Cancer vaccines: an update on recent achievements and prospects for cancer therapy

Abstract

Decades of basic and translational research have led to a momentum shift in dissecting the relationship between immune cells and cancer. This culminated in the emergence of breakthrough immunotherapies that paved the way for oncologists to manage certain hard-to-treat cancers. The application of high-throughput techniques of genomics, transcriptomics, and proteomics was conclusive in making and expediting the manufacturing process of cancer vaccines. Using the latest research technologies has also enabled scientists to interpret complex and multiomics data of the tumour mutanome, thus identifying new tumour-specific antigens to design new generations of cancer vaccines with high specificity and long-term efficacy. Furthermore, combinatorial regimens of cancer vaccines with immune checkpoint inhibitors have offered new therapeutic approaches and demonstrated impressive efficacy in cancer patients over the last few years. In the present review, we summarize the current state of cancer vaccines, including their potential therapeutic effects and the limitations that hinder their effectiveness. We highlight the current efforts to mitigate these limitations and highlight ongoing clinical trials. Finally, a special focus will be given to the latest milestones expected to transform the landscape of cancer therapy and nurture hope among cancer patients.

Keywords: cancer immunity; cancer vaccine; cancer vaccine platforms; immunotherapy; tumour resistance.

Fig. 1

Principles of cancer-immunity interaction. 1: DCs encounter cancer antigens resulting from cancer cell death or from different cancer vaccine platforms, and after DCs internalize cancer antigens, they process them and load them onto MHC (I, II) on their surface membrane. 2: Once DCs have loaded tumour antigens, they migrate to lymph nodes via lymphatic vessels, where they present cancer antigens to lymphocytes via MHC II to CD4 + and MHC I to CD8 + . In addition to costimulatory molecules, they lead to T-cell priming and activation. After T cells expand and differentiate into effector T cells (Th and CTLs), they travel through blood vessels to infiltrate tumour sites; they bind tumour antigens exposed to cancerous cells via MHC molecules and kill them either by releasing inflammatory cytokines (IFN-γ and TNF-α) or inducing cancer cell apoptosis via their cytotoxic molecules (PRFs and GRNZs). Cancer epitopes can be captured by DCs peripherally or intratumourally, allowing the cycle to restart with refreshed and strengthened immune responses. CD40, CD80, CD86, CD40L, and CD28 are clusters of differentiation molecules located on the cell surface; they act as amplifiers of T-cell activation, differentiation, and influencers of their fate. IFN-γ and TNF-α are inflammatory cytokines implicated in several signalling cascades leading to pathogens elimination

Fig. 2

Examples of tumour resistance mechanisms. 1: Tolerogenic dendritic cells (TLDCs) are characterized by weak capture of cancer antigens, low expression of major histocompatibility complex (MHC) and costimulatory molecules, high expression of inhibitory molecules and regulatory cytokines (FAS, PDL-1, TGF-β, and IL-10) and impaired ability to promote T-cell activation and expansion. 2: After TLDCs migrate to the tumour-draining lymph node (TDLN), they bind to T cells via inhibitory molecules, resulting in T-cell deactivation. Moreover, TLDCs induce T-cell anergy by favouring Treg phenotype expansion. 3: Within the TME, cancer cells use their setups to escape the immune system, reducing cancer antigen exposure and altering some immune stimulatory signalling pathways, thus becoming unrecognized and insensitive to T-cell destruction. In addition, the metabolic stress conditions (low glucose levels, hypoxia, acidity, and oxidative stress) of the TME have a detrimental effect on T-cell functions, as they drive them towards exhaustion

Fig. 3

Tumour-associated peptide-based cancer vaccines: the diagram briefly illustrates methods used to select and design personalized tumour peptide-based cancer vaccines. 1 Tumour and normal tissues were harvested from cancerous patients. 2 Comparative transcriptomic analyses were performed to evaluate mRNA transcript expression in both tissues using microarray or NGS techniques. 3 Tumour tissues are also used to characterize and identify MHC peptides by mass spectrometry (MS). Four peptide sequences were identified using search engines to map the acquired spectra on either general protein databases (such as UniProt) or custom proteome databases originating from the transcriptome assembly (proteogenomic approach). 5 A handful of peptides are selected and tested for their immunogenicity by incubating them with peripheral immune cells (PBMCs) from healthy donors. 6 T-cell reactivity towards the screened tumour-associated MHC peptides was assessed by an ICS using flow cytometry, and only highly immunogenic peptides were chosen as the best candidates for vaccine formulations

Fig. 4

Laboratory-scale production of adenovirus vector-based cancer vaccines [119] Based on the desired clinical benefit, recombinant adenovirus vectors (rAdVs) designed with genes of interest, including tumour-associated antigens, were cloned and inserted into shuttle plasmids. Subsequently, genes are integrated into the adenovirus genome. The adenoviral backbone carrying genes of interest might delete viral replication regions (E1 or E3 codon regions) in the case of replication-defective AdV vectors or modify the viral genome to generate adenovirus replicative-competent vectors that replicate exclusively in cancer cells. Once the rAdV backbone vector is engineered, packaging cells (e.g. the HEK 293, A549, and PERC6 cell lines) are transfected with linearized rAdV clones. After the cytopathic effect (CPE) occurred, the adenovirus vectors were restored, the cells were allowed to proliferate, and the cells were harvested when the viral plaques became visible under a microscope. Harvested rAdV vectors were purified by caesium chloride gradient ultracentrifugation and concentrated through flow columns. Their concentration was calculated by spectrophotometry and calculated as the number of virus particles (Vp)/ml. Before formulation, rAdVs undergo quality control testing to confirm their genetic stability and assess their potency and immunogenicity. Production methods can be optimized and scaled up to meet industrial manufacturing process requirements

Fig. 5

Design of recombinant adeno-associated virus (rAAV) vectors. Once the rAAV backbones are constructed, packaging HEK293 cells are transfected to expand the rAAV vectors. After expansion, the rAAV vectors were purified, and their concentration was calculated by spectrophotometry

Fig. 6

Mechanism of action and mitigation strategies for cancer vaccines. This diagram illustrates the mechanism of action of different cancer vaccines covered throughout this review. Diverse mitigation strategies (highlighted in green) are employed to enhance the efficacy of cancer vaccine platforms and unleash the cancer-immunity cycle