A recent Nature Reviews Immunology study discusses challenges related to the event and design of neoantigen cancer vaccines.

Study: Challenges in developing personalized neoantigen cancer vaccines. Image Credit: Lightspring / Shutterstock.com

Development of cancer therapy using neoantigens

Several genetic aspects are related to cancer manifestations, including DNA mutations, deletion, fusions, and translocation. It’s imperative to know the technique of tumorigenesis to discover potential targets essential for developing effective cancer therapies.

After genomic mutations of cancer cells, altered or latest protein products are generated. These proteins are antigenically novel for the host and known as neoantigens, that are recognized as foreign by the host immune system. Based on neoantigens, several immunotherapies, reminiscent of adoptive T-cell therapies and immune checkpoint blockade (ICB) therapy, have been developed.

Cancer-associated neoantigens have been used to develop therapeutic vaccines that specifically goal the tumor without affecting healthy tissues. Most clinical cases exhibit endogenous T-cell responses induced by these vaccines, that are unable to regulate the proliferation of cancer cells. Thus, there stays an urgent need for brand new therapeutic vaccines that may enhance or induce T-cell responses against neoantigens and improve anticancer immunity.

Smaller clinical trials of many neoantigen vaccines, including NCT03897881 for melanoma and NCT04161755 for pancreatic cancer, have shown promise for future use. Nonetheless, before commercialization, several challenges related to these vaccines should be addressed to optimize their safety and efficacy.

Challenges of developing effective neoantigen cancer vaccines

The efficacy of any vaccine will depend on the immunogenicity of its antigen. Next-generation sequencing (NGS) provides invaluable information concerning the individual patient and individual tumors.

Along with these data, bioinformatics evaluation and major histocompatibility complex (MHC)-peptide binding prediction algorithms have facilitated the prediction of potential targets, reminiscent of neoantigen peptides or neopeptides. Whole exome sequencing (WES) of tumors and blood cells will also be used to detect mutations that may generate novel neopeptide sequences.

Computational algorithms, reminiscent of predictor of immunogenic epitopes (PRIME), are used to discover immunogenic peptides; nevertheless, the efficacy of those bioinformatics tools is debatable.

For instance, neopeptides identified through bioinformatics prediction tools didn’t generate significant endogenous antitumor immunity. This unfavorable consequence may very well be linked to tumor mutations based on deletion or insertion, which might result in frameshift translation of polypeptide sequences that will not resemble its wild-type counterpart. These neoantigenes are often called defective ribosomal products (DRiPs), which lack function and structural stability.

It shouldn’t be prudent to depend on pre-existing T-cell immunity to validate neopeptides in patients, as they may not elicit effector cytotoxic T-cell (CTL) responses on account of inefficient cross-presentation. Recent bioinformatics neopeptide prediction tools have encountered challenges on account of the usage of mass spectrometry (MS) to discover neopeptides loaded onto MHC class I molecules on the surface of tumors. Nevertheless, MS-based immunopeptidomics have the potential to discover immunogenic peptides with further refinement in its methodology.

A standard limitation linked with mutation-dependent neoantigens is clonal diversity and intra-tumor heterogeneity present inside primary and metastatic tumors, which indicates that every one neoantigens are usually not potential targets for vaccines. As in comparison with branched mutations, trunk mutations present in tumor cells function higher vaccine targets. Taken together, the identification of suitable immunologically relevant neopeptides is a significant challenge for the event of personalized neoantigen cancer vaccines.

Many cancer types have low mutational burden, which limits the worldwide utility of mutation-dependent neoantigens and indicates the importance of mutation-independent neoantigens.

Recently, scientists have used dark proteome to discover cryptic neoantigen targets for cancer immunotherapy. At present, the neoantigen pool of the dark proteome is poorly characterised, which is used to generate neopeptides with high T-cell receptors (TCR) affinity.

For vaccine development, it will be significant to contemplate the number and length of neopeptides, that are properties which might be often not considered in the course of the development of personalized neoantigen cancer vaccines. The variety of neopeptides required for an efficient vaccine will depend on the character of the epitopes.

Two aspects that influence vaccine efficiency include the shortcoming of T-cells to detect immune-evading tumors and suppression of T-cells by the immunosuppressive tumor microenvironment (TME). Many cells inside TME can inhibit or impair the function of neoantigen vaccine-induced T-cells.

Tumor accessibility is a critical step after the generation of a strong neoantigen-specific T-cell response. Tumor accessibility relies on multiple mechanisms, poor vascularization, physical barriers, and presence of vessels that restrict endothelium crossing by T-cells.

Personalized neoantigen cancer vaccine can be challenged with T-cell exhaustion and dysfunction, which is characterised by lack of effector function, enhanced inhibitory receptor expression, and propensity to undergo cell death. Thus, T-cell exhaustion could significantly restrict the good thing about these vaccines.

Journal reference:

• Katsikis, P. D., Ishii, J. K., & Schliehe, C. (2023) Challenges in developing personalized neoantigen cancer vaccines. Nature Reviews Immunology; 1-15. doi:10.1038/s41577-023-00937-y