Personalized cancer vaccines face two challenges: the immunogenicity of tumor antigens and tumor immune suppression. To eliminate these two obstacles, it can be solved from vaccine formulations and combined tumor vaccination. The vaccine group can enhance the immunogenicity of the tumor antigen by a carrier, a vehicle, an immune-stimulating agent, a preparation for inhibiting the inhibition signal, and a preparation for improving the microenvironment. Cancer vaccination protocols require combination immunotherapies to overcome tumor immune-evasion. More and more evidence suggests that combined with other therapies can target immunosuppressive pathways and fully release the effectiveness of cancer vaccines.
The main mechanism of action of personalized tumor vaccines is to activate tumor-specific T lymphocytes, including CD8+ T lymphocytes and CD4+ T lymphocytes, to kill and inhibit tumor cells through these cells, thereby producing therapeutic effects. T cell activation depends on 3 signals. Tumor-specific, unsensitized T cells are recognized by TCR by MHC class I or class II molecules on the surface of DCs or tumor cells, then producing a first activation signal. Only the first activation signal does not fully activate tumor-specific T lymphocytes, and it also causes T cells to be incapable or induce regulatory T cells (Tregs). For full activation, tumor-specific T cells must receive a second activation signal, also known as costimulatory signals, generated by the interaction of co-stimulatory molecules on the surface of T cells with ligand molecules on the surface of DCs. Activation of CD8+ T cells also requires a third activation signal, the cytokine signal, which determines whether it is activated or enters a tolerant state after receiving antigen and co-stimulation. T lymphocytes activate the expression of inhibitory molecules to transmitting inhibitory signals, thus inhibiting T cell activation inhibition signals maintain T cell activation, and improving micro-environmental signals can relieve immunosuppression. Therefore, the preparation for enhancing the first signal, the second signal, the third signal, or suppressing the T cell activation inhibition signal and the tumor immunosuppressive microenvironment can be used as a personalized tumor vaccine adjuvant.
Materials that improve the stability of tumor antigens, delivered, processed, and presented to T cells can be considered as adjuvants that enhance the first signal. A variety of formulations protect the antigens of individualized tumor vaccines against degradation, including nanoparticles, gold particles, alums, and oil-water-based emulsifiers, lipid-based vesicles and bacterial ghosts. These formulations may also be used as an antigen delivery system to enhance tumor antigen uptake, processing and presentation.Biodegradable particles, including liposomes to acid-degradable hydrogels, synthetic polymers, polylactic-acid-glycolic acid (PLGA), mesoporous silica rods (MSRs), are effective in delivering antigens and activating DCs in vivo.. MSRs are easily injected subcutaneously and spontaneously form a three-dimensional skeleton at the subcutaneous injection site. Due to their biodegradability, they dissolve within a few months after inoculation. Formulations that promote antigen cross-presentation and determinant spreading can also be considered as adjuvants that enhance the first signal. Heat shock proteins have been found to promote cross-presentation of tumor antigens.
Pathogen-associated molecular patterns (PAMPs) and their mimics and endogenous hazard-related membranes molecular patterns (DAMPs) are all likely to be signal 2-triggering adjuvants. PAMPs include TLR agonists such as bacterial lipopolysaccharide (LPS) and its chemical modification monophosphoryl lipid-A (MPL), microbial RNA or DNA, CpG ODN. DAMPs include heat shock proteins, high mobility group box1 (HMGB1), mitochondrial DNA, and ATP. PAMPs and DAMPs up-regulate co-stimulatory molecules of APCs by acting on pattern recognition receptors (PRRs) of innate immune cells, activating innate immune responses. PRRs include Toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors, and retinoic acid-inducible gene-1-like receptors and C-type lectin receptors. PRR agonists may be adjuvants for personalized tumor vaccines because of their up-regulation of APCs costimulatory molecules.
Multiple cytokines provide a third signal for anti-tumor T cell activation, possibly as a personalized tumor
Vaccine adjuvants, such as low-dose GM-CSF, can recruit activated APCs at individualized tumor vaccine injection sites, however, high-dose GM-CSF (>100 μg/time) can amplify myeloid-derived suppressor cells (MDSCs), thus inhibiting T cell function. T cell-agonistic cytokines and tumor vaccines have synergistic effects. A variety of PRR agonists can stimulate innate immune cells to produce inflammatory cytokines, which may become the third signal for tumor-specific T cell activation, such as polyinosinic-polycytidylic acid with poly-lysine (poly ICs: LC) and LPS stimulate DCs to produce inflammatory cytokines， providinga suitable environment for individualized tumor vaccines to function.
The surface of activated T cells can express a variety of T cell inhibitory receptors, also known as immune checkpoint receptors (ICR). ICR antibodies, also known as immune checkpoint inhibitors (ICIs), may also be used as adjuvants for personalized tumor vaccines because they maintain sustained activation of tumor-specific T lymphocytes. Cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD1) are two typical ICRs. CTLA-4 and PD1 inhibit T cell transduction signaling, which limits the activation of tumor-specific T cells and inhibits their killing of tumor cells. Anti-PD-1/ PD-L1 enhances the effect of new epitope vaccines on the activation of TH1+ and CD8+ memory T cells.Solid tumor cells typically "create" immunosuppressive tumor microenvironment by inducing inhibitory cells and inhibitors. Inhibitory cells include regulatory T cells (Tregs), MDSCs, and tumor-associated macrophages (TAMs). Tregs secrete immunosuppressive cytokines such as IL-10 and TGF-β. MDSC can also produce a variety of immunosuppressive molecules such as Arginase I, iNOS, TGF-β and IL-10. TAM is widely seen in tumor tissues and has the function of inhibiting anti-tumor T cells. This immunosuppressive tumor microenvironment will curb the functioning of individualized tumor vaccines. Based on this understanding, "inhibiting inhibitory cells" and "inhibiting inhibitory factors" preparations may become adjuvants for personalized tumor vaccines by altering the immunosuppressive tumor microenvironment.Multi-adjuvant personalized cancer vaccines were prepared using novel epitope synthetic peptides or TLs and various adjuvants.
DCs are the most important APCs for presenting tumor antigens to tumor-specific T cells, and DCs stimulate different immune responses in different tissue compartments. In order to stimulate effective anti-tumor T cell immunity that produces tumor therapeutic effects, personalized tumor vaccines should be vaccinated by a pathway that is effective in activating DCs. Commonly used routes are subcutaneous, intradermal, intramuscular, and intradal. After inoculation, in order for tumor antigens to enter regional draining lymph nodes, DCs should be ensured to maximize exposure to tumor antigens. In addition to the above routes, intratumoral vaccination may also be selected to allow tumor antigens to be taken up by tumor-infiltrating DCs (TIDCs).