In humans, anti-tumour immunity is usually very effective, because our T-cells (a type of a white blood cell) can detect the presence of specific cancer neoantigens. These are short chains of aminoacids (peptides) that appear due to tumour-specific mutations, and mark the cancer cell as foreign. They are highly immunogenic, because they are not present in normal tissues; and therefore, evade central thymic tolerance and activate our immune system to destroy them.
Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their efficient discovery and evaluation only became possible recently, with the availability of massive parallel sequencing for detection of all coding mutations within tumours; and, of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules.
It has been shown that vaccination with these specific neoantigens can expand the pre-existing neoantigen-specific T-cell populations; and, induce a broader repertoire of new T-cell specificities in cancer patients. This can actually tip the intra-tumoral balance, in favour of an enhanced tumour control.
Research studies now demonstrate the feasibility, safety, and immunogenicity of vaccines that target up to 20 predicted personal tumour neoantigens (e.g., Melanoma Neovax anti-PD11). Vaccine-induced polyfunctional CD4+ and CD8+ T-cells can target unique tumour neoantigens; and, not only that, these T-cells can have persistent memory. This because, studies from the Dana-Farber Cancer Institute and Dr. Catherine Wu’s lab, show that patients have a continuous response 5-7-years later after the initial vaccination, with a second-wave of immune response that shows epitope spreading from the initial epitope. What this means, is that the patient immune system was able to recognize and target tumour cells, even when they try to disguise themselves years later.
Researchers have gone further: at Genocea Biosciences they are developing precision neoantigen selection with their branded ATLAS platform. They can optimize the set of neoantigens for inclusion in the vaccine, by excluding inhibitory antigens (called Inhibigens) that suppress the patient’s immune system, blocking the internal growth of the tumour cells.
1 Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217-221, doi:10.1038/nature22991 (2017).