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Shi S, Zhang L, Zheng A, Xie F, Kesse S, Yang Y, Peng J, Xu Y. Enhanced anti-tumor efficacy of electroporation (EP)-mediated DNA vaccine boosted by allogeneic lymphocytes in pre-established tumor models. Cancer Immunol Immunother 2024; 73:248. [PMID: 39358555 PMCID: PMC11447239 DOI: 10.1007/s00262-024-03838-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 09/17/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND Tumor-reactive T cells play a crucial role in anti-tumor responses, but T cells induced by DNA vaccination are time-consuming processes and exhibit limited anti-tumor efficacy. Therefore, we evaluated the anti-tumor effectiveness of reactive T cells elicited by electroporation (EP)-mediated DNA vaccine targeting epidermal growth factor receptor variant III (pEGFRvIII plasmid), in conjunction with adoptive cell therapy (ACT), involving the transfer of lymphocytes from a pEGFRvIII EP-vaccinated healthy donor. METHODS The validation of the established pEGFRvIII plasmid and EGFRvIII-positive cell model was confirmed through immunofluorescence and western blot analysis. Flow cytometry and cytotoxicity assays were performed to evaluate the functionality of antigen-specific reactive T cells induced by EP-mediated pEGFRvIII vaccines, ACT, or their combination. The anti-tumor effectiveness of EP-mediated pEGFRvIII vaccines alone or combined with ACT was evaluated in the B16F10-EGFRvIII tumor model. RESULTS EP-mediated pEGFRvIII vaccines elicited serum antibodies and a robust cellular immune response in both healthy and tumor-bearing mice. However, this response only marginally inhibited early-stage tumor growth in established tumor models. EP-mediated pEGFRvIII vaccination followed by adoptive transfer of lymphocytes from vaccinated healthy donors led to notable anti-tumor efficacy, attributed to the synergistic action of antigen-specific CD4+ Th1 cells supplemented by ACT and antigen-specific CD8+ T cells elicited by the EP-mediated DNA vaccination. CONCLUSIONS Our preclinical studies results demonstrate an enhanced anti-tumor efficacy of EP-mediated DNA vaccination boosted with adoptively transferred, vaccinated healthy donor-derived allogeneic lymphocytes.
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Affiliation(s)
- Sanyuan Shi
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China
| | - Luchen Zhang
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China
| | - Anjie Zheng
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China
| | - Fang Xie
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China
| | - Samuel Kesse
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China
| | - Yang Yang
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China
| | - Jinliang Peng
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China.
| | - Yuhong Xu
- School of Pharmacy, Shanghai Jiao Tong University, No.800, Dongchuan Rd, Shanghai, 200240, People's Republic of China.
- School of Pharmacy, Dali University, No. 22, Snowman Rd, Dali City, 671000, People's Republic of China.
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Tsounis EP, Mouzaki A, Triantos C. Nucleic acid vaccines: A taboo broken and prospect for a hepatitis B virus cure. World J Gastroenterol 2021; 27:7005-7013. [PMID: 34887624 PMCID: PMC8613654 DOI: 10.3748/wjg.v27.i41.7005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/07/2021] [Accepted: 10/14/2021] [Indexed: 02/06/2023] Open
Abstract
Although a prophylactic vaccine is available, hepatitis B virus (HBV) remains a major cause of liver-related morbidity and mortality. Current treatment options are improving clinical outcomes in chronic hepatitis B; however, true functional cure is currently the exception rather than the rule. Nucleic acid vaccines are among the emerging immunotherapies that aim to restore weakened immune function in chronically infected hosts. DNA vaccines in particular have shown promising results in vivo by reducing viral replication, breaking immune tolerance in a sustained manner, or even decimating the intranuclear covalently closed circular DNA reservoir, the hallmark of HBV treatment. Although DNA vaccines encoding surface antigens administered by conventional injection elicit HBV-specific T cell responses in humans, initial clinical trials failed to demonstrate additional therapeutic benefit when administered with nucleos(t)ide analogs. In an attempt to improve vaccine immunogenicity, several techniques have been used, including codon/promoter optimization, coadministration of cytokine adjuvants, plasmids engineered to express multiple HBV epitopes, or combinations with other immunomodulators. DNA vaccine delivery by electroporation is among the most efficient strategies to enhance the production of plasmid-derived antigens to stimulate a potent cellular and humoral anti-HBV response. Preliminary results suggest that DNA vaccination via electroporation efficiently invigorates both arms of adaptive immunity and suppresses serum HBV DNA. In contrast, the study of mRNA-based vaccines is limited to a few in vitro experiments in this area. Further studies are needed to clarify the prospects of nucleic acid vaccines for HBV cure.
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Affiliation(s)
- Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, Patras 26504, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, Patras 26504, Greece
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Affiliation(s)
- Lucyna Cova
- INSERM U1052, Centre de Recherche en Cancérologie de Lyon (CRCL), University Lyon 1, Lyon, France
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Abstract
In the two decades since their initial discovery, DNA vaccines technologies have come a long way. Unfortunately, when applied to human subjects inadequate immunogenicity is still the biggest challenge for practical DNA vaccine use. Many different strategies have been tested in preclinical models to address this problem, including novel plasmid vectors and codon optimization to enhance antigen expression, new gene transfection systems or electroporation to increase delivery efficiency, protein or live virus vector boosting regimens to maximise immune stimulation, and formulation of DNA vaccines with traditional or molecular adjuvants. Better understanding of the mechanisms of action of DNA vaccines has also enabled better use of the intrinsic host response to DNA to improve vaccine immunogenicity. This review summarizes recent advances in DNA vaccine technologies and related intracellular events and how these might impact on future directions of DNA vaccine development.
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Affiliation(s)
- Lei Li
- a Vaxine Pty Ltd, Bedford Park , Adelaide , Australia.,b Department of Diabetes and Endocrinology , Flinders University, Flinders Medical Centre , Adelaide , SA , Australia
| | - Nikolai Petrovsky
- a Vaxine Pty Ltd, Bedford Park , Adelaide , Australia.,b Department of Diabetes and Endocrinology , Flinders University, Flinders Medical Centre , Adelaide , SA , Australia
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