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Rong Y, Ning Y, Zhu J, Feng P, Zhu W, Zhao X, Xiong Z, Ruan C, Jin J, Wang H, Cai T, Zhang S, Yang Y. Oncolytic adenovirus encoding decorin and CD40 ligand inhibits tumor growth and liver metastasis via immune activation in murine colorectal tumor model. MOLECULAR BIOMEDICINE 2024; 5:39. [PMID: 39306655 PMCID: PMC11416448 DOI: 10.1186/s43556-024-00202-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 08/20/2024] [Indexed: 09/25/2024] Open
Abstract
Colorectal cancer (CRC) is the second common cause of cancer mortality worldwide, and it still lacks effective approaches for relapsed and metastatic CRC. Recently, oncolytic virus has been emerged as a promising immune therapeutic strategy. In this study, we develop a novel oncolytic adenovirus, rAd.mDCN.mCD40L, which drive oncolytic activity by telomerase reverse transcriptase promoter (TERTp). rAd.mDCN.mCD40L expressed both mouse genes of decorin (mDCN) and CD40 ligand (mCD40L), and produced effective cytotoxicity in both human and mouse CRC cells. Moreover, oncolytic adenovirus mediated mDCN over-expression inhibited Met expression in vitro. In CT26 subcutaneous tumor model, intratumorally delivery of oncolytic adenoviruses could inhibit tumor growth and liver metastasis, while mDCN and/or mCD40L armed oncolytic adenoviruses produced much more impressive responses. No obvious toxicity was detected in lung, liver and spleen. Moreover, mDCN and/or mCD40L armed oncolytic adenoviruses altered the immune state to activate anti-tumor responses, including increasing CD8+ T effector cells and CD4+ memory T cells, reducing MDSCs and Tregs in peripheral blood. Furthermore, mDCN and/or mCD40L armed oncolytic adenoviruses mediated mDCN and/or mCD40L expression in tumors, and up-regulated Th1 cytokines and reduced Th2 cytokines in tumors, which will be benefit for remodeling tumor microenvironment. Importantly, rAd.mDCN.mCD40L and rAd.mCD40L prevented tumor liver metastasis much more effectively than rAd.Null and rAd.mDCN. Therefore, rAd.mDCN.mCD40L and rAd.mCD40L are promising approaches for CRC therapy.
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Affiliation(s)
- Yejing Rong
- Department of Experimental Medical Science, Ningbo No.2 Hospital, Ningbo, 315010, China
| | - Yingjun Ning
- Department of Experimental Medical Science, Ningbo No.2 Hospital, Ningbo, 315010, China
| | - Jianping Zhu
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Pei Feng
- Ningbo Qianyang Talent Service Co., Ltd, Ningbo, 315020, China
| | - Weixin Zhu
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, 315032, China
| | - Xin Zhao
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, 315032, China
| | - Zi Xiong
- Department of Experimental Medical Science, Ningbo No.2 Hospital, Ningbo, 315010, China
| | - Chunyan Ruan
- Department of Experimental Medical Science, Ningbo No.2 Hospital, Ningbo, 315010, China
| | - Jiachang Jin
- Jiangbei Center For Disease Control and Prevention Ningbo, Ningbo, 315020, China
| | - Hua Wang
- Department of Experimental Haematology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China
| | - Ting Cai
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, 315032, China.
| | - Shun Zhang
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, 315032, China.
| | - Yuefeng Yang
- Department of Experimental Medical Science, Ningbo No.2 Hospital, Ningbo, 315010, China.
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Chattopadhyay S, Hazra R, Mallick A, Gayen S, Roy S. A review exploring the fusion of oncolytic viruses and cancer immunotherapy: An innovative strategy in the realm of cancer treatment. Biochim Biophys Acta Rev Cancer 2024; 1879:189110. [PMID: 38754793 DOI: 10.1016/j.bbcan.2024.189110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 05/02/2024] [Accepted: 05/08/2024] [Indexed: 05/18/2024]
Abstract
Oncolytic viruses (OVs) are increasingly recognized as potent tools in cancer therapy, effectively targeting and eradicating oncogenic conditions while sparing healthy cells. They enhance antitumor immunity by triggering various immune responses throughout the cancer cycle. Genetically engineered OVs swiftly destroy cancerous tissues and activate the immune system by releasing soluble antigens like danger signals and interferons. Their ability to stimulate both innate and adaptive immunity makes them particularly attractive in cancer immunotherapy. Recent advancements involve combining OVs with other immune therapies, yielding promising results. Transgenic OVs, designed to enhance immunostimulation and specifically target cancer cells, further improve immune responses. This review highlights the intrinsic mechanisms of OVs and underscores their synergistic potential with other immunotherapies. It also proposes strategies for optimizing armed OVs to bolster immunity against tumors.
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Affiliation(s)
- Soumyadeep Chattopadhyay
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Rudradeep Hazra
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Arijit Mallick
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Sakuntala Gayen
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Souvik Roy
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India.
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Onciul R, Brehar FM, Toader C, Covache-Busuioc RA, Glavan LA, Bratu BG, Costin HP, Dumitrascu DI, Serban M, Ciurea AV. Deciphering Glioblastoma: Fundamental and Novel Insights into the Biology and Therapeutic Strategies of Gliomas. Curr Issues Mol Biol 2024; 46:2402-2443. [PMID: 38534769 DOI: 10.3390/cimb46030153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 03/06/2024] [Accepted: 03/09/2024] [Indexed: 03/28/2024] Open
Abstract
Gliomas constitute a diverse and complex array of tumors within the central nervous system (CNS), characterized by a wide range of prognostic outcomes and responses to therapeutic interventions. This literature review endeavors to conduct a thorough investigation of gliomas, with a particular emphasis on glioblastoma (GBM), beginning with their classification and epidemiological characteristics, evaluating their relative importance within the CNS tumor spectrum. We examine the immunological context of gliomas, unveiling the intricate immune environment and its ramifications for disease progression and therapeutic strategies. Moreover, we accentuate critical developments in understanding tumor behavior, focusing on recent research breakthroughs in treatment responses and the elucidation of cellular signaling pathways. Analyzing the most novel transcriptomic studies, we investigate the variations in gene expression patterns in glioma cells, assessing the prognostic and therapeutic implications of these genetic alterations. Furthermore, the role of epigenetic modifications in the pathogenesis of gliomas is underscored, suggesting that such changes are fundamental to tumor evolution and possible therapeutic advancements. In the end, this comparative oncological analysis situates GBM within the wider context of neoplasms, delineating both distinct and shared characteristics with other types of tumors.
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Affiliation(s)
- Razvan Onciul
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Neurosurgery Department, Emergency University Hospital, 050098 Bucharest, Romania
| | - Felix-Mircea Brehar
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Neurosurgery, Clinical Emergency Hospital "Bagdasar-Arseni", 041915 Bucharest, Romania
| | - Corneliu Toader
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania
| | | | - Luca-Andrei Glavan
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Bogdan-Gabriel Bratu
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Horia Petre Costin
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - David-Ioan Dumitrascu
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Matei Serban
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Alexandru Vlad Ciurea
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Neurosurgery Department, Sanador Clinical Hospital, 010991 Bucharest, Romania
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Bundgaard Kjellingbro K, Naranjo Freixa C, Hjorth Mikkelsen L, Heegaard S. Challenges in diagnosing canine spindle cell tumours using immunohistochemistry, illustrated by three nonpigmented malignant cases from the nictitating membrane. Acta Vet Scand 2024; 66:7. [PMID: 38396026 PMCID: PMC10893616 DOI: 10.1186/s13028-024-00727-z] [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: 09/12/2023] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND Nonpigmented malignant spindle cell tumours of the membrana nictitans are rare in dogs. In twenty-three years only three cases have been diagnosed in Scandinavia. This study describes the three cases of malignant tumours of the membrana nictitans recorded by the Eye Pathology Section, University of Copenhagen, Denmark, with reference to the clinical appearance and work-up, the treatment and prognosis, and the histopathological description including immunohistochemistry. The three cases are compared to previous publications on canine tumours of the nictitating membrane. We emphasize the importance of using protocols that are adapted to the specific species such as dogs. Opposite the human tissue responses, we even need more than one marker when diagnosing melanomas in dogs. RESULTS The dogs presented were an 8-year-old Dachshund, a 12-year-old Akita and a 14-year-old Shetland Sheepdog. All three dogs were entire females. All three nictitating membrane tumours developed on the right nictitating membrane as firm or multilobulated hyperaemic masses. Two of the tumours were macroscopically nonpigmented, the third being partly pigmented on the surface and ulcerated. According to the histopathology and for two of the cases immunohistochemistry with dog-adapted protocols the diagnoses included one hemangiosarcoma and two amelanotic melanomas. Tumour regrowth developed in all three cases and repeated resections were completed 1, 2 and 3 times, respectively, with recurrence experienced within 1.5 months - 3 years. CONCLUSIONS Nonpigmented malignant spindle cell tumours of the canine membrana nictitans are rare. Treatment of choice should be complete excision with a minimal histologic tumour-free distance and in case of a recurrence a full resection of the nictitating membrane. We strongly recommend a dog-adapted protocol for immunohistochemistry.
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Affiliation(s)
| | | | - Lauge Hjorth Mikkelsen
- Eye Pathology Section, Department of Pathology, Rigshospitalet, University of Copenhagen, Frederik V's Vej 11, 1st Floor, 2100, Copenhagen Ø, Denmark
- Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Frederik V's Vej 11, 1st Floor, 2100, Copenhagen Ø, Denmark
| | - Steffen Heegaard
- Eye Pathology Section, Department of Pathology, Rigshospitalet, University of Copenhagen, Frederik V's Vej 11, 1st Floor, 2100, Copenhagen Ø, Denmark
- Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Frederik V's Vej 11, 1st Floor, 2100, Copenhagen Ø, Denmark
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5
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Tamura K, Fujiyuki T, Moritoh K, Akimoto H, Iizuka K, Sato H, Asano K, Yoneda M, Kai C. Anti-tumor activity of a recombinant measles virus against canine lung cancer cells. Sci Rep 2023; 13:18168. [PMID: 37875555 PMCID: PMC10597997 DOI: 10.1038/s41598-023-42305-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 09/07/2023] [Indexed: 10/26/2023] Open
Abstract
Canine primary lung cancer with metastasis has a poor prognosis with no effective treatment. We previously generated a recombinant measles virus (MV) that lost binding affinity to a principal receptor, SLAM, to eliminate its virulence as a new cancer treatment strategy. The virus, rMV-SLAMblind, targets nectin-4, recently listed as a tumor marker, and exerts antitumor activity against nectin-4-positive canine mammary cancer and urinary bladder transitional cell carcinoma cells. However, the effectivity of rMV-SLAMblind for other types of canine cancers is still unknown. Here we evaluated the antitumor effect of rMV-SLAMblind to canine lung cancer. Nectin-4 is expressed on three canine lung cancer cell lines (CLAC, AZACL1, AZACL2) and rMV-SLAMblind was able to infect these cell lines. CLAC cells showed reduced cell viability after virus infection. In the CLAC xenograft nude mouse model, intratumoral administration of rMV-SLAMblind significantly suppressed tumor growth. In rMV-SLAMblind-treated mice, natural killer cells were activated, and Cxcl10 and Il12a levels were significantly increased in comparison with levels in the control group. In addition, the depletion of NK cells reduced the anti-tumor effect. To understand difference in efficacy among canine lung cancer cell lines, we compared virus growth and gene expression pattern after virus treatment in the three canine lung cancer cell lines; virus growth was highest in CLAC cells compared with the other cell lines and the induction of interferon (IFN)-beta and IFN-stimulated genes was at lower levels in CLAC cells. These results suggested that rMV-SLAMblind exhibits oncolytic effect against some canine lung cancer cells and the cellular response after the virus infection may influence its efficacy.
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Affiliation(s)
- Kei Tamura
- Laboratory Animal Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa, 252-0880, Japan
- Institute of Industrial Science, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo, 153-8505, Japan
| | - Tomoko Fujiyuki
- Laboratory Animal Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
- Institute of Industrial Science, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo, 153-8505, Japan
| | - Kanako Moritoh
- Laboratory Animal Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
- Institute of Industrial Science, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo, 153-8505, Japan
| | - Hayato Akimoto
- Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
| | - Keigo Iizuka
- Laboratory Animal Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa, 252-0880, Japan
| | - Hiroki Sato
- Laboratory Animal Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
- Institute of Industrial Science, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo, 153-8505, Japan
| | - Kazushi Asano
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa, 252-0880, Japan
| | - Misako Yoneda
- Laboratory Animal Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan
- Institute of Industrial Science, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo, 153-8505, Japan
| | - Chieko Kai
- Laboratory Animal Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan.
- Institute of Industrial Science, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo, 153-8505, Japan.
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Pereira Gonçalves J, Fwu Shing T, Augusto Fonseca Alves G, Eduardo Fonseca-Alves C. Immunology of Canine Melanoma. Vet Med Sci 2022. [DOI: 10.5772/intechopen.108430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Malignant melanoma is one of the most important tumors in dogs and is highly metastatic and aggressive disease. In recent years, molecular knowledge regarding canine melanoma has increased, and some chromosomal imbalances and tyrosine kinase pathways have been identified to be dysregulated. Mxoreover, canine melanoma is an immunogenic tumor that provides opportunities to administer immunotherapy to the patient. Podoplanin and chondroitin sulfate proteoglycan-4 (CSPG4) are markers against which monoclonal antibodies have been developed and tested in dogs in vivo with promising results. Owing to the importance of canine melanoma in the veterinary oncology field, this chapter reviews the most important aspects related to immunological involvement in the prognosis and treatment of canine melanoma.
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7
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Pazzi P, Steenkamp G, Rixon AJ. Treatment of Canine Oral Melanomas: A Critical Review of the Literature. Vet Sci 2022; 9:vetsci9050196. [PMID: 35622724 PMCID: PMC9147014 DOI: 10.3390/vetsci9050196] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 01/09/2023] Open
Abstract
Critical appraisal of the available literature for the treatment of canine oral malignant melanoma (OMM) is lacking. This critical review aimed to evaluate the current literature and provide treatment recommendations and possible suggestions for future canine OMM research. PubMed, Web of Science and Google Scholar were searched in June 2021, for terms relevant to treatment of OMM. Inclusion and exclusion criteria were applied and information on clinical response and outcome extracted. Eighty-one studies were included. The overall level of evidence supporting the various canine OMM treatment options was low. The majority of studies included confounding treatment modalities and lacked randomization, control groups and consistency in reporting clinical response and outcomes. Within these limitations, surgery remains the mainstay of therapy. Adjunctive radiotherapy provided good local control and improved median survival times (MST), chemotherapy did not offer survival benefit beyond that of surgery, while electrochemotherapy may offer a potential alternative to radiotherapy. Immunotherapy holds the most promise in extending MST in the surgical adjunctive setting, in particular the combination of gene therapy and autologous vaccination. Prospective, randomized, double-blinded clinical trials, with a lack of confounding factors and reporting based on established guidelines would allow comparison and recommendations for the treatment of canine OMM.
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8
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Raleigh ML, Smith MM, Taney K. Curative Intent Surgery of Oral Malignant Melanoma and Regional Lymph Node Biopsy Assessment in 25 Dogs: 2006-2017. J Vet Dent 2022; 38:193-198. [PMID: 35014552 DOI: 10.1177/08987564211072396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Medical records were searched for dogs that had received curative intent surgery for oral malignant melanoma and ipsilateral excisional regional lymph node biopsy. Twenty-seven dogs were operated on and 25 dogs of these dogs met the inclusion criteria of signalment, post-excision margin status, presence of metastasis for each biopsied lymphocentrum, survival time post-excision, presence of recurrence or metastasis at follow-up or at death/euthanasia, location of the primary tumor, and any postoperative adjuvant treatment. These 25 dogs had complete tumor excision with tumor-free margins and 19 (76%) had postoperative adjuvant therapy. Median survival time after excision for the dogs in this study was 335.5 days. Results of this study support previous work that documents prolonged survival time following complete excision of oral malignant melanoma with tumor-free surgical margins in dogs. Additionally, 4 dogs (16%) had histologically confirmed regional lymph node metastasis at the time of definitive surgery.
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Affiliation(s)
- Matthew L Raleigh
- Center for Veterinary Dentistry and Oral Surgery, Gaithersburg, MD, USA.,Animal Dentistry & Oral Surgery, Leesburg, VA, USA
| | - Mark M Smith
- Center for Veterinary Dentistry and Oral Surgery, Gaithersburg, MD, USA
| | - Kendall Taney
- Center for Veterinary Dentistry and Oral Surgery, Gaithersburg, MD, USA
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9
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Von Rueden SK, Fan TM. Cancer-Immunity Cycle and Therapeutic Interventions- Opportunities for Including Pet Dogs With Cancer. Front Oncol 2021; 11:773420. [PMID: 34869014 PMCID: PMC8639699 DOI: 10.3389/fonc.2021.773420] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 11/01/2021] [Indexed: 12/22/2022] Open
Abstract
The tumor-immune interplay represents a dynamic series of events executed by cellular and soluble participants that either promote or inhibit successful tumor formation and growth. Throughout a tumor’s development and progression, the host organism’s immune system reacts by generating anti-cancer defenses through various incremental and combinatorial mechanisms, and this reactive orchestration is termed the cancer-immunity cycle. Success or failure of the cancer-immunity cycle dictates the fate of both host and tumor as winner or loser. Insights into how the tumor and host immune system continuously adapt to each other throughout the lifecycle of the tumor is necessary to rationally develop new effective immunotherapies. Additionally, the evolving nature of the cancer-immunity cycle necessitates therapeutic agility, requiring real-time serial assessment of immunobiologic markers that permits tailoring of therapies to the everchanging tumor immune microenvironment. In order to accelerate advances in the field of immuno-oncology, this review summarizes the steps comprising the cancer-immunity cycle, and underscores key breakpoints in the cycle that either favor cancer regression or progression, as well as shaping of the tumor microenvironment and associated immune phenotypes. Furthermore, specific large animal models of spontaneous cancers that are deemed immunogenic will be reviewed and proposed as unique resources for validating investigational immunotherapeutic protocols that are informed by the cancer-immunity cycle. Collectively, this review will provide a progressive look into the dynamic interplay between tumor and host immune responses and raise awareness for how large animal models can be included for developing combinatorial and sequenced immunotherapies to maximizing favorable treatment outcomes.
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Affiliation(s)
- Samantha K Von Rueden
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Champaign, IL, United States
| | - Timothy M Fan
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Champaign, IL, United States.,Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States
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10
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Li M, Zhu Y, Bai B, Fang J, Yao W, Li Y, Li S, Li X, Jin N, Jiang R. Suppression effect of a dual cancer-specific oncolytic adenovirus on luciferase-labeled human melanoma cells in vitro and in vivo. Cancer Biomark 2021; 32:251-262. [PMID: 34459386 DOI: 10.3233/cbm-203150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND To explore the suppressive effect of Apoptin-loaded oncolytic adenovirus (Ad-VT) on luciferase-labeled human melanoma cells in vitro and in vivo. METHODS The stable luciferase-expressing human melanoma cells A375-luc or M14-luc were obtained by transfecting the plasmid pGL4.51 and selection with G418, followed by luciferase activity, genetic stability and bioluminescence intensity assays. In vitro, the inhibitory effects of Ad-VT on A375-luc or M14-luc were evaluated using the MTS cell proliferation, FITC-Annexin V apoptosis detection, transwell migration, Matrigel invasion and scratch assays. The inhibition pathway in Ad-VT-infected A375-luc and M14-luc cells were analyzed by JC-1 staining and Western-blot detection of mitochondrial apoptosis-related proteins. In vivo, the suppressive effects of Ad-VT on A375-luc or M14-luc were assessed by living imaging technology, tumor volume, bioluminescence intensity, survival curves and immunohistochemical analysis of the tumors from the xenograft tumor model BALB/c nude mice. RESULTS The growth and migration of A375-luc and M14-luc were significantly inhibited by Ad-VT in vitro. The evaluations of A375-luc and M14-luc tumor models in BALB/c nude mice were successfully performed using living imaging technology. Ad-VT had an anti-tumor effect by reducing tumor growth and increasing survival in vivo. Ad-VT significantly changed the mitochondrial membrane potential by triggering the the mitochondrial release of apoptosis-related proteins, AIF (apoptosis inducing factor), ARTS (Apoptosis-Related Proteins), and Cyto-c (cytochrome c) from the mitochondria. CONCLUSION Ad-VT reduced the mitochondrial membrane potential in A375-luc or M14-luc cells and induced the mitochondrial release of AIF, ARTS and Cyto-C. Ad-VT induced apoptosis in A375-luc or M14-luc cells via the mitochondrial apoptotic pathway.
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Affiliation(s)
- Min Li
- Department of Dermatology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Yilong Zhu
- Academicians Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, Jilin, China.,Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, Jilin, China
| | - Bing Bai
- Academicians Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Jinbo Fang
- Academicians Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Wei Yao
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, Jilin, China.,Center for Disease Control and Prevention, Agency for Offices Administration, Central Military Commission, Beijing, China
| | - Yiquan Li
- Academicians Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, Jilin, China.,Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, Jilin, China
| | - Shanzhi Li
- Academicians Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Xiao Li
- Department of Dermatology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.,Academicians Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, Jilin, China.,Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, Jilin, China
| | - Ningyi Jin
- Department of Dermatology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.,Academicians Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, Jilin, China.,Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, Jilin, China
| | - Rihua Jiang
- Department of Dermatology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
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11
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Klingemann H. Immunotherapy for Dogs: Still Running Behind Humans. Front Immunol 2021; 12:665784. [PMID: 34421888 PMCID: PMC8374065 DOI: 10.3389/fimmu.2021.665784] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 07/16/2021] [Indexed: 11/13/2022] Open
Abstract
Despite all good intentions, dogs are still running behind humans in effective cancer immunotherapies. The more effective treatments in humans, like infusions of CAR-T and NK-cells are not broadly pursued for canines due to significant costs, the rather complicated logistics and the lack of targetable surface antigens. Monoclonal antibodies are challenging to develop considering the limited knowledge about canine target antigens and about their mode of action. Although immunogenic vaccines could be less costly, this approach is hampered by the fact that cancer by itself is immuno-suppressive and any preceding chemotherapy may suppress any clinically meaningful immune response. This review - rather than providing a comprehensive listing of all available immunotherapies for dogs, aims at pointing out the issues that are holding back this field but which hopefully can be addressed so that dogs can "catch up" with what is available to humans.
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12
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Saellstrom S, Sadeghi A, Eriksson E, Segall T, Dimopoulou M, Korsgren O, Loskog AS, Tötterman TH, Hemminki A, Ronnberg H. Adenoviral CD40 Ligand Immunotherapy in 32 Canine Malignant Melanomas-Long-Term Follow Up. Front Vet Sci 2021; 8:695222. [PMID: 34368282 PMCID: PMC8342889 DOI: 10.3389/fvets.2021.695222] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/25/2021] [Indexed: 01/13/2023] Open
Abstract
Malignant melanoma is a serious disease in both humans and dogs, and the high metastatic potential results in poor prognosis for many patients. Its similarities with human melanoma make spontaneous canine melanoma an excellent model for comparative studies of novel therapies and tumor biology. Gene therapy using adenoviruses encoding the immunostimulatory gene CD40L (AdCD40L) has shown promise in initial clinical trials enrolling human patients with various malignancies including melanoma. We report a study of local AdCD40L treatment in 32 cases of canine melanoma (23 oral, 5 cutaneous, 3 ungual and 1 conjunctival). Eight patients were World Health Organization (WHO) stage I, 9 were stage II, 12 stage III, and 3 stage IV. One to six intratumoral injections of AdCD40L were given every seven days, combined with cytoreductive surgery in 20 cases and only immunotherapy in 12 cases. Tumor tissue was infiltrated with T and B lymphocytes after treatment, suggesting immune stimulation. The best overall response based on result of immunotherapy included 7 complete responses, 5 partial responses, 5 stable and 2 progressive disease statuses according to the World Health Organization response criteria. Median survival was 285 days (range 20–3435 d). Our results suggest that local AdCD40L therapy is safe and could have beneficial effects in dogs, supporting further treatment development. Clinical translation to human patients is ongoing.
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Affiliation(s)
- Sara Saellstrom
- University Animal Hospital, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden
| | - Arian Sadeghi
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Emma Eriksson
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Thomas Segall
- National Veterinary Institute, Department of Pathology and Wildlife Diseases, Uppsala, Sweden
| | - Maria Dimopoulou
- University Animal Hospital, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Angelica Si Loskog
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Thomas H Tötterman
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Akseli Hemminki
- Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.,Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland
| | - Henrik Ronnberg
- Center of Clinical Comparative Oncology (C3O), Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden
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13
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Guillén A, Stiborova K, Ressel L, Blackwood L, Finotello R, Amores-Fuster I, Jama N, Killick D. Immunohistochemical expression and prognostic significance of MAGE-A in canine oral malignant melanoma. Res Vet Sci 2021; 137:226-234. [PMID: 34023546 DOI: 10.1016/j.rvsc.2021.05.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 04/12/2021] [Accepted: 05/12/2021] [Indexed: 11/18/2022]
Abstract
Canine oral malignant melanoma (COMM) is considered a chemo-resistant cancer with a poor long-term prognosis. The melanoma-associated antigen A (MAGE-A) genes, which belong to the cancer-testis antigen family, are expressed in several different canine cancers but not in normal somatic tissue. This study evaluates the expression of MAGE-A proteins and their prognostic role in COMM. The study was conducted in 2 parts. During the first part, biopsies from oral malignant melanomas from 43 dogs were examined and immunohistochemically assessed for expression of MAGE-A proteins. For the second part, the association between MAGE-A expression and outcome was assessed using follow-up data which was available for 20 dogs whose primary tumour had been controlled with surgery +/- radiation therapy. MAGE-A proteins were expressed in 88.4% (38/43) of oral malignant melanomas and had a predominantly cytoplasmic expression pattern. Immunopositivity was observed in more than 50% of the cells in 21 dogs (48.8%). Immunostaining intensity was classified as weak, moderate and intense in 16 (37%), 16 (37%) and 6 (14%) cases, respectively. No staining for MAGE-A was seen in 5 dogs (11%). Dogs whose COMM had weak MAGE-A staining intensity had a median survival time (MST) of 320 days while this was 129 days for dogs with moderate and intense immunostaining (p = 0.161). Dogs whose COMM had >50% of positive staining neoplastic cells had an MST of 141 days and dogs with a staining <50% had an MST of 320 days (p = 0.164). MAGE-A expression did not influence survival in our cohort.
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Affiliation(s)
- Alexandra Guillén
- Department of Small Animal Clinical Science, Institute of Infection, Veterinary and Ecological Science, University of Liverpool, Neston CH64 7TE, UK.
| | - Katerina Stiborova
- Department of Small Animal Clinical Science, Institute of Infection, Veterinary and Ecological Science, University of Liverpool, Neston CH64 7TE, UK
| | - Lorenzo Ressel
- Department of Veterinary Anatomy Physiology and Pathology, Institute of Infection, Veterinary and Ecological Science, University of Liverpool, Neston CH64 7TE, UK
| | - Laura Blackwood
- Department of Small Animal Clinical Science, Institute of Infection, Veterinary and Ecological Science, University of Liverpool, Neston CH64 7TE, UK
| | - Riccardo Finotello
- Department of Small Animal Clinical Science, Institute of Infection, Veterinary and Ecological Science, University of Liverpool, Neston CH64 7TE, UK
| | - Isabel Amores-Fuster
- Department of Small Animal Clinical Science, Institute of Infection, Veterinary and Ecological Science, University of Liverpool, Neston CH64 7TE, UK
| | - Nimo Jama
- Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - David Killick
- Department of Small Animal Clinical Science, Institute of Infection, Veterinary and Ecological Science, University of Liverpool, Neston CH64 7TE, UK
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14
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Safety studies and viral shedding of intramuscular administration of oncolytic vaccinia virus TG6002 in healthy beagle dogs. BMC Vet Res 2020; 16:307. [PMID: 32843040 PMCID: PMC7446062 DOI: 10.1186/s12917-020-02524-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 08/14/2020] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Cancer is a leading cause of mortality for both humans and dogs. As spontaneous canine cancers appear to be relevant models of human cancers, developing new therapeutic approaches could benefit both species. Oncolytic virotherapy is a promising therapeutic approach in cancer treatment. TG6002 is a recombinant oncolytic vaccinia virus deleted in the thymidine kinase and ribonucleotide reductase genes and armed with the suicide gene FCU1 that encodes a protein which catalyses the conversion of the non-toxic 5-fluorocytosine into the toxic metabolite 5-fluorouracil. Previous studies have shown the ability of TG6002 to infect and replicate in canine tumor cell lines, and demonstrated its oncolytic potency in cell lines, xenograft models and canine mammary adenocarcinoma explants. Moreover, 5-fluorouracil synthesis has been confirmed in fresh canine mammary adenocarcinoma explants infected with TG6002 with 5-fluorocytosine. This study aims at assessing the safety profile and viral shedding after unique or repeated intramuscular injections of TG6002 in seven healthy Beagle dogs. RESULTS Repeated intramuscular administrations of TG6002 at the dose of 5 × 107 PFU/kg resulted in no clinical or biological adverse effects. Residual TG6002 in blood, saliva, urine and feces of treated dogs was not detected by infectious titer assay nor by qPCR, ensuring the safety of the virus in the dogs and their environment. CONCLUSIONS These results establish the good tolerability of TG6002 in healthy dogs with undetectable viral shedding after multiple injections. This study supports the initiation of further studies in canine cancer patients to evaluate the oncolytic potential of TG6002 and provides critical data for clinical development of TG6002 as a human cancer therapy.
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15
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Ylösmäki E, Cerullo V. Design and application of oncolytic viruses for cancer immunotherapy. Curr Opin Biotechnol 2019; 65:25-36. [PMID: 31874424 DOI: 10.1016/j.copbio.2019.11.016] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 11/12/2019] [Accepted: 11/14/2019] [Indexed: 12/28/2022]
Abstract
The approval of the first oncolytic virus (OV) for the treatment of metastatic melanoma and the recent discovery that the use of oncolytic viruses may enhance cancer immunotherapies targeted against various immune checkpoint proteins have attracted great interest in the field of cancer virotherapy. OVs are designed to target and kill cancer cells leaving normal cell unharmed. OV infection and concomitant cancer cell killing stimulate anti-tumour immunity and modulates tumour microenvironment towards less immunosuppressive phenotype. The intrinsic capacity of OVs to turn immunologically cold tumours into immunologically hot tumours, and to increase immune cell and cytokine infiltration, can be further enhanced by arming OVs with transgenes that increase their immunostimulatory activities and direct immune responses specifically towards cancer cells. These OVs, specifically engineered to be used as cancer immunotherapeutics, can be synergized with other immune modulators or cytotoxic agents to achieve the most potent immunotherapy for cancer.
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Affiliation(s)
- Erkko Ylösmäki
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
| | - Vincenzo Cerullo
- Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
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16
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Thamm DH. Canine Cancer: Strategies in Experimental Therapeutics. Front Oncol 2019; 9:1257. [PMID: 31803625 PMCID: PMC6873901 DOI: 10.3389/fonc.2019.01257] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 10/31/2019] [Indexed: 12/13/2022] Open
Abstract
Cancer is the most common cause of death in adult dogs. Many features of spontaneously developing tumors in pet dogs contribute to their potential utility as a human disease model. These include similar environmental exposures, similar clonal evolution as it applies to important factors such as immune avoidance, a favorable body size for imaging and serial biopsy, and a relatively contracted time course of disease progression, which makes evaluation of temporal endpoints such as progression free or overall survival feasible in a comparatively short time frame. These criteria have been leveraged to evaluate novel local therapies, demonstrate proof of tumor target inhibition or tumor localization, evaluate potential antimetastatic approaches, and assess the efficacy, safety and immune effects of a variety of immune-based therapeutics. Some of these canine proof of concept studies have been instrumental in informing subsequent human clinical trials. This review will cover key aspects of clinical trials in dogs with spontaneous neoplasia, with examples of how these studies have contributed to human cancer therapeutic development.
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Affiliation(s)
- Douglas H Thamm
- Flint Animal Cancer Center, Colorado State University, Fort Collins, CO, United States.,Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO, United States.,University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO, United States
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17
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Finocchiaro LME, Agnetti L, Fondello C, Glikin GC. Combination of cytokine-enhanced vaccine and chemo-gene therapy as surgery adjuvant treatments for spontaneous canine melanoma. Gene Ther 2019; 26:418-431. [PMID: 30858538 DOI: 10.1038/s41434-019-0066-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 02/20/2019] [Accepted: 02/21/2019] [Indexed: 11/09/2022]
Abstract
After 6 years of follow-up treating 364 canine melanoma patients, we present here results about the proof-of-concept, safety, and efficacy of a new surgery adjuvant combined gene therapy. The adjuvant treatment (AT) group was divided in three arms as follows: (i) complete surgery plus vaccine (CS-V), (ii) complete surgery plus combined treatment (CS-CT), and (iii) partial surgery plus combined treatment (PS-CT). Besides the genetic vaccines composed by tumor extracts and lipoplexes carrying human interleukin-2 and granulocyte-macrophage colony-stimulating factor genes, the patients were subjected to combined treatment received in the post-surgical bed injections of lipid-complexed thymidine kinase suicide gene plus ganciclovir and canine interferon-β gene plus bleomycin. As compared with surgery-only treated controls (So), CS-CT and CS-V treatments significantly increased the fraction of local disease-free (from 20 to 89 and 74%) and distant metastases-free patients (M0: from 45 to 87 and 84%). Although less effective than CS arms, PS-CT arm demonstrated a significantly improved control of metastatic disease (M0: 80%) compared with So (M0: 44%). In addition, AT produced a significant 9.3- (CS-CT), 6.5- (CS-V), and 5.4-fold (PS-CT) increase of overall survival as compared with their respective So controls. In general terms, the AT changed a lethal disease into a chronic disease where 70% of CS-CT, 51% of CS-V, and 14% of PS-CT patients died of melanoma unrelated causes. These surgery adjuvant treatments delayed or prevented post-surgical recurrence and distant metastasis, and improved disease-free and overall survival while maintaining quality of life. These successful outcomes encourage assaying a similar scheme for human melanoma.
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Affiliation(s)
- Liliana M E Finocchiaro
- Unidad de Transferencia Genética, Instituto de Oncología "Ángel H. Roffo", Universidad de Buenos Aires, Buenos Aires, Argentina.
| | - Lucrecia Agnetti
- Unidad de Transferencia Genética, Instituto de Oncología "Ángel H. Roffo", Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Chiara Fondello
- Unidad de Transferencia Genética, Instituto de Oncología "Ángel H. Roffo", Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Gerardo C Glikin
- Unidad de Transferencia Genética, Instituto de Oncología "Ángel H. Roffo", Universidad de Buenos Aires, Buenos Aires, Argentina
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18
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A Review of Immunotherapeutic Strategies in Canine Malignant Melanoma. Vet Sci 2019; 6:vetsci6010015. [PMID: 30759787 PMCID: PMC6466282 DOI: 10.3390/vetsci6010015] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 02/06/2019] [Accepted: 02/08/2019] [Indexed: 12/13/2022] Open
Abstract
In dogs, melanomas are relatively common tumors and the most common form of oral malignancy. Biological behavior is highly variable, usually aggressive, and frequently metastatic, with reported survival times of three months for oral or mucosal melanomas in advanced disease stages. Classical clinical management remains challenging; thus, novel and more efficacious treatment strategies are needed. Evidence-based medicine supports the role of the immune system to treat neoplastic diseases. Besides, immunotherapy offers the possibility of a precise medicinal approach to treat cancer. In recent years, multiple immunotherapeutic strategies have been developed, and are now recognized as a pillar of treatment. In addition, dogs represent a good model for translational medicine purposes. This review will cover the most relevant immunotherapeutic strategies for the treatment of canine malignant melanoma, divided among five different categories, namely, monoclonal antibodies, nonspecific immunotherapy activated by bacteria, vaccines, gene therapy, and lymphokine-activated killer cell therapy.
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19
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Fan TM, Selting KA. Exploring the Potential Utility of Pet Dogs With Cancer for Studying Radiation-Induced Immunogenic Cell Death Strategies. Front Oncol 2019; 8:680. [PMID: 30697532 PMCID: PMC6340932 DOI: 10.3389/fonc.2018.00680] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 12/27/2018] [Indexed: 01/21/2023] Open
Abstract
Radiotherapy serves as a foundational pillar for the therapeutic management of diverse solid tumors through the generation of lethal DNA damage and induction of cell death. While the direct cytotoxic effects of radiation therapy remain a cornerstone for cancer management, in the era of immunooncology there is renewed and focused interest in exploiting the indirect bystander activities of radiation, termed abscopal effects. In radioimmunobiologic terms, abscopal effects describe the radiotherapy-induced regression of cancerous lesions distant from the primary site of radiation delivery and rely upon the induction of immunogenic cell death and consequent systemic anticancer immune activation. Despite the promise of radiation therapy for awaking potent anticancer immune responses, the purposeful harnessing of abscopal effects with radiotherapy remain clinically elusive. In part, failure to fully leverage and clinically implement the promise of radiation-induced abscopal effects stems from limitations associated with existing conventional tumor models which inadequately recapitulate the complexity of malignant transformation and the dynamic nature of tumor immune surveillance. To supplement this existing gap in modeling systems, pet dogs diagnosed with solid tumors including melanoma and osteosarcoma, which are both metastatic and immunogenic in nature, could potentially serve as unique resources for exploring the fundamental underpinnings required for maximizing radiation-induced abscopal effects. Given the spontaneous course of cancer development in the context of operative immune mechanisms, pet dogs treated with radiotherapy for metastatic solid tumors might be leveraged as valuable model systems for realizing the science and best clinical practices necessary to generate potent abscopal effects with anti-metastatic immune activities.
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Affiliation(s)
- Timothy M Fan
- Comparative Oncology Research Laboratory, Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign Urbana, IL, United States
| | - Kimberly A Selting
- Comparative Oncology Research Laboratory, Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign Urbana, IL, United States
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20
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Eriksson E, Milenova I, Wenthe J, Moreno R, Alemany R, Loskog A. IL-6 Signaling Blockade during CD40-Mediated Immune Activation Favors Antitumor Factors by Reducing TGF-β, Collagen Type I, and PD-L1/PD-1. THE JOURNAL OF IMMUNOLOGY 2019; 202:787-798. [PMID: 30617223 DOI: 10.4049/jimmunol.1800717] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 11/22/2018] [Indexed: 12/14/2022]
Abstract
IL-6 plays a role in cancer pathogenesis via its connection to proteins involved in the formation of desmoplastic stroma and to immunosuppression by driving differentiation of myeloid suppressor cells together with TGF-β. Inhibition of IL-6 signaling in the tumor microenvironment may, thus, limit desmoplasia and myeloid suppressor cell differentiation. CD40 signaling can further revert myeloid cell differentiation toward antitumor active phenotypes. Hence, the simultaneous use of IL-6 blockade with CD40 stimuli may tilt the tumor microenvironment to promote antitumor immune responses. In this paper, we evaluated the mechanisms of LOAd713, an oncolytic adenovirus designed to block IL-6R signaling and to provide myeloid cell activation via a trimerized membrane-bound isoleucine zipper (TMZ) CD40L. LOAd713-infected pancreatic cancer cells were killed by oncolysis, whereas infection of stellate cells reduced factors involved in stroma formation, including TGF-β-1 and collagen type I. Virus infection prevented IL-6/GM-CSF-mediated differentiation of myeloid suppressors, but not CD163 macrophages, whereas infection of dendritic cells led to upregulation of maturation markers, including CD83, CD86, IL-12p70, and IFN-γ. Further, IL-6R blockade prevented upregulation of programed death ligand 1 (PD-L1) and PD-1 on the stimulated dendritic cells. These results suggest that LOAd713 can kill infected tumor cells and has the capacity to affect the tumor microenvironment by stimulating stellate cells and myeloid suppressors with TMZ-CD40L and IL-6R blockade. Gene transfer of murine TMZ-CD40L prolonged survival in an animal model. LOAd713 may be an interesting therapeutic option for cancers connected to IL-6 signaling, such as pancreatic cancer.
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Affiliation(s)
- Emma Eriksson
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden
| | - Ioanna Milenova
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden
| | - Jessica Wenthe
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden
| | - Rafael Moreno
- L'Institut d'Investigació Biomèdica de Bellvitge-Institut Català d'Oncologia, L'Hospitalet de Llobregat, 08908 Barcelona, Spain; and
| | - Ramon Alemany
- L'Institut d'Investigació Biomèdica de Bellvitge-Institut Català d'Oncologia, L'Hospitalet de Llobregat, 08908 Barcelona, Spain; and
| | - Angelica Loskog
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden; .,Lokon Pharma AB, 751 83 Uppsala, Sweden
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21
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Sánchez D, Cesarman-Maus G, Amador-Molina A, Lizano M. Oncolytic Viruses for Canine Cancer Treatment. Cancers (Basel) 2018; 10:cancers10110404. [PMID: 30373251 PMCID: PMC6266482 DOI: 10.3390/cancers10110404] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/16/2018] [Accepted: 10/23/2018] [Indexed: 12/17/2022] Open
Abstract
Oncolytic virotherapy has been investigated for several decades and is emerging as a plausible biological therapy with several ongoing clinical trials and two viruses are now approved for cancer treatment in humans. The direct cytotoxicity and immune-stimulatory effects make oncolytic viruses an interesting strategy for cancer treatment. In this review, we summarize the results of in vitro and in vivo published studies of oncolytic viruses in different phases of evaluation in dogs, using PubMed and Google scholar as search platforms, without time restrictions (to date). Natural and genetically modified oncolytic viruses were evaluated with some encouraging results. The most studied viruses to date are the reovirus, myxoma virus, and vaccinia, tested mostly in solid tumors such as osteosarcomas, mammary gland tumors, soft tissue sarcomas, and mastocytomas. Although the results are promising, there are issues that need addressing such as ensuring tumor specificity, developing optimal dosing, circumventing preexisting antibodies from previous exposure or the development of antibodies during treatment, and assuring a reasonable safety profile, all of which are required in order to make this approach a successful therapy in dogs.
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Affiliation(s)
- Diana Sánchez
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico.
| | - Gabriela Cesarman-Maus
- Department of Hematology, Instituto Nacional de Cancerología, Mexico City 14080, Mexico.
| | - Alfredo Amador-Molina
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico.
| | - Marcela Lizano
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico.
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22
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Strauss BE, Silva GRO, de Luna Vieira I, Cerqueira OLD, Del Valle PR, Medrano RFV, Mendonça SA. Perspectives for cancer immunotherapy mediated by p19Arf plus interferon-beta gene transfer. Clinics (Sao Paulo) 2018; 73:e479s. [PMID: 30208166 PMCID: PMC6113850 DOI: 10.6061/clinics/2018/e479s] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 05/22/2018] [Indexed: 12/13/2022] Open
Abstract
While cancer immunotherapy has gained much deserved attention in recent years, many areas regarding the optimization of such modalities remain unexplored, including the development of novel approaches and the strategic combination of therapies that target multiple aspects of the cancer-immunity cycle. Our own work involves the use of gene transfer technology to promote cell death and immune stimulation. Such immunogenic cell death, mediated by the combined transfer of the alternate reading frame (p14ARF in humans and p19Arf in mice) and the interferon-β cDNA in our case, was shown to promote an antitumor immune response in mouse models of melanoma and lung carcinoma. With these encouraging results, we are now setting out on the road toward translational and preclinical development of our novel immunotherapeutic approach. Here, we outline the perspectives and challenges that we face, including the use of human tumor and immune cells to verify the response seen in mouse models and the incorporation of clinically relevant models, such as patient-derived xenografts and spontaneous tumors in animals. In addition, we seek to combine our immunotherapeutic approach with other treatments, such as chemotherapy or checkpoint blockade, with the goal of reducing dosage and increasing efficacy. The success of any translational research requires the cooperation of a multidisciplinary team of professionals involved in laboratory and clinical research, a relationship that is fostered at the Cancer Institute of Sao Paulo.
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Affiliation(s)
- Bryan E Strauss
- Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
- *Corresponding author. E-mail: /
| | - Gissele Rolemberg Oliveira Silva
- Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Igor de Luna Vieira
- Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Otto Luiz Dutra Cerqueira
- Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Paulo Roberto Del Valle
- Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Ruan Felipe Vieira Medrano
- Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Samir Andrade Mendonça
- Laboratório de Vetores Virais, Centro de Investigação Translacional em Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
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23
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Ilyinskaya GV, Mukhina EV, Soboleva AV, Matveeva OV, Chumakov PM. Oncolytic Sendai Virus Therapy of Canine Mast Cell Tumors (A Pilot Study). Front Vet Sci 2018; 5:116. [PMID: 29915788 PMCID: PMC5995045 DOI: 10.3389/fvets.2018.00116] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 05/15/2018] [Indexed: 12/21/2022] Open
Abstract
Background: Canine mastocytomas (mast cell tumors) represent a common malignancy among many dog breeds. A typical treatment strategy for canine mastocytomas includes surgery, chemo- and radio-therapy, although in many cases the therapy fails and the disease progression resumes. New treatment approaches are needed. Aims: The goal of this pilot study was to examine safety and efficacy of oncolytic Sendai virus therapy administered to canine patients with cutaneous or subcutaneous mastocytomas. Materials and Methods: Six canine patients, with variable grades and stages of the disease, received virus therapy, either as a monotherapy, or in combination with surgery. The therapy included two or more virus applications administered weekly or biweekly. Each application of Sendai virus (107-108.6 EID50) consisted of multiple individual 0.01-0.1 ml injections delivered intratumorally, intradermally around a tumor, and under a tumor bed. Results: The treatment was well tolerated, with minor transitory side effects. Of the six dogs, two did not receive surgery or any other treatment besides the virus injections. The other four animals underwent radical or debulking surgeries, and in three of them the subsequent administration of Sendai virus completely cleared locally recurrent or/and remaining tumor masses. Five dogs demonstrated a complete response to the treatment, the animals remained disease free during the time of observation (2-3 years). One dog responded only partially to the virotherapy; its after-surgical recurrent tumor and some, but not all, metastases were cleared. This dog had the most advanced stage of the disease with multiple enlarged lymph nodes and cutaneous metastases. Conclusion: The results of the pilot study suggest that Sendai virus injections could be safe and efficient for the treatment of dogs affected by mastocytomas.They also suggest the need of further studies for finding optimal schemes and schedules for this kind of therapy.
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Affiliation(s)
- Galina V. Ilyinskaya
- Engelhardt Institute of Molecular Biology, Moscow, Russia
- Blokhin Cancer Research Center, Moscow, Russia
| | - Elena V. Mukhina
- Veterinary Clinic of Herzen Oncology Research Institute, Moscow, Russia
| | - Alesya V. Soboleva
- Engelhardt Institute of Molecular Biology, Moscow, Russia
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, Moscow, Russia
| | | | - Peter M. Chumakov
- Engelhardt Institute of Molecular Biology, Moscow, Russia
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, Moscow, Russia
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24
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Finocchiaro LME, Glikin GC. Recent clinical trials of cancer immunogene therapy in companion animals. World J Exp Med 2017; 7:42-48. [PMID: 28589078 PMCID: PMC5439171 DOI: 10.5493/wjem.v7.i2.42] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Revised: 03/22/2017] [Accepted: 05/05/2017] [Indexed: 02/06/2023] Open
Abstract
This mini-review presents the results of veterinary clinical trials on immunogene therapy published from 2014 to 2016. A variety of tumors, among them melanoma (canine and equine), mastocytoma (canine), mammary adenocarcinoma (canine) and fibrosarcoma (feline) were treated by using diverse strategies. Non-viral vectors were usually employed to transfer genes of cytokines, suicide enzymes and/or tumor associated antigens. In general terms, minor or no adverse collateral effects were related to these procedures, and treated patients frequently improved their conditions (better quality of life, delayed or suppressed recurrence or metastatic spread, increased survival). Some of these new methodologies have a promising future if applied as adjuvant treatments of standard approaches. The auspicious results, derived from immunogene therapy studies carried out in companion animals, warrant their imperative usage in veterinary clinical oncology. Besides, they provide a strong preclinical basis (safety assays and proofs of concept) for analogous human clinical trials.
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25
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Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment. Gene Ther 2016; 24:92-103. [PMID: 27906162 PMCID: PMC5441514 DOI: 10.1038/gt.2016.80] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 10/30/2016] [Accepted: 11/11/2016] [Indexed: 12/12/2022]
Abstract
CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate T-helper 1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer. Further, the CD40L mechanisms of action were elucidated in cancer models. The results demonstrated that the virus transferring TMZ-CD40L had oncolytic capacity in pancreatic cancer cells and could control tumor progression. TMZ-CD40L was a potent stimulator of human myeloid cells and T-cell responses. Further, CD40L-mediated stimulation increased tumor-infiltrating T cells in vivo, which may be due to a direct activation of endothelial cells to upregulate receptors for lymphocyte attachment and transmigration. In conclusion, CD40L-mediated gene therapy is an interesting concept for the treatment of tumors with high levels of M2 macrophages, such as pancreatic cancer, and an oncolytic virus as carrier of CD40L may further boost tumor killing and immune activation.
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26
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Ellmark P, Mangsbo SM, Furebring C, Norlén P, Tötterman TH. Tumor-directed immunotherapy can generate tumor-specific T cell responses through localized co-stimulation. Cancer Immunol Immunother 2016; 66:1-7. [PMID: 27714433 PMCID: PMC5222923 DOI: 10.1007/s00262-016-1909-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 09/29/2016] [Indexed: 12/22/2022]
Abstract
The most important goals for the field of immuno-oncology are to improve the response rate and increase the number of tumor indications that respond to immunotherapy, without increasing adverse side effects. One approach to achieve these goals is to use tumor-directed immunotherapy, i.e., to focus the immune activation to the most relevant part of the immune system. This may improve anti-tumor efficacy as well as reduce immune-related adverse events. Tumor-directed immune activation can be achieved by local injections of immune modulators in the tumor area or by directing the immune modulator to the tumor using bispecific antibodies. In this review, we focus on therapies targeting checkpoint inhibitors and co-stimulatory receptors that can generate tumor-specific T cell responses through localized immune activation.
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Affiliation(s)
- Peter Ellmark
- Alligator Bioscience AB, Medicon Village, 223 63, Lund, Sweden.
- Department of Immunotechnology, Lund University, Lund, Sweden.
| | - Sara M Mangsbo
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | | | - Per Norlén
- Alligator Bioscience AB, Medicon Village, 223 63, Lund, Sweden
| | - Thomas H Tötterman
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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27
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Loskog A, Maleka A, Mangsbo S, Svensson E, Lundberg C, Nilsson A, Krause J, Agnarsdóttir M, Sundin A, Ahlström H, Tötterman TH, Ullenhag G. Immunostimulatory AdCD40L gene therapy combined with low-dose cyclophosphamide in metastatic melanoma patients. Br J Cancer 2016; 114:872-80. [PMID: 27031851 PMCID: PMC4984796 DOI: 10.1038/bjc.2016.42] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Revised: 01/13/2016] [Accepted: 02/01/2016] [Indexed: 01/13/2023] Open
Abstract
Background: Current approaches for treating metastatic malignant melanoma (MM) are not effective enough and are associated with serious adverse events. Due to its immunogenicity, melanoma is an attractive target for immunostimulating therapy. In this phase I/IIa study, local AdCD40L immunostimulatory gene therapy was evaluated in patients with MM. Methods: AdCD40L is an adenovirus carrying the gene for CD40 ligand. Patients that failed standard treatments were enrolled. Six patients received four weekly intratumoral AdCD40L injections. Next, nine patients received low-dose cyclophosphamide conditioning before the first and fourth AdCD40L injection. The blood samples were collected at multiple time points for chemistry, haematology and immunology evaluations. Radiology was performed at enrolment and repeated twice after the treatment. Results: AdCD40L was safe with mild transient reactions. No objective responses were recorded by MRI, however, local and distant responses were seen on FDG-PET. The overall survival at 6 months was significantly better when cyclophosphamide was added to AdCD40L. The patients with the best survival developed the highest levels of activated T cells and experienced a pronounced decrease of intratumoral IL8. Conclusions: AdCD40L therapy for MM was well tolerated. Local and distant responses along with better survival in the low-dose cyclophosphamide group are encouraging.
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Affiliation(s)
- Angelica Loskog
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden
| | - Aglaia Maleka
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden.,Department of Oncology, Uppsala University Hospital, 75185 Uppsala, Sweden
| | - Sara Mangsbo
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden
| | - Emma Svensson
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden
| | - Christina Lundberg
- Division of Radiology, Uppsala University Hospital, 75185 Uppsala, Sweden
| | - Anders Nilsson
- Division of Radiology, Uppsala University Hospital, 75185 Uppsala, Sweden
| | - Johan Krause
- Division of Radiology, Uppsala University Hospital, 75185 Uppsala, Sweden
| | - Margrét Agnarsdóttir
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden.,Department of Pathology and Cytology, Uppsala University Hospital, 75185 Uppsala, Sweden
| | - Anders Sundin
- Division of Radiology, Uppsala University Hospital, 75185 Uppsala, Sweden.,Department of Surgical Sciences, Uppsala University, 75185 Uppsala, Sweden
| | - Håkan Ahlström
- Division of Radiology, Uppsala University Hospital, 75185 Uppsala, Sweden.,Department of Surgical Sciences, Uppsala University, 75185 Uppsala, Sweden
| | - Thomas H Tötterman
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden
| | - Gustav Ullenhag
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden.,Department of Oncology, Uppsala University Hospital, 75185 Uppsala, Sweden
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28
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Treggiari E, Grant JP, North SM. A retrospective review of outcome and survival following surgery and adjuvant xenogeneic DNA vaccination in 32 dogs with oral malignant melanoma. J Vet Med Sci 2016; 78:845-50. [PMID: 26781703 PMCID: PMC4905841 DOI: 10.1292/jvms.15-0510] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
A xenogeneic DNA vaccination has been licensed for use in dogs with locally controlled stage II and III oral malignant melanoma (OMM). At present, there are limited outcome data for dogs with OMM treated with surgery and immunotherapy. The aim of this study is to retrospectively review the outcome and survival of 32 dogs affected by OMM that were treated with a combination of surgery and the xenogeneic DNA vaccination (with the addition of radiotherapy in some cases) and to determine the influence of surgical margins and delay in receiving vaccination. The overall median survival time (MST) was 335 days (95% CI: 301-540 days), and the overall median progression-free survival (PFS) was 160 days (mean 182 days, 95% CI: 132-232 days). Stage, completeness of surgical margins and delay in administration of the vaccine did not appear to statistically influence survival or PFS, although these results may reflect the low statistical power of the study due to small numbers. Further studies are required to assess whether the addition of any adjuvant treatment to surgery, including immunotherapy, is able to significantly prolong survival in cases of canine oral melanoma.
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29
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Cancer immunology and canine malignant melanoma: A comparative review. Vet Immunol Immunopathol 2016; 169:15-26. [DOI: 10.1016/j.vetimm.2015.11.003] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 08/28/2015] [Accepted: 11/09/2015] [Indexed: 11/20/2022]
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30
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Kemp V, Hoeben RC, van den Wollenberg DJM. Exploring Reovirus Plasticity for Improving Its Use as Oncolytic Virus. Viruses 2015; 8:E4. [PMID: 26712782 PMCID: PMC4728564 DOI: 10.3390/v8010004] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 12/04/2015] [Accepted: 12/15/2015] [Indexed: 12/13/2022] Open
Abstract
Reoviruses are non-enveloped viruses with a segmented double stranded RNA genome. In humans, they are not associated with serious disease. Human reoviruses exhibit an inherent preference to replicate in tumor cells, which makes them ideally suited for use in oncolytic virotherapies. Their use as anti-cancer agent has been evaluated in several clinical trials, which revealed that intra-tumoral and systemic delivery of reoviruses are well tolerated. Despite evidence of anti-tumor effects, the efficacy of reovirus in anti-cancer monotherapy needs to be further enhanced. The opportunity to treat both the primary tumor as well as metastases makes systemic delivery a preferred administration route. Several pre-clinical studies have been conducted to address the various hurdles connected to systemic delivery of reoviruses. The majority of those studies have been done in tumor-bearing immune-deficient murine models. This thwarts studies on the impact of the contribution of the immune system to the tumor cell eradication. This review focuses on key aspects of the reovirus/host-cell interactions and the methods that are available to modify the virus to alter these interactions. These aspects are discussed with a focus on improving the reovirus' antitumor efficacy.
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Affiliation(s)
- Vera Kemp
- Department of Molecular Cell Biology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
| | - Rob C Hoeben
- Department of Molecular Cell Biology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
| | - Diana J M van den Wollenberg
- Department of Molecular Cell Biology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
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31
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Abstract
Harnessing the ability of the immune system to eradicate cancer has been a long-held goal of oncology. Work from the last two decades has finally brought immunotherapy into the forefront for cancer treatment, with demonstrable clinical success for aggressive tumors where other therapies had failed. In this review, we will discuss a range of therapies that are in different stages of clinical or preclinical development for companion animals with cancer, and which share the common objective of eliciting adaptive, anti-tumor immune responses. Even though challenges remain, manipulating the immune system holds significant promise to create durable responses and improve outcomes in companion animals with cancer. Furthermore, what we learn from this process will inform and accelerate development of comparable therapies for human cancer patients.
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32
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MacNeill AL. On the potential of oncolytic virotherapy for the treatment of canine cancers. Oncolytic Virother 2015; 4:95-107. [PMID: 27512674 PMCID: PMC4918385 DOI: 10.2147/ov.s66358] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Over 6 million dogs are diagnosed with cancer in the USA each year. Treatment options for many of these patients are limited. It is important that the veterinary and scientific communities begin to explore novel treatment protocols for dogs with cancer. Oncolytic viral therapy is a promising treatment option that may prove to be relatively inexpensive and effective against several types of cancer. The efficacy of oncolytic virus therapies has been clearly demonstrated in murine cancer models, but the positive outcomes observed in mice are not always seen in human cancer patients. These therapies should be thoroughly evaluated in dogs with spontaneously arising cancers to provide needed information about the potential effectiveness of virus treatment for human cancers and to promote the health of our companion animals. This article provides a review of the results of oncolytic virus treatment of canine cancers.
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Affiliation(s)
- Amy L MacNeill
- Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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33
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Zhang X, Teodoro JG, Nadeau JL. Intratumoral gold-doxorubicin is effective in treating melanoma in mice. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2015; 11:1365-75. [PMID: 25888279 DOI: 10.1016/j.nano.2015.04.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Revised: 03/18/2015] [Accepted: 04/01/2015] [Indexed: 01/31/2023]
Abstract
UNLABELLED Intratumoral injection of ultra-small gold nanoparticles (AuNPs) conjugated to doxorubicin (Au-Dox) is effective against both murine B16 and human SK-MEL-28 tumors in mice. Au-Dox suppresses growth of B16 tumors in immunocompetent mice by >70% for at least 19 days. In SK-MEL-28 xenografts, Au-Dox suppresses tumor growth almost completely for >13 weeks, while tumors treated with Dox alone demonstrate accelerated growth after 10 weeks. Histological analysis shows significant apoptosis and necrosis in Au-Dox treated tumors. Intratumoral injection is significantly more effective than intravenous injection, which leads to significant accumulation in liver and kidney with sub-therapeutic concentrations of Au-Dox. However, IV injection does not lead to significant damage in non-target organs, so improved targeting should permit this mode of delivery with little risk of systemic toxicity. The current construct is suitable for tumors accessible to intratumoral injection and represents a viable approach doxorubicin-resistant solid tumors. FROM THE CLINICAL EDITOR Drug resistance is a significant problem in the fight against cancer. The authors describe a new approach in combating drug resistance in tumor cells by conjugating ultrasmall gold nanoparticles to doxorubicin. They tested the efficacy in in-vivo models using two melanoma cell lines. The promising results obtained from intra-tumoral injections contribute a way in future drug designs showing that conjugation to nanoparticles could lead to more effective and synergistic killing of tumor cells.
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Affiliation(s)
- Xuan Zhang
- Department of Biomedical Engineering, McGill University, Montreal QC Canada
| | - Jose G Teodoro
- Department of Biochemistry, McGill University, Montreal QC Canada; Goodman Cancer Research Centre, McGill University, Montreal QC Canada
| | - Jay L Nadeau
- Department of Biomedical Engineering, McGill University, Montreal QC Canada.
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34
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Killick DR, Stell AJ, Catchpole B. Immunotherapy for canine cancer--is it time to go back to the future? J Small Anim Pract 2015; 56:229-41. [PMID: 25704119 DOI: 10.1111/jsap.12336] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 12/04/2014] [Accepted: 12/17/2014] [Indexed: 12/19/2022]
Abstract
Over the last 50 years, the significance of the immune system in the development and control of cancer has been much debated. However, recent discoveries provide evidence for a role of immunological mechanisms in the detection and destruction of cancer cells. Forty years ago veterinary oncologists were already investigating the feasibility of treating neoplasia by enhancing anticancer immunity. Unfortunately, this research was hindered by lack of a detailed understanding of cancer immunology, this limited the specificity and success of these early approaches. The great forward strides made in our understanding of onco-immunology in recent years have provided the impetus for a resurgence of interest in anticancer immunotherapy for canine patients. In this article both these initial trials and the exciting novel immunotherapeutics currently in development are reviewed.
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Affiliation(s)
- D R Killick
- School of Veterinary Science, University of Liverpool, Neston, CH64 7TE
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35
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Riccardo F, Aurisicchio L, Impellizeri JA, Cavallo F. The importance of comparative oncology in translational medicine. Cancer Immunol Immunother 2015; 64:137-48. [PMID: 25548094 PMCID: PMC11029667 DOI: 10.1007/s00262-014-1645-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 12/15/2014] [Indexed: 12/20/2022]
Abstract
Human cancer is so complex that in vivo preclinical models are needed if effective therapies are to be developed. Naturally occurring cancers in companion animals are therefore a great resource, as shown by the remarkable growth that comparative oncology has seen over the last 30 years. Cancer has become a leading cause of death in companion animals now that more pets are living long enough to develop the disease. Furthermore, more owners are seeking advanced and novel therapies for their pets as they are very much considered family members. Living in the same environments, pets and humans are often afflicted by the same types of cancer which show similar behavior and, in some species, express the same antigen molecules. The treatment of pet tumors using novel therapies is of compelling translational significance.
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Affiliation(s)
- Federica Riccardo
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center, University of Turin, Via Nizza, 52, 10126 Turin, Italy
| | | | | | - Federica Cavallo
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center, University of Turin, Via Nizza, 52, 10126 Turin, Italy
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36
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Abstract
Translation of cancer gene transfer confronts many familiar-and some distinctive-ethical challenges. In what follows, I survey three major ethical dimensions of cancer gene transfer development. Subheading 1 centers on the ethics of planning, designing, and reporting animal studies. Subheading 2 describes basic elements of human subjects protection as pertaining to cancer gene transfer. In Subheading 3, I describe how cancer gene transfer researchers have obligations to downstream consumers of the evidence they produce.
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Affiliation(s)
- Jonathan Kimmelman
- Studies in Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit/McGill University, 3647 Peel Street, Montreal, QC, Canada, H3A 1X1,
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37
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Autio K, Knuuttila A, Kipar A, Pesonen S, Guse K, Parviainen S, Rajamäki M, Laitinen-Vapaavuori O, Vähä-Koskela M, Kanerva A, Hemminki A. Safety and biodistribution of a double-deleted oncolytic vaccinia virus encoding CD40 ligand in laboratory Beagles. Mol Ther Oncolytics 2014; 1:14002. [PMID: 27119092 PMCID: PMC4782937 DOI: 10.1038/mto.2014.2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 05/26/2014] [Indexed: 12/13/2022] Open
Abstract
We evaluated adverse events, biodistribution and shedding of oncolytic vaccinia virus encoding CD40 ligand in two Beagles, in preparation for a phase 1 trial in canine cancer patients. Dog 1 received one dose of vaccinia virus and was euthanized 24 hours afterwards, while dog 2 received virus four times once weekly and was euthanized 7 days after that. Dogs were monitored for adverse events and underwent a detailed postmortem examination. Blood, saliva, urine, feces, and organs were collected for virus detection. Dog 1 had mild fever and lethargy while dog 2 experienced a possible seizure 5.5 hours after first virus administration. Viral DNA declined quickly in the blood after virus administration in both dogs but was still detectable 1 week later by quantitative polymerase chain reaction. Only samples taken directly after virus infusion contained infectious virus. Small amounts of viral DNA, but no infectious virus, were detected in a few saliva and urine samples. Necropsies did not reveal any relevant pathological changes and virus DNA was detected mainly in the spleen. The dogs in the study did not have cancer, and thus adverse events could be more common and viral load higher in dogs with tumors which allow viral amplification.
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Affiliation(s)
- Karoliina Autio
- Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Anna Knuuttila
- Finnish Centre for Laboratory Animal Pathology and Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
| | - Anja Kipar
- Finnish Centre for Laboratory Animal Pathology and Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
| | - Sari Pesonen
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Kilian Guse
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Suvi Parviainen
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Minna Rajamäki
- Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
| | - Outi Laitinen-Vapaavuori
- Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
| | - Markus Vähä-Koskela
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Anna Kanerva
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
- Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - Akseli Hemminki
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
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38
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Clinical trials of immunogene therapy for spontaneous tumors in companion animals. ScientificWorldJournal 2014; 2014:718520. [PMID: 25506617 PMCID: PMC4251357 DOI: 10.1155/2014/718520] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 10/02/2014] [Indexed: 12/23/2022] Open
Abstract
Despite the important progress obtained in the treatment of some pets' malignancies, new treatments need to be developed. Being critical in cancer control and progression, the immune system's appropriate modulation may provide effective therapeutic options. In this review we summarize the outcomes of published immunogene therapy veterinary clinical trials reported by many research centers. A variety of tumors such as canine melanoma, soft tissue sarcomas, osteosarcoma and lymphoma, feline fibrosarcoma, and equine melanoma were subjected to different treatment approaches. Both viral and mainly nonviral vectors were used to deliver gene products as cytokines, xenogeneic tumor associated antigens, specific ligands, and proapoptotic regulatory factors. In some cases autologous, allogenic, or xenogeneic transgenic cytokine producing cells were assayed. In general terms, minor or no adverse collateral effects appeared during this kind of therapies and treated patients usually displayed a better course of the disease (longer survival, delayed or suppressed recurrence or metastatic spread, and improvement of the quality of life). This suggests the utility of these methodologies as standard adjuvant treatments. The encouraging outcomes obtained in companion animals support their ready application in veterinary clinical oncology and serve as preclinical proof of concept and safety assay for future human gene therapy trials.
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39
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Cancedda S, Rohrer Bley C, Aresu L, Dacasto M, Leone VF, Pizzoni S, Gracis M, Marconato L. Efficacy and side effects of radiation therapy in comparison with radiation therapy and temozolomide in the treatment of measurable canine malignant melanoma. Vet Comp Oncol 2014; 14:e146-e157. [DOI: 10.1111/vco.12122] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 08/17/2014] [Accepted: 09/16/2014] [Indexed: 01/13/2023]
Affiliation(s)
- S. Cancedda
- Centro Oncologico Veterinario; Sasso Marconi Italy
| | - C. Rohrer Bley
- Division of Radiation Oncology, Vetsuisse-Faculty; University of Zurich; Zurich Switzerland
| | - L. Aresu
- Department of Comparative Biomedicine and Food Science; University of Padua; Legnaro Italy
| | - M. Dacasto
- Department of Comparative Biomedicine and Food Science; University of Padua; Legnaro Italy
| | - V. F. Leone
- Centro Oncologico Veterinario; Sasso Marconi Italy
| | - S. Pizzoni
- Centro Oncologico Veterinario; Sasso Marconi Italy
| | - M. Gracis
- Clinica Veterinaria San Siro; Milan Italy
| | - L. Marconato
- Centro Oncologico Veterinario; Sasso Marconi Italy
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40
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Mangsbo SM, Broos S, Fletcher E, Veitonmäki N, Furebring C, Dahlén E, Norlén P, Lindstedt M, Tötterman TH, Ellmark P. The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T-cell-dependent tumor immunity. Clin Cancer Res 2014; 21:1115-26. [PMID: 25316820 DOI: 10.1158/1078-0432.ccr-14-0913] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here, we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013. EXPERIMENTAL DESIGN We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 was investigated in human and murine in vitro models. The in vivo effect was investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse. RESULTS Activation of dendritic cells (DC) by ADC-1013 results in upregulation of the costimulatory molecules CD80 and CD86, and secretion of IL12. ADC-1013 also activates DCs from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated DCs induce antigen-specific T-cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant antitumor effects and long-term tumor-specific immunity. Furthermore, ADC-1013 demonstrates significant antitumor effects in a human bladder cancer transplanted into immunodeficient NSG mice. CONCLUSIONS Our data demonstrate that ADC-1013 induces long-lasting antitumor responses and immunologic memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.
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Affiliation(s)
- Sara M Mangsbo
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Sissela Broos
- Department of Immunotechnology, Lund University, Lund, Sweden
| | - Erika Fletcher
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | | | | | | | | | - Malin Lindstedt
- Department of Immunotechnology, Lund University, Lund, Sweden
| | - Thomas H Tötterman
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Peter Ellmark
- Department of Immunotechnology, Lund University, Lund, Sweden. Alligator Bioscience AB, Lund, Sweden.
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41
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Autio K, Knuuttila A, Kipar A, Ahonen M, Parviainen S, Diaconu I, Kanerva A, Hakonen T, Vähä-Koskela M, Hemminki A. Anti-tumour activity of oncolytic Western Reserve vaccinia viruses in canine tumour cell lines, xenografts, and fresh tumour biopsies. Vet Comp Oncol 2014; 14:395-408. [PMID: 25302859 DOI: 10.1111/vco.12119] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 08/29/2014] [Accepted: 09/09/2014] [Indexed: 12/13/2022]
Abstract
Cancer is one of the most common reasons for death in dogs. One promising approach is oncolytic virotherapy. We assessed the oncolytic effect of genetically modified vaccinia viruses in canine cancer cells, in freshly excised tumour biopsies, and in mice harbouring canine tumour xenografts. Tumour transduction efficacy was assessed using virus expressing luciferase or fluorescent marker genes and oncolysis was quantified by a colorimetric cell viability assay. Oncolytic efficacy in vivo was evaluated in a nude mouse xenograft model. Vaccinia virus was shown to infect most tested canine cancer cell lines and primary surgical tumour tissues. Virus infection significantly reduced tumour growth in the xenograft model. Oncolytic vaccinia virus has antitumour effects against canine cancer cells and experimental tumours and is able to replicate in freshly excised patient tumour tissue. Our results suggest that oncolytic vaccinia virus may offer an effective treatment option for otherwise incurable canine tumours.
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Affiliation(s)
- K Autio
- Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.,Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - A Knuuttila
- Finnish Centre for Laboratory Animal Pathology and Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
| | - A Kipar
- Finnish Centre for Laboratory Animal Pathology and Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
| | - M Ahonen
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - S Parviainen
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - I Diaconu
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - A Kanerva
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.,Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - T Hakonen
- Oncos Therapeutics Ltd, Helsinki, Finland
| | - M Vähä-Koskela
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - A Hemminki
- Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.,TILT Biotherapeutics Ltd, Helsinki, Finland
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42
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White AG, Wolsic CL, Campbell KL, Lavergne SN. Canine progenitor epidermal keratinocytes express various inflammatory markers, including interleukin-8 and CD40, which are affected by certain antibiotics. Vet Dermatol 2014; 25:493-502, e81-2. [DOI: 10.1111/vde.12164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/28/2014] [Indexed: 12/24/2022]
Affiliation(s)
- Amelia G. White
- Veterinary Clinical Medicine; College of Veterinary Medicine; University of Illinois; 1008 W Hazelwood Drive Urbana IL 61802 USA
| | - Cassandra L. Wolsic
- Comparative Biosciences; College of Veterinary Medicine; University of Illinois; 2001 South Lincoln Avenue Urbana IL 61802 USA
| | - Karen L. Campbell
- Veterinary Clinical Medicine; College of Veterinary Medicine; University of Illinois; 1008 W Hazelwood Drive Urbana IL 61802 USA
| | - Sidonie N. Lavergne
- Comparative Biosciences; College of Veterinary Medicine; University of Illinois; 2001 South Lincoln Avenue Urbana IL 61802 USA
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43
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Viral oncolysis - can insights from measles be transferred to canine distemper virus? Viruses 2014; 6:2340-75. [PMID: 24921409 PMCID: PMC4074931 DOI: 10.3390/v6062340] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 06/03/2014] [Accepted: 06/04/2014] [Indexed: 12/12/2022] Open
Abstract
Neoplastic diseases represent one of the most common causes of death among humans and animals. Currently available and applied therapeutic options often remain insufficient and unsatisfactory, therefore new and innovative strategies and approaches are highly needed. Periodically, oncolytic viruses have been in the center of interest since the first anecdotal description of their potential usefulness as an anti-tumor treatment concept. Though first reports referred to an incidental measles virus infection causing tumor regression in a patient suffering from lymphoma several decades ago, no final treatment concept has been developed since then. However, numerous viruses, such as herpes-, adeno- and paramyxoviruses, have been investigated, characterized, and modified with the aim to generate a new anti-cancer treatment option. Among the different viruses, measles virus still represents a highly interesting candidate for such an approach. Numerous different tumors of humans including malignant lymphoma, lung and colorectal adenocarcinoma, mesothelioma, and ovarian cancer, have been studied in vitro and in vivo as potential targets. Moreover, several concepts using different virus preparations are now in clinical trials in humans and may proceed to a new treatment option. Surprisingly, only few studies have investigated viral oncolysis in veterinary medicine. The close relationship between measles virus (MV) and canine distemper virus (CDV), both are morbilliviruses, and the fact that numerous tumors in dogs exhibit similarities to their human counterpart, indicates that both the virus and species dog represent a highly interesting translational model for future research in viral oncolysis. Several recent studies support such an assumption. It is therefore the aim of the present communication to outline the mechanisms of morbillivirus-mediated oncolysis and to stimulate further research in this potentially expanding field of viral oncolysis in a highly suitable translational animal model for the benefit of humans and dogs.
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44
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Gentschev I, Patil SS, Petrov I, Cappello J, Adelfinger M, Szalay AA. Oncolytic virotherapy of canine and feline cancer. Viruses 2014; 6:2122-37. [PMID: 24841386 PMCID: PMC4036544 DOI: 10.3390/v6052122] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 04/22/2014] [Accepted: 04/30/2014] [Indexed: 12/13/2022] Open
Abstract
Cancer is the leading cause of disease-related death in companion animals such as dogs and cats. Despite recent progress in the diagnosis and treatment of advanced canine and feline cancer, overall patient treatment outcome has not been substantially improved. Virotherapy using oncolytic viruses is one promising new strategy for cancer therapy. Oncolytic viruses (OVs) preferentially infect and lyse cancer cells, without causing excessive damage to surrounding healthy tissue, and initiate tumor-specific immunity. The current review describes the use of different oncolytic viruses for cancer therapy and their application to canine and feline cancer.
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Affiliation(s)
- Ivaylo Gentschev
- Department of Biochemistry, University of Wuerzburg, Wuerzburg D-97074, Germany.
| | - Sandeep S Patil
- Department of Biochemistry, University of Wuerzburg, Wuerzburg D-97074, Germany.
| | - Ivan Petrov
- Department of Biochemistry, University of Wuerzburg, Wuerzburg D-97074, Germany.
| | - Joseph Cappello
- Genelux Corporation, San Diego Science Center, San Diego, CA 92109, USA.
| | - Marion Adelfinger
- Department of Biochemistry, University of Wuerzburg, Wuerzburg D-97074, Germany.
| | - Aladar A Szalay
- Department of Biochemistry, University of Wuerzburg, Wuerzburg D-97074, Germany.
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45
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CD40L gene therapy tilts the myeloid cell profile and promotes infiltration of activated T lymphocytes. Cancer Gene Ther 2014; 21:95-102. [PMID: 24481488 DOI: 10.1038/cgt.2014.2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 12/20/2013] [Accepted: 12/21/2013] [Indexed: 01/09/2023]
Abstract
CD40 ligand (CD40L) is a potent stimulator of tumor immunity via its activation of dendritic cells, which in turn initiate T-cell activation. However, T cells are inhibited by suppressive myeloid cells, which constitute an important part of immune evasion. We hypothesized that CD40L may revert the function of suppressive myeloid cells to generate a T-cell stimulatory environment, and this was investigated in the murine bladder cancer model MB49/C57BL/6. Upon intratumoral adenoviral CD40L (AdCD40L) gene therapy, the infiltration of CD11b(+)Gr-1(+) cells was significantly reduced, whereas activated T cells were increased. In vitro, CD40L-expressing MB49 cells tilted the myeloid subpopulations in favor of granulocytic CD11b(+)Gr-1(high) myeloid cells instead of monocytic CD11b(+)Gr-1(int/low) myeloid cells. Further, the level of macrophages in splenocyte co-cultures with MB49 cells was evaluated. In cultures with MB49 cells expressing CD40L, the overall level of macrophages was reduced and the remaining cells were differentiated into M1-like cells. Hence, these data support that CD40L tilts myeloid immune cell populations in favor of anti-tumor immunity (M1) instead of immunosuppression (CD11b(+)Gr-1(int/low) and M2), and this was accompanied by an increased level of activated T cells in the tumor tissue.
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46
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A pRb-responsive, RGD-modified, and hyaluronidase-armed canine oncolytic adenovirus for application in veterinary oncology. Mol Ther 2014; 22:986-98. [PMID: 24448161 DOI: 10.1038/mt.2014.7] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 01/14/2014] [Indexed: 01/10/2023] Open
Abstract
Human and canine cancer share similarities such as genetic and molecular aspects, biological complexity, tumor epidemiology, and targeted therapeutic treatment. Lack of good animal models for human adenovirotherapy has spurred the use of canine adenovirus 2-based oncolytic viruses. We have constructed a canine oncolytic virus that mimics the characteristics of our previously published human adenovirus ICOVIR17: expression of E1a controlled by E2F sites, deletion of the pRb-binding site of E1a, insertion of an RGD integrin-binding motif at the fiber Knob, and expression of hyaluronidase under the major late promoter/IIIa protein splicing acceptor control. Preclinical studies showed selectivity, increased cytotoxicity, and strong hyaluronidase activity. Intratumoral treatment of canine osteosarcoma and melanoma xenografts in mice resulted in inhibition of tumor growth and prolonged survival. Moreover, we treated six dogs with different tumor types, including one adenoma, two osteosarcomas, one mastocitoma, one fibrosarcoma, and one neuroendocrine hepatic carcinoma. No virus-associated adverse effects were observed, but toxicity associated to tumor lysis, including disseminated intravascular coagulation and systemic failure, was found in one case. Two partial responses and two stable diseases warrant additional clinical testing.
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47
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Hemminki A. Oncolytic immunotherapy: where are we clinically? SCIENTIFICA 2014; 2014:862925. [PMID: 24551478 PMCID: PMC3914551 DOI: 10.1155/2014/862925] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Accepted: 12/16/2013] [Indexed: 05/08/2023]
Abstract
Following a century of preclinical and clinical work, oncolytic viruses are now proving themselves in randomized phase 3 trials. Interestingly, human data indicates that these agents have potent immunostimulatory activity, raising the possibility that the key consequence of oncolysis might be induction of antitumor immunity, especially in the context of viruses harboring immunostimulatory transgenes. While safety and efficacy of many types of oncolytic viruses, including adenovirus, herpes, reo, and vaccinia seem promising, few mechanisms of action studies have been performed with human substrates. Thus, the relative contribution of "pure" oncolysis, the immune response resulting from oncolysis, and the added benefit of adding a transgene remain poorly understood. Here, the available clinical data on oncolytic viruses is reviewed, with emphasis on immunological aspects.
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Affiliation(s)
- Akseli Hemminki
- Cancer Gene Therapy Group, Haartman Institute, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland
- TILT Biotherapeutics Ltd., P. Hesperiankatu 37A22, 00260 Helsinki, Finland
- *Akseli Hemminki:
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