Individualized cancer immunotherapy

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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.

Contents

The human immune system is generally able to recognize and fight cancer cells. However, this ability is usually insufficient and the cancer continues to spread. [1] 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, that includes numerous genetic alterations. As opposed to a preformed drug, individualized cancer vaccination is a therapy that targets specific cancer mutations of the individual patient's tumor. [2] The production of vaccines tailored to match a person's individual constellation of cancer mutations has become a new field of research. [3]

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. [2] 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. [4]

Background

Cancer is characterized by an accumulation of genetic alterations. A tumor may acquire up to thousands of different somatic 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. [5]

Somatic mutations in the tumor genome can cause tumors to express mutant proteins (neoantigens) that are recognized by autologous T cells as foreign and constitute cancer vaccine targets. [2] [6] 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. [7] [8] [9]

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. [10]

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. [10] A requirement for the recognition of neoantigens by the immune system is that the neoantigens and their antigenic determinants, the neoepitopes, are processed and presented by human leukocyte antigen (HLA) molecules. [5] These molecules may be recognized by CD8+ cytotoxic T lymphocytes as foreign neoepitopes and, with the help of CD4+ T lymphocytes, trigger an immune response leading to tumor-specific killing. [4] 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. [10]

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. [11] Each patient has an individual mutational signature (mutanome), and only a very small portion of the mutations are shared between patients. [10] [12] A concept is therefore that an immunotherapy directed at neoantigens needs to be individualized.[ citation needed ]

The development of sequencing technology 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. [5] [13]

Preclinical research

In animal models, several independent studies have shown that vaccines consisting of computationally predicted neoepitopes mediated anti-tumor activity in mice. [13] [14] [15] [16] [17]

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, messenger RNA, DNA plasmids, viral vectors, engineered bacteria, and antigen-loaded dendritic cells. [2]

Patients with melanoma

In 2015, a first step towards individualized neoantigen vaccination was achieved by treating three melanoma 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. [18]

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. [19] 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. [19]

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 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. [20]

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. [21]

Keskin et al. investigated individualized neoantigen vaccines in eight glioblastoma patients after surgical resection and conventional radiotherapy. The study group observed that the vaccine increased the number of tumor-infiltrating T cells that migrated from the peripheral blood into the brain. [22]

Manufacturing process of mutation-based vaccines

Individualized cancer vaccines typically consist of multiple predicted neoepitopes. The manufacturing process involves several steps.[ citation needed ]

Tumor biopsies and healthy tissue (e.g., peripheral blood cells) of a patient diagnosed with cancer are examined by NGS. Tumor-specific mutations in protein-coding genes 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. [4]

The intended output is an on-demand vaccine with a unique composition tailored to the patient's individual cancer mutanome. [10]

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. [19] The development of iNeST is driven by biotech companies [23] [24]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. The term antigen originally referred to a substance that is an antibody generator. Antigens can be proteins, peptides, polysaccharides, lipids, or nucleic acids.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

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", being prepared from samples taken from the patient, and are specific to that patient.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAbs) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those cells. Alternatively, in radioimmunotherapy a radioactive dose localizes a target cell line, delivering lethal chemical doses. Antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses. This is known as immune checkpoint therapy.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

<span class="mw-page-title-main">Cancer immunology</span> Study of the role of the immune system in cancer

Cancer immunology is an interdisciplinary branch of biology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

<span class="mw-page-title-main">SSX2</span> Mammalian protein found in Homo sapiens

Protein SSX2 is a protein that in humans is encoded by the SSX2 gene.

Vaccine therapy is a type of treatment that uses a substance or group of substances to stimulate the immune system to destroy a tumor or infectious microorganisms such as bacteria or viruses.

Gustav Gaudernack is a scientist working in the development of cancer vaccines and cancer immunotherapy. He has developed various strategies in immunological treatment of cancer. He is involved in several ongoing cellular and immuno-gene therapeutic clinical trials and his research group has put major efforts into the development of various T cell-based immunotherapeutic strategies.

Racotumomab is a therapeutic cancer vaccine for the treatment of solid tumors that is currently under clinical development by Recombio, an international public-private consortium with the participation of the Center of Molecular Immunology at Havana, Cuba (CIM) and researchers from Buenos Aires University and National University of Quilmes in Argentina. It induces the patient's immune system to generate a response against a cancer-specific molecular target with the purpose of blocking tumor growth, slowing disease progression and ultimately increasing patient survival.

Cancer/testis (CT) antigens are a group of proteins united by their importance in development and in cancer immunotherapy. In general, expression of these proteins is restricted to male germ cells in the adult animal. However, in cancer these developmental antigens are often re-expressed and can serve as a locus of immune activation. Thus, they are often classified as tumor antigens. The expression of CT antigens in various malignancies is heterogeneous and often correlates with tumor progression. CT antigens have been described in melanoma, liver cancer, lung cancer, bladder cancer, and pediatric tumors such as neuroblastoma. Gametogenesis offers an important role for many of these antigens in the differentiation, migration, and cell division of primordial germ cells, spermatogonia spermatocytes and spermatids. Because of their tumor-restricted expression and strong in vivo immunogenicity, CT antigens are identified as ideal targets for tumor specific immunotherapeutic approaches and prompted the development of several clinical trials of CT antigens-based vaccine therapy. CT antigens have been found to have at least 70 families so far, including about 140 members, most of which are expressed during spermatogenesis. Their expression are mainly regulated by epigenetic events, specifically, DNA methylation.

<span class="mw-page-title-main">Hans-Georg Rammensee</span>

Hans-Georg Rammensee is a German immunologist and cancer researcher. He has been Chair Professor and Head of the Department of Immunology at the University of Tübingen since 1996. Rammensee has contributed essentially to the research fields of MHC biology and tumor immunology and to the development of cancer immunotherapies.

Individualized medicine tailors treatment to a single patient. The term refers to an individual, truly personalized medicine that strives to treat each patient on the basis of his own individual biology.

The mutanome is the entirety of somatic cancer mutations in an individual tumor.

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 to cancer.

<span class="mw-page-title-main">Uğur Şahin</span> German oncologist (born 1965)

Uğur Şahin is a German oncologist and immunologist. He is the CEO of BioNTech, which developed one of the major vaccines against COVID-19. His main fields of research are cancer research and immunology.

<span class="mw-page-title-main">Özlem Türeci</span> German physician, scientist and entrepreneur

Özlem Türeci is a German physician, scientist and entrepreneur. In 2008, she co-founded the biotechnology company BioNTech, which in 2020 developed the first messenger RNA-based vaccine approved for use against COVID-19. Türeci has served as BioNTech's chief medical officer since 2018. Since 2021, she has been Professor of Personalized Immunotherapy at the Helmholtz Institute for Translational Oncology (HI-TRON) and Johannes Gutenberg University Mainz. Türeci and her spouse, Uğur Şahin, have won a number of awards.

<span class="mw-page-title-main">Tumor mutational burden</span>

Tumour mutational burden is a genetic characteristic of tumorous tissue that can be informative to cancer research and treatment. It is defined as the number of non-inherited mutations per million bases (Mb) of investigated genomic sequence, and its measurement has been enabled by next generation sequencing. TMB has shown potential as a predictive biomarker with several applications, including associations reported between different TMB levels and patient response to immune checkpoint inhibitor (ICI) therapy in a variety of cancers.

Whole-cell vaccines are a type of vaccine that has been prepared in the laboratory in such a way to express immune cells such as cytokines, chemokines and other costimulatory molecules. When administered to the patients, these molecules will stimulate the immune system of the patient. The whole-cell vaccine simultaneously targets multiple antigens to activate the immune system and induces antigen-specific T-cell responses.

References

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