The mutanome is the entirety of somatic
cancer mutations in an individual tumor.
Description
Carcinogenesis is largely driven by changes in the
DNA sequence of the
genomes of cancer cells.
This process leads to a unique repertoire of mutations (′the mutanome′) in every patient's tumor.
The mutanome encodes peptides that can be targets for
T cells, which play a central role in the immune response.
A description of individual mutanomes of human tumors has been made feasible by the introduction of
Next Generation Sequencing Technology (NGS).
Cancer mutanomes can be defined by comparing
exome sequencing data obtained by NGS of individual healthy tissue with sequences from tumor-derived
nucleic acid
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
s.
As the vast majority of cancer-associated mutations are patient specific, shared mutations are rare, even within the same type of cancer.
Neoantigens and neoepitopes
The mutanome encodes a pattern of tumor-specific mutated peptides referred to as
neoantigen
Tumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an immune response in the host. Tumor antigens are useful tumor markers in identifying tumor cells with diagnostic tests and are potential candidates for use in c ...
s or m-peptides. Neoantigens are products of mutations that first occur in the course of cancer development. Each and every tumor has its own unique neoantigenic pattern, and even within the same type of cancer, only a small percentage of neoantigens are shared.
Neoantigens are presented on
major histocompatibility complex
The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are calle ...
(MHC) molecules of tumor cells.
The antigenic determinants of neoantigens –
neoepitope Neoepitopes are a class of major histocompatibility complex (MHC) bounded peptides. They represent the antigenic determinants of neoantigens. Neoepitopes are recognized by the immune system as targets for T cells and can elicit immune response t ...
s – are recognized by the immune system as a target for T cells, thus triggering immune responses against cancer.
A neoepitope is an epitope the immune system has not encountered before. Therefore, it is not subject to tolerance mechanisms of the immune system.
Since the mutated gene product is only expressed in tumors, but not on healthy cells, neoepitopes may evoke vigorous T cell response.
Mutanome immunotherapy
The vast majority of cancer mutations are unique to the individual patient,
and a significant portion of mutations (21-45%) are immunogenic.
Therefore, the patients' individual mutanome and the neoepitopes are used as the basis for a novel strategy against cancer, which is referred to as
individualized cancer immunotherapy
Individualized cancer immunotherapy, also referred to as individualized immuno-oncology, is a novel concept for therapeutic cancer vaccines that are truly personalized to a single individual.
The human immune system is generally able to recognize ...
.
uses the body's own immune defense system and is based on the recognition by cytotoxic and helper T cells with antitumor activity.
Mutanome-specific vaccines
Strategies to immunotherapeutically address the individual mutanome are currently under investigation.
Ongoing mutanome
cancer vaccine
A cancer vaccine is a vaccine that either treats existing cancer or prevents development of cancer. Vaccines that treat existing cancer are known as ''therapeutic'' cancer vaccines or tumor antigen vaccines. Some of the vaccines are "autologous", ...
trials use synthetic peptides and antigen-encoding
DNA or
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
as formats.
For an individualized treatment, neoepitopes that are thought to elicit a strong immune response are selected out of the patient's mutanome.
An increasingly explored concept for individualized cancer immunotherapy is the treatment of a patient with immunogenic
mRNA vaccines for a given patient's individual cancer mutanome (IVAC - Individualized Vaccine Against Cancer).
The IVAC concept is based on decoding the individual mutanome by NGS and on-demand mRNA manufacturing for use in single patients to produce therapeutic vaccines against cancer.
Since 2016, the IVAC concept has been developed as
Individualized Neoantigen Specific Therapy (iNeST).
The process of NSG based cancer mutanome mapping, target selection, prioritization approaches, synthetic mRNA vaccine manufacturing and delivery is also referred to a
MERIT(mutanome engineered RNA immunotherapy).
By vaccination with the synthetic mRNA, which contains the blueprint of a mutant tumor peptide,
T lymphocytes are activated against the tumor.
References
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External links
The MERIT (Mutanome Engineered RNA Immuno-Therapy) project– European Union funded Initiative
GAPVAC (Glioma Actively Personalized Vaccine Consortium)– European Union funded Initiative
Medical genetics
Biotechnology
Applied genetics
Genomics
Vaccines
Cancer vaccines