HOME

TheInfoList



OR:

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 and fight
cancer cells Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...
. However, this ability is usually insufficient and the cancer continues to spread. Cancer immunotherapy is based on harnessing and potentiating the ability of the immune system to fight cancer. Each tumor has its own individual genetic fingerprint, the
mutanome 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 mutati ...
, that includes numerous genetic alterations. As opposed to a preformed drug, individualized cancer vaccination is a therapy that targets specific cancer
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
of the individual patient's tumor. The production of vaccines tailored to match a person's individual constellation of cancer mutations has become a new field of research. The concept of individualized cancer immunotherapy aims to identify individual mutations in the tumor of a patient, that are crucial for the proliferation, survival or metastasis of tumor cells. For this purpose, the individual genetic blueprint of the tumor is decrypted by sequencing and, using this blueprint as a template, a synthetic vaccine tailored to the tumor of the individual patient is prepared. This vaccine is designed to control and train the body's immune system to fight the cancer.


Background

Cancer is characterized by an accumulation of genetic alterations. A tumor may acquire up to thousands of different
somatic Somatic may refer to: * Somatic (biology), referring to the cells of the body in contrast to the germ line cells ** Somatic cell, a non-gametic cell in a multicellular organism * Somatic nervous system, the portion of the vertebrate nervous sys ...
mutations during the process of initiation and progression. A smaller number of cancer mutations interfere with normal cell regulation and help to drive cancer growth. Somatic mutations in the tumor genome can cause tumors to express mutant
proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
(
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) that are recognized by autologous T cells as foreign and constitute cancer vaccine targets. Tumor Mutational Burden (TMB, the number of mutations within a targeted genetic region in the cancerous cell's DNA) have been thus suggested to correlate with patient survival post immunotherapy, although the findings are disputed. Such neoantigens are specifically expressed by tumor tissue and are not found on the surface of normal cells. They can upregulate tumor-specific T cells in patients without killing normal cells. T cells are key effectors of anticancer immunity. They are capable of distinguishing tumor cells from normal ones by recognizing HLA-bound cancer-specific peptides. A requirement for the recognition of neoantigens by the immune system is that the neoantigens and their antigenic determinants, the
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 processed and presented by human leukocyte antigen (HLA)
molecules A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioche ...
. These molecules may be recognized by CD8+
cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...
T lymphocytes as foreign neoepitopes and, with the help of CD4+ T lymphocytes, trigger an immune response leading to tumor-specific killing. CD8+ T cells are specialized for direct tumor cell killing. CD4+ T cells can interact with antigen-presenting cells such as dendritic cells to recruit other immune cells or stimulate
effector cells In cell biology, an effector cell is any of various types of cell that actively responds to a stimulus and effects some change (brings it about). Examples of effector cells include: * The muscle, gland or organ cell capable of responding to a ...
. Most cancer neoantigens in humans arise from unique mutations. A patient's cancer is intra- as well as interlesionally heterogeneous and changes its composition over time. Each patient has an individual mutational signature (mutanome), and only a very small portion of the mutations are shared between patients. A concept is therefore that an immunotherapy directed at neoantigens needs to be individualized. The development of
sequencing technology DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. The ...
has improved the accuracy of identification and localization of neoantigens. With the advent of next-generation sequencing (NGS), it has become possible to systematically predict cancer neoantigens for individual patients.


Preclinical research

In animal models, several independent studies have shown that vaccines consisting of computationally predicted neoepitopes mediated anti-tumor activity in mice.


First-in-human clinical trials

The translation of individualized neoepitope vaccines into clinical oncology is under investigation. Formats under consideration for individualized vaccines are synthetic
peptides Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...
,
messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...
, DNA
plasmids A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; how ...
, viral vectors, engineered bacteria, and antigen-loaded dendritic cells.


Patients with melanoma

In 2015, a first step towards individualized neoantigen vaccination was achieved by treating three
melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
patients with autologous dendritic cells loaded with a personalized mixture of seven peptides (neoantigens) that were predicted to bind to human leukocyte antigens (HLA). The neoantigen-loaded dendritic cells were cultured in vitro for autologous transfusion. Results showed that the vaccine enhanced the existing immune response and elicited a neoantigen-specific T cell response that was not detected prior to injection. Sahin et al. were the first to identify suitable neoantigens using next generation sequencing (NGS) and used them to produce customized RNA vaccines capable of encoding these neoantigens. A total of 13 patients with melanoma received the RNA vaccine, eight of which had no tumor development during the follow-up. Immune surveillance analysis of peripheral blood mononuclear cells (PBMCs) in patients demonstrated that the RNA vaccines expanded preexisting T cells and induced de novo T cell responses against neoepitopes not recognized prior to vaccination. Another study group (Ott et al.) identified neoantigens in six melanoma patients and used them to create a customized vaccine for each patient with long
peptides Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...
representing up to 20 mutations per patient. After surgical resection of the tumor, the vaccine was injected. The results showed that the tumor did not reappear in four patients during an observation period of 32 months after vaccination.


Patients with glioblastoma

Hilf et al. administered individualized neoantigen vaccines to 15 patients with glioblastoma. The vaccine triggered T cell immune responses to the predicted neoantigens. Keskin et al. investigated individualized neoantigen vaccines in eight glioblastoma patients after surgical resection and conventional
radiotherapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radia ...
. The study group observed that the vaccine increased the number of tumor-infiltrating T cells that migrated from the peripheral blood into the brain.


Manufacturing process of mutation-based vaccines

Individualized cancer vaccines typically consist of multiple predicted neoepitopes. The manufacturing process involves several steps. Tumor biopsies and healthy tissue (e.g., peripheral blood cells) of a patient diagnosed with cancer are examined by
NGS NGS may refer to: Places * NGSO (NGS orbit), non-geostationary orbit * Nagasaki Airport (IATA airport code: NGS) in Omura, Nagasaki, Japan Organisations * National Galleries of Scotland, representing the national art collection of Scotland * Na ...
. Tumor-specific mutations in protein-coding
genes In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
are then identified by comparison of sequences from tumor and normal DNA. Computational tools classify these mutations for the highest likelihood of immunogenicity, that is, for the predicted expression and binding affinity of neoepitopes on HLA molecules. The top rankers are then used for the production of the vaccine. The intended output is an on-demand vaccine with a unique composition tailored to the patient's individual cancer mutanome.


Individualized NeoAntigen Specific Immunotherapy (iNeST)

The research approach to mobilize an immune response tailored to the individual tumor of a patient is also referred to as individualized neoantigen-specific immunotherapy (iNeST). iNeST is based on the specific tumor mutations (neoantigens) of a single patient, with the aim of triggering high-affinity immune responses of T cells to the individual patient-specific cancer. The development of iNeST is driven by biotech companies


References

{{reflist Medical genetics Biotechnology Applied genetics Genomics Vaccines Cancer vaccines