravenous and intratumoral viral delivery systems. The results indicated that virus infection promoted tumor-specific immunity by increasing the production of antitumor antibodies. Moreover, virus reinjection was performed and a more rapid viral clearance was observed in immunocompetent mice compared with first virus infection. Conclusion The thymidine kinase-deleted vaccinia Guang9 strain, which has the properties of tumor specificity and antitumor immunity, is a promising candidate vector for cancer therapy.
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Affiliation(s)
- Yuedi Ding
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, People's Republic of China
| | - Jun Fan
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, People's Republic of China
| | - Lili Deng
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, People's Republic of China
| | - Ying Peng
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, People's Republic of China
| | - Bin Zhou
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, People's Republic of China
| | - Biao Huang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, People's Republic of China
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Cao F, Nguyen P, Hong B, DeRenzo C, Rainusso NC, Rodriguez Cruz T, Wu MF, Liu H, Song XT, Suzuki M, Wang LL, Yustein JT, Gottschalk S. Engineering Oncolytic Vaccinia Virus to redirect Macrophages to Tumor Cells. ACTA ACUST UNITED AC 2020; 4. [PMID: 33829146 DOI: 10.1002/acg2.99] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Oncolytic virotherapy has been tested in numerous early phase clinical studies. However, the antitumor activity of oncolytic viruses thus far has been limited. Numerous strategies are being explored to enhance their antitumor activity by activating the adaptive arm of the immune system. We reasoned that it might also be possible to engineer oncolytic viruses to redirect tumor-associated macrophages to tumor cells for therapeutic benefit. We engineered an oncolytic vaccinia virus (VV) to disrupt the CD47/SIRPα interaction by expressing a chimeric molecule that consists of the ectodomain of SIRPα and the Fc domain of IgG4 (SIRPα-Fc-VV). SIRPα-Fc-VV readily replicated in tumor cells and redirected M1 as well as M2 macrophages to tumor cells in vitro. In contrast, control VVs that either encoded YFP (YFP-VV) or SIRPα (SIRPα-VV) did not. In vivo, SIRPα-Fc-VV had greater antitumor activity than YFP-VV and SIRPα-VV in an immune competent osteosarcoma model resulting in a significant survival advantage. Pretreatment with cytoxan further augmented the antitumor activity of SIRPα-Fc-VV. Thus, arming oncolytic viruses with SIRPα-Fc may present a promising strategy to enhance their antitumor activity for the virotherapy of solid tumors.
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Affiliation(s)
- Felicia Cao
- Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.,Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.,Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA
| | - Phuong Nguyen
- Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.,Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.,Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.,Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Bangxing Hong
- Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Christopher DeRenzo
- Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.,Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.,Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Nino C Rainusso
- Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.,Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Tania Rodriguez Cruz
- Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Meng-Fen Wu
- Biostatistics Shared Resource, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Hao Liu
- Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Xiao-Tong Song
- Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Masataka Suzuki
- Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Lisa L Wang
- Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.,Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Jason T Yustein
- Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.,Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Stephen Gottschalk
- Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.,Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.,Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.,Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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Ghavimi S, Apfel T, Azimi H, Persaud A, Pyrsopoulos NT. Management and Treatment of Hepatocellular Carcinoma with Immunotherapy: A Review of Current and Future Options. J Clin Transl Hepatol 2020; 8:168-176. [PMID: 32832397 PMCID: PMC7438354 DOI: 10.14218/jcth.2020.00001] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 05/13/2020] [Accepted: 05/16/2020] [Indexed: 02/06/2023] Open
Abstract
With mortality rates of liver cancer doubling in the last 20 years, this disease is on the rise and has become the fifth most common cancer in men and the seventh most common cancer in women. Hepatocellular carcinoma (HCC) represents approximately 90% of all primary liver cancers and is a major global health concern. Patients with HCC can be managed curatively with surgical resection or with liver transplantation, if they are diagnosed at an early stage. Unfortunately, most patients with HCC present with advanced stages of the disease and have underlying liver dysfunction, which allows only 15% of patients to be eligible for curative treatment. Several different treatment modalities are available, including locoregional therapy radiofrequency ablation, microwave ablation, percutaneous ethanol injection, trans-arterial chemoembolization, transarterial radio-embolization, cryoablation, radiation therapy, stereotactic radiotherapy, systemic chemotherapy, molecularly targeted therapies, and immunotherapy. Immunotherapy has recently become a promising method for inhibiting HCC tumor progression, recurrence, and metastasis. The term "Immunotherapy" is a catch-all, encompassing a wide range of applications and targets, including HCC vaccines, adoptive cell therapy, immune checkpoint inhibitors, and use of oncolytic viruses to treat HCC. Immunotherapy in HCC is a relatively safe option for treating patients with advanced disease in the USA who are either unable to receive or failed sorafenib/lenvatinib therapy and thus may offer an additional survival benefit for these patients. The purpose of this review is to elaborate on some of the most recent advancements in immunotherapy.
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Affiliation(s)
- Shima Ghavimi
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Tehila Apfel
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Hamed Azimi
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Alana Persaud
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Nikolaos T. Pyrsopoulos
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
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Chaurasiya S, Fong Y, Warner SG. Optimizing Oncolytic Viral Design to Enhance Antitumor Efficacy: Progress and Challenges. Cancers (Basel) 2020; 12:cancers12061699. [PMID: 32604787 PMCID: PMC7352900 DOI: 10.3390/cancers12061699] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/19/2020] [Accepted: 06/23/2020] [Indexed: 12/15/2022] Open
Abstract
The field of oncolytic virotherapy has seen remarkable advancements in last two decades, leading to approval of the first oncolytic immuno-virotherapy, Talimogene Laherparepvec, for the treatment of melanoma. A plethora of preclinical and clinical studies have demonstrated excellent safety profiles of other oncolytic viruses. While oncolytic viruses show clinical promise in already immunogenic malignancies, response rates are inconsistent. Response rates are even less consistent in immunosuppressed tumor microenvironments like those found in liver, pancreas, and MSI-stable colon cancers. Therefore, the efficacy of oncolytic viruses needs to be improved for more oncolytic viruses to enter mainstream cancer therapy. One approach to increase the therapeutic efficacy of oncolytic viruses is to use them as primers for other immunotherapeutics. The amenability of oncolytic viruses to transgene-arming provides an immense opportunity for investigators to explore different ways of improving the outcome of oncolytic therapy. In this regard, genes encoding immunomodulatory proteins are the most commonly studied genes for arming oncolytic viruses. Other transgenes used to arm oncolytic viruses include those with the potential to favorably modulate tumor stroma, making it possible to image the virus distribution and increase its suitability for combination with other therapeutics. This review will detail the progress made in arming oncolytic viruses with a focus on immune-modulatory transgenes, and will discuss the challenges that need to be addressed for more armed oncolytic viruses to find widespread clinical use.
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Li Y, Shen Y, Zhao R, Samudio I, Jia W, Bai X, Liang T. Oncolytic virotherapy in hepato-bilio-pancreatic cancer: The key to breaking the log jam? Cancer Med 2020; 9:2943-2959. [PMID: 32130786 PMCID: PMC7196045 DOI: 10.1002/cam4.2949] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 02/13/2020] [Accepted: 02/14/2020] [Indexed: 02/07/2023] Open
Abstract
Traditional therapies have limited efficacy in hepatocellular carcinoma, pancreatic cancer, and biliary tract cancer, especially for advanced and refractory cancers. Through a deeper understanding of antitumor immunity and the tumor microenvironment, novel immunotherapies are becoming available for cancer treatment. Oncolytic virus (OV) therapy is an emerging type of immunotherapy that has demonstrated effective antitumor efficacy in many preclinical studies and clinical studies. Thus, it may represent a potential feasible treatment for hard to treat gastrointestinal (GI) tumors. Here, we summarize the research progress of OV therapy for the treatment of hepato-bilio-pancreatic cancers. In general, most OV therapies exhibits potent, specific oncolysis both in cell lines in vitro and the animal models in vivo. Currently, several clinical trials have suggested that OV therapy may also be effective in patients with refractory hepato-bilio-pancreatic cancer. Multiple strategies such as introducing immunostimulatory genes, modifying virus capsid and combining various other therapeutic modalities have been shown enhanced specific oncolysis and synergistic anti-cancer immune stimulation. Combining OV with other antitumor therapies may become a more effective strategy than using virus alone. Nevertheless, more studies are needed to better understand the mechanisms underlying the therapeutic effects of OV, and to design appropriate dosing and combination strategies.
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Affiliation(s)
- Yuwei Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.,Innovation Center for the study of Pancreatic Diseases, Hangzhou, China
| | - Yinan Shen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.,Innovation Center for the study of Pancreatic Diseases, Hangzhou, China
| | | | | | - William Jia
- Virogin Biotech Canada Ltd, Vancouver, Canada
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.,Innovation Center for the study of Pancreatic Diseases, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.,Innovation Center for the study of Pancreatic Diseases, Hangzhou, China
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Wang M, Luo Y, Sun T, Mao C, Jiang Y, Yu X, Li Z, Xie T, Wu F, Yan H, Teng L. The Ectopic Expression of SurvivinT34A and FilC Can Enhance the Oncolytic Effects of Vaccinia Virus in Murine Gastric Cancer. Onco Targets Ther 2020; 13:1011-1025. [PMID: 32099404 PMCID: PMC7006861 DOI: 10.2147/ott.s230902] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 01/16/2020] [Indexed: 01/13/2023] Open
Abstract
Background/Aims Anti-tumor vaccines have been shown to be effective in cancer therapeutics ever since the anti-HPV vaccine was developed. Compared to conventional chemotherapy, anti-tumor vaccines can specifically target cancer cells and they have lower side effects. We developed a recombinant vaccinia virus (VACV) (Western Reserve) WR strain, and we tested its anti-tumor effects in an animal model. Methods A recombinant VACV WR strain expressing mutant survivin T34A (SurT34A) and FilC was constructed and validated. Its oncolytic effect was tested in vitro using a CCK-8 assay, and its tolerance and anti-tumor effects were tested in a murine gastric cancer model. The proportion of lymphocytes in the spleen and tumor was determined after antibody-mediated immuno-depletion. Results The recombinant VACV showed a stronger replication ability in tumor cells, and it was safe in vivo, even at high doses. The combination of vv-SurT34A and vv-FilC resulted in a stronger anti-tumor effect compared to either construct alone. However, the inhibitory effect of vv-SurT34A was stronger than the combination. The recombinant VACV activated the host immune response, as indicated by lymphocyte infiltration in the spleen and tumor tissues. Conclusion The recombinant VACV WR strain expressing SurT34A and FilC is a safe and effective anti-tumor vaccine.
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Affiliation(s)
- Minglong Wang
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Yanxi Luo
- Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China
| | - Ting Sun
- Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China
| | - Chenyu Mao
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Yili Jiang
- Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China
| | - Xiongfei Yu
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Zhongqi Li
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Tian Xie
- Holistic Integrative Pharmacy Institutes, Hangzhou Normal University, Hangzhou, People's Republic of China
| | - Fusheng Wu
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Hui Yan
- Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China.,Holistic Integrative Pharmacy Institutes, Hangzhou Normal University, Hangzhou, People's Republic of China
| | - Lisong Teng
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
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Abstract
Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor‐derived antigens and subsequent activation of tumor‐specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV‐10 and toll‐like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa‐Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T‐VEC), a genetically modified herpes simplex virus type 1–based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T‐VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM‐CSF (16.3% vs. 2.1%; p < .001). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T‐VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T‐VEC in the treatment of advanced melanoma as a model for future solid tumor indications. Implications for Practice This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T‐VEC is the only U.S. Food and Drug Administration (FDA)‐approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T‐VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T‐VEC, the only U.S. FDA‐approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T‐VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies. This review highlights recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on talimogene laherparepvec in the treatment of advanced melanoma as a model for future solid tumor indications.
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Affiliation(s)
- Omid Hamid
- The Angeles Clinic and Research InstituteLos AngelesCaliforniaUSA
| | | | - Igor Puzanov
- Roswell Park Comprehensive Cancer CenterBuffaloNew YorkUSA
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Reghupaty SC, Sarkar D. Current Status of Gene Therapy in Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:cancers11091265. [PMID: 31466358 PMCID: PMC6770843 DOI: 10.3390/cancers11091265] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 08/21/2019] [Accepted: 08/27/2019] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer related deaths world-wide. Liver transplantation, surgical resection, trans-arterial chemoembolization, and radio frequency ablation are effective strategies to treat early stage HCC. Unfortunately, HCC is usually diagnosed at an advanced stage and there are not many treatment options for late stage HCC. First-line therapy for late stage HCC includes sorafenib and lenvatinib. However, these treatments provide only an approximate three month increase in survival. Besides, they cannot specifically target cancer cells that lead to a wide array of side effects. Patients on these drugs develop resistance within a few months and have to rely on second-line therapy that includes regorafenib, pembrolizumab, nivolumab, and cabometyx. These disadvantages make gene therapy approach to treat HCC an attractive option. The two important questions that researchers have been trying to answer in the last 2-3 decades are what genes should be targeted and what delivery systems should be used. The objective of this review is to analyze the changing landscape of HCC gene therapy, with a focus on these two questions.
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Affiliation(s)
- Saranya Chidambaranathan Reghupaty
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA.
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Harrington K, Freeman DJ, Kelly B, Harper J, Soria JC. Optimizing oncolytic virotherapy in cancer treatment. Nat Rev Drug Discov 2019; 18:689-706. [PMID: 31292532 DOI: 10.1038/s41573-019-0029-0] [Citation(s) in RCA: 337] [Impact Index Per Article: 56.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2019] [Indexed: 02/07/2023]
Abstract
In the wake of the success of modern immunotherapy, oncolytic viruses (OVs) are currently seen as a potential therapeutic option for patients with cancer who do not respond or fail to achieve durable responses following treatment with immune checkpoint inhibitors. OVs offer a multifaceted therapeutic platform because they preferentially replicate in tumour cells, can be engineered to express transgenes that augment their cytotoxic and immunostimulatory activities, and modulate the tumour microenvironment to optimize immune-mediated tumour eradication, both at locoregional and systemic sites of disease. Lysis of tumour cells releases tumour-specific antigens that trigger both the innate and adaptive immune systems. OVs also represent attractive combination partners with other systemically delivered agents by virtue of their highly favourable safety profiles. Rational combinations of OVs with different immune modifiers and/or antitumour agents, based on mechanisms of tumour resistance to immune-mediated attack, may benefit the large, currently underserved, population of patients who respond poorly to immune checkpoint inhibition.
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Affiliation(s)
- Kevin Harrington
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
| | | | - Beth Kelly
- Oncology R&D, AstraZeneca, Gaithersburg, MD, USA
| | | | - Jean-Charles Soria
- Oncology R&D, AstraZeneca, Gaithersburg, MD, USA.,Department of Medicine and Medical Oncology, Université Paris-Sud, Orsay, France
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Abstract
INTRODUCTION Over the last decade, advances in biological therapies have resulted in remarkable clinical responses for the treatment of some previously incurable cancers. Oncolytic virotherapy is one of these promising novel strategies for cancer therapy. A successful oncolytic virus promotes tumor cell oncolysis and elicits a robust long-term anti-tumor immunity. AREAS COVERED Oncolytic poxviruses (Vaccinia virus and Myxoma virus) demonstrated encouraging results in multiple pre-clinical tumor models and some clinical trials for the treatment of various cancers. This review summarizes the advances made on poxvirus oncolytic virotherapy in the last five years. EXPERT OPINION Many challenges remain in poxvirus oncolytic virotherapy. Two key goals to achieve are enhancing the efficiency of viral delivery to tumor sites and overcoming local tumor immune-evasion. Additional efforts are necessary to explore the best combination of virotherapy with standard available treatments, particularly immunotherapies. By addressing these issues, this new modality will continue to improve as an adjunct biotherapy to treat malignant diseases.
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Affiliation(s)
- Lino E Torres-Domínguez
- a Biodesign Center for Immunotherapy, Vaccines and Virotherapy , Arizona State University , Tempe , AZ , USA
| | - Grant McFadden
- a Biodesign Center for Immunotherapy, Vaccines and Virotherapy , Arizona State University , Tempe , AZ , USA
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Martinez-Quintanilla J, Seah I, Chua M, Shah K. Oncolytic viruses: overcoming translational challenges. J Clin Invest 2019; 129:1407-1418. [PMID: 30829653 DOI: 10.1172/jci122287] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Oncolytic virotherapy (OVT) is a promising approach in which WT or engineered viruses selectively replicate and destroy tumor cells while sparing normal ones. In the last two decades, different oncolytic viruses (OVs) have been modified and tested in a number of preclinical studies, some of which have led to clinical trials in cancer patients. These clinical trials have revealed several critical limitations with regard to viral delivery, spread, resistance, and antiviral immunity. Here, we focus on promising research strategies that have been developed to overcome the aforementioned obstacles. Such strategies include engineering OVs to target a broad spectrum of tumor cells while evading the immune system, developing unique delivery mechanisms, combining other immunotherapeutic agents with OVT, and using clinically translatable mouse tumor models to potentially translate OVT more readily into clinical settings.
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Affiliation(s)
| | - Ivan Seah
- Center for Stem Cell Therapeutics and Imaging and
| | - Melissa Chua
- Center for Stem Cell Therapeutics and Imaging and.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Khalid Shah
- Center for Stem Cell Therapeutics and Imaging and.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
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Locy H, de Mey S, de Mey W, De Ridder M, Thielemans K, Maenhout SK. Immunomodulation of the Tumor Microenvironment: Turn Foe Into Friend. Front Immunol 2018; 9:2909. [PMID: 30619273 PMCID: PMC6297829 DOI: 10.3389/fimmu.2018.02909] [Citation(s) in RCA: 182] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 11/27/2018] [Indexed: 12/23/2022] Open
Abstract
Immunotherapy, where the patient's own immune system is exploited to eliminate tumor cells, has become one of the most prominent new cancer treatment options in the last decade. The main hurdle for classical cancer vaccines is the need to identify tumor- and patient specific antigens to include in the vaccine. Therefore, in situ vaccination represents an alternative and promising approach. This type of immunotherapy involves the direct intratumoral administration of different immunomodulatory agents and uses the tumor itself as the source of antigen. The ultimate aim is to convert an immunodormant tumor microenvironment into an immunostimulatory one, enabling the immune system to eradicate all tumor lesions in the body. In this review we will give an overview of different strategies, which can be exploited for the immunomodulation of the tumor microenvironment and their emerging role in the treatment of cancer patients.
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Affiliation(s)
- Hanne Locy
- Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel, Brussels, Belgium
| | - Sven de Mey
- Department of Radiotherapy, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Wout de Mey
- Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel, Brussels, Belgium
| | - Mark De Ridder
- Department of Radiotherapy, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Kris Thielemans
- Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel, Brussels, Belgium
| | - Sarah K. Maenhout
- Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel, Brussels, Belgium
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Penghui Y, Fang S, Ruilan W, Guanglin L, Hongjing G, Yueqiang D, Zhongpeng Z, Xiaolan Y, Zhaohai W, Shaogeng Z, Xiliang W. Oncolytic Activity of a Novel Influenza A Virus Carrying Granulocyte-Macrophage Colony-Stimulating Factor in Hepatocellular Carcinoma. Hum Gene Ther 2018; 30:330-338. [PMID: 30205709 DOI: 10.1089/hum.2018.095] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Oncolytic virotherapy is a promising strategy for the treatment of cancer. Influenza A virus has shown potential as an oncolytic agent. In this study, a recombinant PR8 influenza viral vector, called delNS1-GM-CSF, was generated with a partial deletion in NS and the granulocyte-macrophage colony-stimulating factor (GM-CSF) coding sequence inserted into the influenza nonstructural protein 1 gene. The morphological characteristics of delNS1-GM-CSF were examined. The delNS1-GM-CSF virus replicated well in various cell lines, including MDCK, A549, SMCC7721, and HepG2 cells. Moreover, selective cytotoxicity of the virus was observed in various hepatocellular carcinoma (HCC) cell lines, while no effect was demonstrated in the normal liver cell line LO2, as indicated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide and crystal violet assays. Importantly, using a model based on the growth of HepG2 cells as a xenograft in nude mice, it was found that a reassortant delNS1-GM-CSF virus inhibited tumor growth significantly following intratumoral injection in a dose-dependent manner. Ex vivo results showed that the tumor inhibition efficacy of delNS1-GM-CSF was observed in HCC clinical samples. Taken together, these results are the first to demonstrate that influenza A viruses may have potential as oncolytic virotherapeutic agents against HCC.
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Affiliation(s)
- Yang Penghui
- 1 Department of Hepatobiliary, Beijing 302 Hospital, Beijing, P.R. China.,2 State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, P.R. China
| | - Sun Fang
- 1 Department of Hepatobiliary, Beijing 302 Hospital, Beijing, P.R. China
| | - Wang Ruilan
- 1 Department of Hepatobiliary, Beijing 302 Hospital, Beijing, P.R. China
| | - Lei Guanglin
- 1 Department of Hepatobiliary, Beijing 302 Hospital, Beijing, P.R. China
| | - Gu Hongjing
- 2 State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, P.R. China
| | - Duan Yueqiang
- 2 State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, P.R. China
| | - Zhao Zhongpeng
- 2 State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, P.R. China
| | - Yang Xiaolan
- 2 State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, P.R. China
| | - Wang Zhaohai
- 1 Department of Hepatobiliary, Beijing 302 Hospital, Beijing, P.R. China
| | - Zhang Shaogeng
- 1 Department of Hepatobiliary, Beijing 302 Hospital, Beijing, P.R. China
| | - Wang Xiliang
- 2 State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, P.R. China
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