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Neoantigen – Definition, Origin & Cancer Therapy

Neoantigens are foreign protein structures arising from mutations in cancer cells that can be recognized and targeted by the immune system.

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Things worth knowing about "Neoantigen"

Neoantigens are foreign protein structures arising from mutations in cancer cells that can be recognized and targeted by the immune system.

What Is a Neoantigen?

A neoantigen is a novel antigen – a protein structure – found on the surface of tumor cells, arising from somatic mutations in the DNA of cancer cells. Unlike normal self-proteins, neoantigens are recognized by the immune system as foreign because they do not occur in healthy cells. They play a central role in modern cancer immunotherapy.

How Neoantigens Arise

Neoantigens form when the genetic material (DNA) of a cell is altered by mutations. These mutations can result from several mechanisms:

Point mutations: Changes in individual base pairs in the DNA sequence
Insertions or deletions: Addition or removal of DNA segments leading to altered proteins (frameshifts)
Chromosomal rearrangements: Restructuring of larger DNA segments
Viral integrations: Incorporation of viral genes into the cell genome, as seen in certain virus-associated cancers

These mutations lead to the production of altered proteins that the immune system may classify as non-self.

Role in the Immune Response

The immune system contains specialized cells called T cells (cytotoxic T lymphocytes). These cells can recognize neoantigens displayed on the surface of tumor cells via the MHC complex (major histocompatibility complex). When a T cell identifies a neoantigen, it can selectively destroy the cancer cell. Generally, the more neoantigens a tumor expresses, the stronger the immune response against it.

Clinical Relevance and Applications in Cancer Therapy

Neoantigens have attracted enormous interest in oncology in recent years, as they form the basis for highly specific, personalized cancer therapies:

Personalized Cancer Vaccines

Neoantigen-based cancer vaccines are produced individually for each patient. Tumor tissue is genetically analyzed to identify specific mutations and the resulting neoantigens. A tailored vaccine is then developed to train the immune system to recognize and attack these tumor-specific antigens.

Checkpoint Inhibitors

Tumors with a high number of mutations – referred to as a high tumor mutational burden (TMB) – typically express many neoantigens. Patients with high TMB often respond better to immune checkpoint inhibitors, such as pembrolizumab or nivolumab, which enhance the natural immune response against the tumor.

Adoptive T Cell Transfer

In this therapeutic approach, T cells are collected from the patient, modified in the laboratory to more effectively recognize neoantigens, and then infused back into the patient. This represents another avenue for personalized immunotherapy.

Diagnosis and Identification

Identifying neoantigens requires advanced genomic technologies:

Next-Generation Sequencing (NGS): High-throughput sequencing to analyze the entire tumor genome for mutations
Bioinformatic analyses: Computational prediction of which mutations actually produce immunogenic neoantigens
MHC binding predictions: Calculation of whether a given neoantigen can be effectively presented by the MHC complex and recognized by T cells

Opportunities and Challenges

Neoantigens offer great promise for precise, low-toxicity cancer therapy because they are tumor-specific and do not affect healthy tissue. Current challenges include:

High costs and technical complexity of neoantigen identification and vaccine manufacturing
Tumor heterogeneity: different tumor cells within the same patient may carry different neoantigens
Time required for individualized vaccine production
Not all neoantigens trigger a sufficiently strong immune response

References

Schumacher, T. N. & Schreiber, R. D. (2015). Neoantigens in cancer immunotherapy. Science, 348(6230), 69–74. DOI: 10.1126/science.aaa4971
Sahin, U. & Tureci, O. (2018). Personalized vaccines for cancer immunotherapy. Science, 359(6382), 1355–1360. DOI: 10.1126/science.aar7112
National Cancer Institute (NCI). Tumor Antigens. Available at: https://www.cancer.gov (accessed 2024).

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