Abstract
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.
Highlights
Over the last few years, immunotherapy has received increasing attention as a strategy for cancer treatment, and many different approaches are being developed to improve the clinical outcome in cancer patients [1]
Results of completed clinical trials Many already completed clinical trials tested the efficacy of DNA vaccines against different tumor types, such as breast, cervical, pancreatic and prostate cancers, multiple myeloma, and melanoma
VGX-3100 elicited significantly increased frequencies of antigen-specific activated CD8+ T cells and a higher humoral response compared to the placebo, making it the first therapeutic vaccine to elicit a complete adaptive immune response in patients with preinvasive cervical disease caused by HPV-16 and 18 [123]
Summary
Over the last few years, immunotherapy has received increasing attention as a strategy for cancer treatment, and many different approaches are being developed to improve the clinical outcome in cancer patients [1]. DNA vaccines are plasmids designed to deliver genes encoding TAs, eliciting or augmenting the adaptive immune response towards TA-bearing tumor cells. Quaglino et al found that the plasmid encoding the chimeric neu-Her-2 antigen was superior to both the fully autologous and the fully xenogeneic vaccines in inducing a protective antitumor immune response against ErbB2+ tumors [48] Starting from these results, other DNA vaccines were constructed by shuffling genes from mouse, rat, human and other species, improving the antigen immunogenicity and vaccine efficacy [49–52]. The presence of immunodominant and unconventional epitopes simultaneously delivered by a polyepitope DNA vaccine can induce a broad CTL response specific to multiple antigens [69] In this way, it is possible to overcome the antigen mutation or deletion by tumor cells, the variation or absence of the appropriate T cell repertoire and the MHC haplotype in patients [69]. - Vaccine: 100 μg, 6 doses every 2 W and 12, 24, 36 and 48 or 100 μg at W 0, 2, 12, 14, 24, 26, 36, 38, 48, 50
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