Neoantigens – promising targets for cancer immunotherapy

Cancer is a condition in which cells grow and divide uncontrollably (Cancer, 2017), and is the second leading cause of death worldwide (Cancer Today, n.d.) contributing to one in six deaths. There are over 200 different types of cancer, and they can be grouped into 4 main types by the location they are found: carcinomas (skin or tissues covering internal organs and glands), sarcomas (tissues that support the body including bones, muscles and fat), leukaemias (blood cells) and lymphomas (lymphatic system) (What Is Cancer?, 2012). 

Previously, cancer treatment options were limited to surgery, chemotherapy, and radiotherapy. Recently, the advancement of technologies has contributed to scientific discoveries around cancer development, progression, immune evasion and crosstalk with the tumour microenvironment. New approaches of cancer therapies such as immunotherapy, which leverages the patient’s immune system in fighting cancer cells, arose from these discoveries. 

 studies (Y. Zhang & Zhang, 2020) have led to the development of several major types of immunotherapies including cancer vaccines, adoptive cell transfer, cytokines, and monoclonal antibody therapy (e.g. immune checkpoint inhibitors) (Liu et al., 2022; Y. Zhang & Zhang, 2020). They are thought to promote survival rate and have reduced side effects compared to traditional cancer therapies. 

Neoantigens – an overview 

An antigen is a molecule, allergen, or foreign particle that could bind to immune system cells or a specific antibody. Neoantigens are a type of antigen that are formed by tumour cells due to tumour-specific alterations such as mutations in the genome. They are recognized as foreign by the immune system and trigger an immune response (Xie et al., 2023), have high specificity and are relatively difficult to cause central tolerance and autoimmune reaction when compared to traditional tumour-associated antigens (Xu et al., 2020). Tumour-associated antigens are not unique to tumour cells, whereas neoantigens are a subtype of tumour-specific antigens which only expressed in tumour cells. 

For neoantigen immunotherapies, synthetic neopeptides are administrated to patients to stimulate the patient’s immune cells to recognise and kill cancers (Biswas et al., 2023). 

Identification of neoantigens 

Due to the nature of neoantigens, they are highly specific, vary from individual to individual, and usually do not involve any oncogenes. Therefore, identifying neoantigens is critical for developing therapies targeting tumour cells (Peng et al., 2019). 

First, DNA or RNA is extracted from tumour and somatic samples to identify neoantigens (Z. Zhang et al., 2021). This polynucleotide is sequenced to identify any mutations. Then, neopetides of appropriate lengths are designed based on these mutations. Computational tools are used for predicting the binding affinity of these neopeptides and for testing their desired response. 

Conclusion and perspective

Neoantigens have been proven to be highly immunogenic and tumour-specific and they can provide long-term immune protection against cancer by building immunological memory. Tremendous progress has been made in neoantigen-based therapies in the areas of neoantigen identification, prediction and screening (Zhao et al., 2021). Clinical trials using neoantigen vaccines have demonstrated the expected therapeutic effect with high safety and efficacy (Peng et al., 2019). With technological innovations in bioinformatic approaches and the development of sequencing technologies, neoantigen-based therapies have a positive development prospect. 

However, some challenges remain in optimizing the neoantigen vaccines in several aspects. For example, the time required for identifying and manufacturing neoantigen takes a minimum of 6-8 weeks, which is challenging for patients with a short treatment window (Zhao et al., 2021). Moreover, questions such as developing neoantigen vaccines with low mutation load remain unexplored (Xu et al., 2020).  

In conclusion, the use of neoantigen vaccines has demonstrated encouraging clinical outcomes. By exploring its potential in combined therapies with checkpoint inhibitors, surgery, chemotherapy and radiotherapy, neoantigen-based therapies hold a high potential in the treatment of cancer. 

References:

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Image credit: National Cancer Institute via unsplash

Image description: Human colorectal cancer cells with cell nuclei stained blue