The Five Immune Forces Impacting DNA-Based Cancer Immunotherapeutic Strategy

Abstract

DNA-based vaccine strategy is increasingly realized as a viable cancer treatment approach. Strategies to enhance immunogenicity utilizing tumor associated antigens have been investigated in several pre-clinical and clinical studies. The promising outcomes of these studies have suggested that DNA-based vaccines induce potent T-cell effector responses and at the same time cause only minimal side-effects to cancer patients. However, the immune evasive tumor microenvironment is still an important hindrance to a long-term vaccine success. Several options are currently under various stages of study to overcome immune inhibitory effect in tumor microenvironment. Some of these approaches include, but are not limited to, identification of neoantigens, mutanome studies, designing fusion plasmids, vaccine adjuvant modifications, and co-treatment with immune-checkpoint inhibitors. In this review, we follow a Porter's analysis analogy, otherwise commonly used in business models, to analyze various immune-forces that determine the potential success and sustainable positive outcomes following DNA vaccination using non-viral tumor associated antigens in treatment against cancer.

4-1BBL as a Mediator of Cross-Talk between Innate, Adaptive, and Regulatory Immunity against Cancer

“…Vaccines that rely on antigen specificity offer the greatest advantage compared to other non-specific conventional therapies such as tumor resection, radiotherapy, and antitumor chemotherapy [32]. However, given the existence of resistance mechanisms in 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 [11], the need arises to associate these antigens with molecules that improve the immune response [33].…”

Combination of immune checkpoint blockade with DNA cancer vaccine induces potent antitumor immunity against P815 mastocytoma

“…Immunotherapy is an established approach to treat cancer based on the observation that the immune system can mount destructive responses against tumors. A major goal of immunotherapy is to develop a specific immune response against tumor-associated antigens (TAAs), which are derived from proteins that are specifically or preferentially expressed in tumor cells in comparison to non-transformed healthy cells 1 . DNA vaccines represent a good strategy to prime T cell responses against TAAs 2 .…”

Immunogenicity of Tumor Initiating Stem Cells: Potential Applications in Novel Anticancer Therapy

“…Expression of neo-antigens in TISCs is a result of genomic DNA mutations resulting in the production of tumor-associated antigens (64, 65). As the antigenic peptide epitopes of these neo-antigens are not significantly affected by central T-cell tolerance compared with non-mutated self-antigens (Figure 3), these neo-antigens could offer attractive peptide-base anti-cancer vaccine strategies (66). With the advent of mass spectrometry and next-generation exome sequencing tools, neo-antigens are expected to play a critical role in personalized cancer medicine (67, 68).…”