Therapeutic cancer vaccines: From biological mechanisms and engineering to ongoing clinical trials

Abstract

Therapeutic vaccines are currently at the forefront of medical innovation. Various endeavors have been made to develop more consolidated approaches to producing nucleic acid-based vaccines, both DNA and mRNA vaccines. These innovations have continued to propel therapeutic platforms forward, especially for mRNA vaccines, after the successes that drove emergency FDA approval of two mRNA vaccines against SARS-CoV-2. These vaccines use modified mRNAs and lipid nanoparticles to improve stability, antigen translation, and delivery by evading innate immune activation. Simple alterations of mRNA structure- such as non-replicating, modified, or self-amplifying mRNAs- can provide flexibility for future vaccine development. For protein vaccines, the use of long synthetic peptides of tumor antigens instead of short peptides has further enhanced antigen delivery success and peptide stability. Efforts to identify and target neoantigens instead of antigens shared between tumor cells and normal cells have also improved protein-based vaccines. Other approaches use inactivated patient-derived tumor cells to elicit immune responses, or purified tumor antigens are given to patient-derived dendritic cells that are activated in vitro prior to reinjection. This review will discuss recent developments in therapeutic cancer vaccines such as, mode of action and engineering new types of anticancer vaccines, in order to summarize the latest preclinical and clinical data for further discussion of ongoing clinical endeavors in the field.

Keywords: Cancer vaccines; Checkpoint inhibitors; Neoadjuvant; Neoantigens; SARS-CoV-2; Synthetic long peptides; mRNA vaccines.

Fig. 1

The Main Types of Cancer Therapeutic Vaccines: Cancer vaccines primarily deliver antigens either nucleic acids, proteins, peptides, or patient-derived cells. Within nucleic acid-based vaccines, RNA has various approaches that differ with RNA structure manipulation and delivery compared to DNA, which is restricted by exclusively relying on plasmids to deliver antigen-encoding genetic materials. Both mRNA and DNA are taken up by cells and eventually translated into protein antigens APCs present to activate T cells. Cellular vaccines depend on patient-derived cells to deliver isolated tumor cells that are killed, or the patient’s DCs are activated in vitro with purified tumor antigens before reinjection. All therapeutic cancer vaccine types aim for antigen presentation followed by T cell activation and tumor rejection. Abbreviations: DC, Dendritic Cells; SAM, virus-derived self-amplifying mRNAs; SLP, synthetic long peptide.

Fig. 2

Identification of neoantigens: Tumor-specific mutations are identified using whole-exome sequencing (WES), confirmed by RNA sequencing, then ranked by predicted affinity binding to HLA types; finally, neoantigens are synthesized based on mutated alleles followed by ex vivo T-cell reactivity analysis to confirm the immunogenicity.