癌症免疫治療-Beat Cancer Soon

來自專欄癌症研究札記6 人贊了文章

Our immune system, an underappreciated gift from nature, is an intricate network uniquely adept at identifying and eliminating foreign invaders such as bacteria, virus, fungi, parasites while distinguishing them from our bodys healthy tissue.

Cancer, a genetic disease, is caused by the accumulation of errors that occur as cells divide or damages to DNA caused by certain environmental exposures, and the abnormal modifying of gene expression, which changes normal cell growth and survival pathway.

Cancer cells frequently express abnormal proteins that are different from our "self" antigen.

Tumors evolve mechanisms to escape immune control by a process called immune editing. It is made up of three phases: elimination, equilibrium, and escape.

Three phases of cancer immune editing: elimination, equilibrium, and escape

Elimination

Can our own immune system identify cancer antigens and eliminate cancer cells? Our natural immune system does raise a complex response to developing tumors. In 1909, Ehrlich, a German Jewish physician, and scientist and the Nobel Prize winner, hypothesized that our immune system patrols our body to recognize and destroy the cells that become cancerous. This is called cancer immune surveillance. However, it took more than 50 years for the idea of cancer immune surveillance be widely accepted until when experimental knockout mouse animal models were developed.

Abundant of compelling research data show that the cancer immune surveillance composed of cells and molecules of innate and adaptive immunity of our natural immune system may eliminate the developing tumor and protect the host from tumor formation.

Equilibrium

Most of the cancer cells have a feature of genomic instability. Tumors under immune surveillance harbor thousands of mutations. Those mutations eventually give rise to a new phenotype that displays reduced immunogenicity. These tumors are great at playing hide and seek to avoid recognition from the immune system and survive. The immune surveillance selects and favors the growth of these tumors.

Escape

There are a variety of tumors derived soluble factors. Some of them prevent the differentiation and maturation of immune cells. Others inhibit the killing of tumor cell by immune cells. They also can induce the cytokines that inhibit the immune response. Growing tumor cells in a body are surrounded by non-tumor cells. These cells compete with immune cells to bind to the tumor antigens. Due to the insufficient level of tumor antigens, tumors are ignored by T cells. In addition, the lack of tumor antigen recognition by immune cells results in the change of signals on immune effector cells. The changed signals inhibit the proliferation but increase the programmed death of lymphocytes. Immature immune cells further inhibit the maturation of some immune cells and T cell activation, resulting in the immunological tolerance.

Cancer Immunotherapy Strategies

Although cancer progression involves a wide variety of ways to overcome the host immunity, cancer immunotherapy can potentially rev up an immune response to fight off cancer. A range of cancer immunotherapy strategies has proven effective in patients.

Adoptive T cell therapy

Adoptive T cell therapy (ACT) is the transfer of natural or genetically modified tumor-specific T cells that have been expanded ex vivo to achieve a greater number of patients to treat cancers. There are major two sources or types of T cells used for adoptive therapy. They are tumor infiltrating lymphocytes (TILs), and T cells engineered to express a receptor that is a fusion between an antibody and the T cell receptor intracellular machinery, so-called chimeric antigen receptors (CARs).

1. TILs can recognize tumor-specific antigens. TIL therapy involves extracting lymphocytes from tumor tissue, ex vivo expansion with IL-2, a canonical T cell growth factor, followed by reinfusion.
2. CARs include an extracellular antibody single-chain variable region joined with the intracellular portion of a T cell receptor. CARs combine the cytotoxic activity of a CD8+ T cell with the high-affinity monoclonal antibodies which has the MHC-independent antigen recognition capacity.

Monoclonal Antibody

1. Conjugation of monoclonal antibody with anti-cancer drugs

Monoclonal antibodies (mAbs) are identical immunoglobulins, generated from a single B cell clone. These antibodies have unique antigen specificity that allows them to bind to epitopes on cancer cells.

The therapeutic mAbs are typical of the IgG class. mAbs can be conjugated with chemotherapy drugs, radioactive particles, toxins, nanoparticles, liposomes, or biodegradable polymers targeting these medical agents into cancer cells. This strategy limits toxicity in normal tissue.

2. Triggering the antibody dependent cell-mediated cytotoxity

Antibody-dependent cell-mediated cytotoxicity (ADCC) is a biological process that contributes to the targeting and killing of antibody-coated cells by immune cells and is triggered by IgG1 isotype mAbs in the presence of natural killer (NK) cells. The Fc region of IgG1 can bind to CD16 molecule on NK cells to activate them.

NK cells use interferon-? (IFN?) and other various cytokines to cross talk with other immune cells, such as dendritic cells, macrophages or other NK cells. Activated NK cells that lyse the mAbs coated tumor cells lead to the release of tumor antigens, which can be cross-presented by dendritic cells to cytotoxic T cells, priming them for the additional cytotoxic T cell killing activity for tumor cells. Therefore, the binding of an IgG1 isotype mAb to both its target tumor antigen and the CD16 receptor on NK cells can stimulate the priming and activation of both immune effector cells of the innate and adaptive immune systems.

3.Blocking the immune checkpoints

mAbs also can function as the Immunomodulator to block the immune checkpoints. Immune checkpoints are negative regulators of the immune system, that play critical roles in maintaining immune homeostasis, self-tolerance, preventing autoimmunity and protecting tissues from immune collateral damage. These immune checkpoints are often 「hijacked」 by tumors to restrain the ability of the immune system to mount an effective anti-tumor response. Blocking immune checkpoints rather than directly destroy tumor cells, is thus a promising approach for activating anti-tumor immunity. They can provide durable, long-term survival benefits. The mostly studied immune checkpoint receptors are the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and PD-1/ programmed death ligand 1 or 2 (PD-L1 or PD-L2).

An example of Combination of Therapeutic Antibodies Targeting Tumor Cells and Immune Checkpoint Receptors

Cetuximab is an anti-human epidermal growth factor receptor (EGFR) mAb. EGFR is a transmembrane receptor that is activated by binding to its natural ligands, mainly EGF or transforming growth factor alpha (TGF-α). Binding to EGFR by its natural ligands results in a conformational change in the receptor, which promotes homodimerization with other EGFR molecules or heterodimerization with other HER family members (especially Her-2). The dimerization of EGFR results in subsequent autoactivation of the tyrosine kinase from the intracellular domain of the receptor. This process activates an intracellular signaling pathway, leading to the inhibition of apoptosis, activation of cell proliferation and angiogenesis, as well as an increase in metastatic spread potential. In squamous cell carcinoma of the head and neck (SCCHN), EGFR and its ligand, TGF-α, are overexpressed in 80–90% of cases. Cetuximab inhibits the binding of EGFR to its ligands and blocks the downstream signal transduction pathways, leading to proliferation inhibition and apoptosis induction in tumor cells. In addition, the IgG1 backbone can stimulate ADCC that contributes to the targeting and killing of antibody-coated tumor cells in the presence of NK cells.

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