Coadministration of a Plasmid Encoding HIV-1 Gag Enhances the Efficacy of Cancer DNA Vaccines

DNA vaccine can be modified to increase protein production and modulate immune response. To enhance the efficiency of a P815 mastocytoma DNA vaccine, the P1A gene sequence was optimized by substituting specific codons with synonymous ones while modulating the number of CpG motifs. The P815A murine antigen production was increased with codon-optimized plasmids. The number of CpG motifs within the P1A gene sequence modulated the immunogenicity by inducing a local increase in the cytokines involved in innate immunity. After prophylactic immunization with the optimized vaccines, tumor growth was significantly delayed and mice survival was improved. Consistently, a more pronounced intratumoral recruitment of CD8+ T cells and a memory response were observed. Therapeutic vaccination was able to delay tumor growth when the codon-optimized DNA vaccine containing the highest number of CpG motifs was used. Our data demonstrate the therapeutic potential of optimized P1A vaccine against P815 mastocytoma, and they show the dual role played by codon optimization on both protein production and innate immune activation.

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“… 44 The upregulation of these cytokines was correlated with the potentiation of the immune response induced by the delivered DNA. 44 , 45 …”

Section: Resultsmentioning

confidence: 99%

Codon-Optimized P1A-Encoding DNA Vaccine: Toward a Therapeutic Vaccination against P815 Mastocytoma

Lopes

Vanvarenberg

Préat

et al. 2017

Molecular Therapy - Nucleic Acids

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“…Optimized cancer DNA vaccines demonstrated good efficacy in different preclinical models [37], especially in prophylactic models, and showed a great safety profile in humans. Unfortunately, the success in therapeutic vaccination is still limited even in preclinical models [37, 40]. This limitation is mostly due to the different mechanisms of resistance during tumor development, such as a loss or change of epitopes recognized by immune cells, T cell exhaustion, antigen tolerance, and the infiltration of immunosuppressive cells (regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), etc.…”

Section: Introductionmentioning

confidence: 99%

Cancer DNA vaccines: current preclinical and clinical developments and future perspectives

Lopes

Vandermeulen

Préat

2019

J Exp Clin Cancer Res

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267

181

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The recent developments in immuno-oncology have opened an unprecedented avenue for the emergence of vaccine strategies. Therapeutic DNA cancer vaccines are now considered a very promising strategy to activate the immune system against cancer. In the past, several clinical trials using plasmid DNA vaccines demonstrated a good safety profile and the activation of a broad and specific immune response. However, these vaccines often demonstrated only modest therapeutic effects in clinical trials due to the immunosuppressive mechanisms developed by the tumor. To enhance the vaccine-induced immune response and the treatment efficacy, DNA vaccines could be improved by using two different strategies. The first is to increase their immunogenicity by selecting and optimizing the best antigen(s) to be inserted into the plasmid DNA. The second strategy is to combine DNA vaccines with other complementary therapies that could improve their activity by attenuating immunosuppression in the tumor microenvironment or by increasing the activity/number of immune cells. A growing number of preclinical and clinical studies are adopting these two strategies to better exploit the potential of DNA vaccination. In this review, we analyze the last 5-year preclinical studies and 10-year clinical trials using plasmid DNA vaccines for cancer therapy. We also investigate the strategies that are being developed to overcome the limitations in cancer DNA vaccination, revisiting the rationale for different combinations of therapy and the different possibilities in antigen choice. Finally, we highlight the most promising developments and critical points that need to be addressed to move towards the approval of therapeutic cancer DNA vaccines as part of the standard of cancer care in the future.

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“…GET of multiple genes has been previously used for CRISPR/Cas9 technology [ 20 ] and for the preparation of induced pluripotent stem cells [ 21 ]. Moreover, it has also been used for the combined delivery of DNA vaccines and immune adjuvants [ 22 ] and for the delivery of multiple therapeutic genes in vivo [ 23 ]. The latter was also confirmed in this study, since the RT-PCR results showed that after GET, both TNFα and IL-12 mRNA levels increased significantly.…”

Section: Discussionmentioning

confidence: 99%

Antitumor in situ vaccination effect of TNFα and IL-12 plasmid DNA electrotransfer in a murine melanoma model

Kamenšek

Čemažar

Tratar

et al. 2018

Cancer Immunol Immunother

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Gene electrotransfer (GET) is one of the most efficient non-viral gene therapy approaches for the localized transfer of multiple genes into tumors in vivo; therefore, it is especially promising for delivering different cytokines that are toxic if administered systemically. In this study, we used concomitant intratumoral GET of two cytokines: tumor necrosis factor alpha (TNFα), a potent cytotoxic cytokine to induce in situ vaccination, and interleukin 12 (IL-12), an immunostimulatory cytokine to boost the primed local immune response into a systemic one. After performing GET in murine melanoma tumors, both TNFα and IL-12 mRNA levels were significantly increased, which resulted in a pronounced delay in tumor growth of 27 days and a prolonged survival time of mice. An antitumor immune response was confirmed by extensive infiltration of immune cells in the tumor site, and expansion of the effector immune cells in the sentinel lymph nodes. Furthermore, the effect of in situ vaccination was indicated by the presence of vitiligo localized to the treatment area and resistance of the mice to secondary challenge with tumor cells. Intratumoral GET of two cytokines, one for in situ vaccination and one for an immune boost, proved feasible and effective in eliciting a potent and durable antitumor response; therefore, further studies of this approach are warranted.

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Coadministration of a Plasmid Encoding HIV-1 Gag Enhances the Efficacy of Cancer DNA Vaccines

Cited by 20 publications

References 35 publications

Codon-Optimized P1A-Encoding DNA Vaccine: Toward a Therapeutic Vaccination against P815 Mastocytoma

Codon-Optimized P1A-Encoding DNA Vaccine: Toward a Therapeutic Vaccination against P815 Mastocytoma

Cancer DNA vaccines: current preclinical and clinical developments and future perspectives

Antitumor in situ vaccination effect of TNFα and IL-12 plasmid DNA electrotransfer in a murine melanoma model

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