Metastatic castration-resistant prostate cancer (mCRPC) is a challenging disease to treat, with poor outcomes for patients. One antitumor vaccine, sipuleucel-T, has been approved as a treatment for mCRPC. DNA vaccines are another form of immunotherapy under investigation. DNA immunizations elicit antigen-specific T cells that cause tumor cell lysis, which should translate to meaningful clinical responses. They are easily amenable to design alterations, scalable for large-scale manufacturing, and thermo-stable for easy transport and distribution. Hence, they offer advantages over other vaccine formulations. However, clinical trials with DNA vaccines as a monotherapy have shown only modest clinical effects against tumors. Standard therapies for CRPC including androgen-targeted therapies, radiation therapy and chemotherapy all have immunomodulatory effects, which combined with immunotherapies such as DNA vaccines, could potentially improve treatment. In addition, many investigational drugs are being developed which can augment antitumor immunity, and together with DNA vaccines can further enhance antitumor responses in preclinical models. We reviewed the literature available prior to July 2020 exploring the use of DNA vaccines in the treatment of prostate cancer. We also examined various approved and experimental therapies that could be combined with DNA vaccines to potentially improve their antitumor efficacy as treatments for mCRPC.

Background: We have previously shown that immune checkpoint receptors, including PD-1, are upregulated on T cells at the time of their activation, and that blockade of these receptors can improve the efficacy of antitumor vaccines. In the present study, we sought to determine whether, and by what mechanisms, the timing of PD-1 blockade with respect to vaccination affects antitumor T cell function. Methods: TRAMP-C1 or E.G7-OVA tumor-bearing mice received PD-1 blockade at different timing intervals with a tumor-associated antigen vaccine. Tumor growth, survival, and immune-infiltrating populations were assessed. In vitro models of T cell activation using OT-I T cells and PD-(L)1 axis disruption with a PD-1 blocking antibody or PD-L1 ^KO dendritic cells were used. Results: Mice receiving PD-1 blockade at the time of T cell activation with vaccine had better antitumor outcomes in comparison to mice receiving PD-1 blockade before or after immunization. T cells activated in vitro in the presence of PD-(L)1 axis disruption had a more differentiated, functional phenotype with decreased CD28 and CCR7 expression and increased production of the Tc1 cytokines IL-2, TNFα, and IFNγ. Intriguingly, a small subset of undifferentiated cells (CD28+) was of a stem-like Tc17 phenotype (IL-17α+, TCF1+). Tumor-bearing mice receiving T cells activated in the presence of PD-(L)1-axis disruption had better antitumor outcomes and a greater number of complete responses. Conclusions: These data indicate that PD-1 blockade, when used with antitumor vaccines, acts primarily at the time of T cell activation, not exclusively within the tumor microenvironment. Consequently, PD-1 blockade may be best used when delivered concurrently with T cell activating agents such as vaccines.

Immunotherapy is now an established therapy for nearly a third of patients with cancer. Most therapies, typically using cytokines or checkpoint blockade therapy, rely on global activation of immune effector cells. The ability of vaccines to activate specific populations of cells has led to a renewed interest in their ability to treat cancers, either alone or with other immune therapies or other conventional therapies. The COVID-19 pandemic sparked a new interest in nucleic acid vaccines with the development of new technologies and the short manufacturing time for vaccine implementation. Nucleic acid-based cancer vaccines have been studied for decades, but have shown modest anti-tumor efficacy as monotherapies, as many of these vaccines encode for shared tumor-associated antigens (TAAs) and must overcome immune tolerance. New developments, technologies, routes of delivery, and combination therapies have paved the way for new approaches and clinical trials involving nucleic acid vaccines for the treatment of cancer. Here we review mRNA and pDNA vaccines for the treatment of cancer, including similarities and differences in their mechanisms of action, an overview of these treatment modalities in preclinical and clinical studies, methods to improve these vaccine strategies, and exciting new combination approaches in development.

Peptide vaccines offer a direct way to initiate an immunogenic response to a defined antigen epitope. However, peptide vaccines are unstable in vivo, subject to rapid enzymatic proteolysis. Replacement of an α-amino acid residue with a homologous β-amino acid residue (native side chain, but backbone extended by a single CH₂ unit) impairs proteolysis at nearby amide bonds. Therefore, antigen analogues containing α-to-β replacements have been examined for functional mimicry of native all-α antigens. Another group previously took this approach in the ovalbumin (OVA) antigen model by evaluating single α-to-β analogues of the murine major histocompatibility complex (MHC) I-restricted peptide SIINFEKL. We re-examined this set of α/β SIINFEKL antigens. We tested the susceptibility to proteolysis in mouse serum and their ability to activate OVA-antigen-specific CD8 T cells in vitro. Additionally, we tested the α/β antigens in vivo for their ability to induce an antigen-specific immunogenic response in naïve mice and in OVA-expressing tumor-bearing mice. The α/β antigens were comparable to the native antigen in their susceptibility to proteolysis in serum. Each α/β antigen was capable of activating antigen-specific CD8 T cells in vitro. However, antigen-specific CD8 T cells induced against α/β antigens in vivo were not cross-reactive to the native antigen. Moreover, immunization with α/β analogues did not elicit anti-tumor effects in tumor-bearing mice. We conclude that even though α/β analogues of the SIINFEKL antigen can elicit a T cell-based response, this class of backbone-modified peptides is not promising from the perspective of antitumor vaccine development.

Cancer remains one of the most pressing global health challenges, with immunotherapy being a promising treatment option. However, numerous clinical challenges, such as recurrence and resistance, persist, underscoring the urgent need for a deeper understanding of the mechanisms that influence immune responses in cancer. Polo-like kinases (PLK), a family of enzymes with five members, PLK1 through PLK5, have been implicated in cancer progression, and their inhibition is being actively explored for cancer management. Although past studies of the PLK family are largely confined to their role in the cell cycle and corresponding chromatin dynamics, recent research has unveiled important connections between PLKs and cancer immunity, particularly in relation to critical signaling pathways such as interferon (IFN) signaling, immunogenic cell death, transforming growth factor beta (TGFβ) signaling, and FAS/FASL signaling. Although much of the research has focused on PLK1, additional members of the PLK family are beginning to attract attention due to their potential implications in cancer immunity. Understanding the intricate role of PLKs in cancer immunity is an emerging field with tremendous potential. This review offers a comprehensive overview of current knowledge connecting the members of the PLK family with cancer immunology and provides considerations for further research to uncover how PLK signaling can be strategically targeted to optimize cancer immunotherapy and enhance clinical responses.

Background: Peptide-loaded antigen-presenting cell (APC)-based vaccines have been under investigation as a therapeutic approach for treating cancer. However, in general they have demonstrated limited efficacy in clinical trials. Dendritic cells (DCs) have been the primary choice for APC-based vaccines given their ability to cross-present antigens. B cells have been less studied as APCs for vaccines. Here we compare the phenotype and anti-tumor activity of activated T cells that result from peptide-specific priming using either B cells or DCs. Methods: B cells and DCs were isolated from C57Bl/6 mice, and either treated or not treated with lipopolysaccharide (LPS) for maturation, and then either loaded or not loaded with SIINFEKL peptide to prime CD8+ T cells from OT-1 mice. Activated T cells were then analyzed for their phenotype and anti-tumor efficacy. Results: We report that both immature B cells and immature DCs were similarly capable of activating antigen-specific CD8+ T cells. However, LPS-matured DCs generated a stronger CD8+ T cell activation profile in vitro compared to LPS-matured B cells. Immature B cells, mature DCs and immature DCs all generated a similar anti-tumor response upon adoptive transfer of primed CD8+ T cells to tumor-bearing mice. Conclusions: Collectively, our data suggests that B cells and DCs are each capable of priming CD8+ T cells and generating anti-tumor responses. Given that B cells are relatively easier to culture and expand compared to DCs, our study suggests that, following further validation, B cells could be further investigated as APCs for peptide-based human cancer vaccines.