Cancer immunotherapy (sometimes called immuno-oncology, abbreviated IO) is the use of the immune system to treat cancer. Immunotherapies can be categorized as active, passive or hybrid (active and passive). These approaches exploit the fact that cancer cells often have molecules on the surface that can be detected by the immune system, known as tumor-associated antigens (TAAs); they are often proteins or other macromolecules (eg carbohydrates). Active immunotherapy directs the immune system to attack tumor cells by targeting TAA. Passive immunotherapy enhances existing anti-tumor responses and includes the use of monoclonal antibodies, lymphocytes and cytokines.
Among other things, some antibody therapy is approved in various jurisdictions to treat various cancers. Antibodies are proteins produced by the immune system that bind to the target antigen on the cell surface. The immune system usually uses them to fight pathogens. Each antibody is specific to one or more proteins. Those who bind tumor antigens treat cancer. Cell surface receptors are common targets for antibody therapy and include CD20, CD274 and CD279. Once bound to a cancer antigen, antibodies can induce antibody-mediated cell cytotoxicity, activate complement system, or prevent receptors interacting with their ligand, all of which can cause cell death. Approved antibodies include alemtuzumab, ipilimumab, nivolumab, ofatumumab and rituximab.
Active cellular therapy usually involves the removal of immune cells from the blood or from the tumor. Those specific to the tumor were cultured and returned to the patient where they attacked the tumor; as an alternative, immune cells can be genetically engineered to express tumor-specific receptors, cultured and returned to the patient. Cell types that can be used in this way are natural killer cells, lymphokine-activated lymphocytes, cytotoxic T cells, and dendritic cells. However, a new study by Stanford University scientists has created a method of treating tumors that do not require the patient's immune cells to be excreted from their bodies. Their method uses a combination of two immune-boosting agents injected into the tumor to trigger an immune T cell response that then eradicates the tumor.
Interleukin-2 and interferon-? is a cytokine, a protein that regulates and coordinates the behavior of the immune system. They have the ability to increase anti-tumor activity and thus can be used as a passive cancer treatment. Interferon-? used in the treatment of hair-celled leukemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukemia and malignant melanoma. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma.
Video Cancer immunotherapy
cellular immunotherapy
Dendritic cell therapy
Dendritic cell therapy provokes an anti-tumor response by causing dendritic cells to present tumor antigen to the lymphocytes, which activates them, multiplying them to kill other cells presenting antigens. Dendritic cells are antigen presenting cells (APCs) in the mammalian immune system. In the treatment of cancer, they help target cancer antigen. The only approved cellular cancer therapy based on dendritic cells is sipuleucel-T.
One method of inducing dendritic cells to present tumor antigens is by vaccinating with autologous lining of the tumor or short peptide (a small part of the protein corresponding to the protein antigen of the cancer cell). These peptides are often given in combination with adjuvant (immunogenic substances high) to enhance the immune response and anti-tumor. Other adjuvants include proteins or other chemicals that attract and/or activate dendritic cells, such as granulocyte macrophage colony-stimulating factor (GM-CSF).
Dendritic cells can also be activated in vivo by making the tumor cells express GM-CSF. This can be achieved by genetically modified tumor cells to produce GM-CSF or by infecting tumor cells with oncolytic virus expressing GM-CSF.
Another strategy is to remove dendritic cells from the patient's blood and activate them outside the body. Dendritic cells are activated in the presence of tumor antigens, which may be tumor-specific peptide/protein-or tumor-cell tumor (breakdown of damaged tumor cells). These cells (with optional adjuvant) infused and provoked an immune response.
Dendritic cell therapy includes the use of antibodies that bind receptors on the surface of dendritic cells. Antigen may be added to the antibody and may cause mature dendritic cells and provide immunity to the tumor. Dendritic cell receptors such as TLR3, TLR7, TLR8 or CD40 have been used as antibody targets.
Approved drugs
Sipuleucel-T (Provenge) is approved for the treatment of metastatic resistant prostate cancer without symptoms or minimal symptoms in 2010. This treatment consists of removing antigen cells that present from the blood by leukapheresis and grow it with PA2024 fusion protein made from GM-CSF and prostate-specific prostatic acid phosphatase (PAP) and re-infused. This process is repeated three times.
CAR-T cell therapy
Approved drugs
Tisagenlecleucel (Kymriah), chimeric antigen receptor therapy (CAR-T), has been approved by the FDA in 2017 to treat acute lymphoblastic leukemia. This treatment removes CD19 positive cells (B-cells) from the body (including sick cells, but also cells that produce normal antibodies).
Axicabtagene ciloleucel (Yescarta) is another CAR-T therapy, approved in 2017 for the treatment of large spread B-cell lymphomas.
Maps Cancer immunotherapy
Antibody Therapy
Antibodies are a key component of the adaptive immune response, playing a central role in recognizing foreign antigens and stimulating the immune response. Antibodies are Y-shaped proteins produced by several B cells and are composed of two regions: antigen-binding fragments (Fab), which bind to the antigen, and the crystallizable fragment regions (Fc), which interact with the so-called Fc receptors expressed on the surface of various types immune cells include macrophages, neutrophils, and NK cells. Many immunotherapeutic regimens involving antibodies. Technology engineers monoclonal antibodies and produce antibodies against specific antigens, such as those present on tumor surfaces. These antibodies are specific to tumor antigens, can then be injected into the tumor
Type of antibody
Conjugation
Two types are used in cancer care:
- The bare monoclonal antibody is an antibody with no additional elements. Most antibody therapies use this type of antibody.
- Conjugated monoclonal antibodies combine with other molecules, which are cytotoxic or radioactive. Toxic chemicals are commonly used as chemotherapy drugs, but other toxins can be used. Antibodies bind to specific antigens on the surface of cancer cells, directing therapy to tumors. Antibodies connected with radioactive compounds are referred to as radiolabelled. Chemolabelled antibodies or immunotoxins are characterized by chemotherapy or toxic molecules, respectively.
Fc Regions
Fc's ability to bind to Fc receptors is important because it allows antibodies to activate the immune system. Fc regions vary: they exist in different subtypes and can be further modified, for example by the addition of sugars in a process called glycosylation. Changes in the Fc region may alter the ability of the antibody to involve Fc receptors and, by extension, will determine the type of immune response that triggers antibodies. Many cancer immunotherapy drugs, including PD-1 and PD-L1 inhibitors, are antibodies. For example, an immune blocking blocker targeting PD-1 is an antibody designed to bind PD-1 expressed by T cells and reactivate these cells to remove the tumor. Anti-PD-1 drugs not only contain the Fab region that binds PD-1 but also Fc. Experimental work shows that the portion of Fc of a cancer immunotherapy drug can affect treatment outcomes. For example, anti-PD-1 drugs with Fc regions binding Fc inhibitor receptors may decrease therapeutic efficacy. Further imaging studies show that the Fc region of anti-PD-1 drugs can bind to Fc receptors expressed by tumor-related macrophages. This process removes the drug from the intended target (ie the PD-1 molecule expressed on the surface of T cells) and limits therapeutic efficacy. Furthermore, antibodies targeting CD40 co-stimulatory proteins require engagement with selective Fc receptors for optimal therapeutic efficacy. Together, this study underscores the importance of Fc status in an antibody-based immune-based targeting strategy.
Human/non-human balance
Antibodies are also referred to as murine, chimeric, humanized and human. Murine antibodies come from different species and carry the risk of an immune response. Chimeric antibodies try to reduce the immunogenicity of murine antibodies by replacing parts of antibodies with suitable human peers, known as constant regions. The human antibodies are almost completely human; only complementarity determines the area of ​​the variable region derived from the murine sources. Human antibodies have been produced using unmodified human DNA.
Mechanism of cell death
Antibody-dependent_cell-mediated_cytotoxicity_.28ADCC.29 "> Cell-mediated cytotoxicity that depends on antibody (ADCC) antibodies ) range>
The cell-mediated cytotoxicity that depends on the antibody (ADCC) antibodies requires antibodies to bind to the surface of the target cell. Antibodies are formed from the binding regions (Fab) and Fc regions that can be detected by the immune system cells through their Fc surface receptor. Fc receptors are found in many immune system cells, including natural killer cells. When a natural killer cell finds cells coated with antibodies, the last Fc region interacts with their Fc receptor, releasing perforin and granzim B to kill tumor cells. Examples include Rituximab, Ofatumumab and Alemtuzumab. The antibodies under development have altered the Fc region that has a higher affinity for a specific Fc receptor type, Fc? RIIIA, which can dramatically increase effectiveness.
Complement
The complement system includes blood proteins that can cause cell death after cell-binding antibodies (classic complement pathways, among complementary activation modes). Generally the system deals with foreign pathogens, but can be activated with therapeutic antibodies to cancer. The system can be triggered if antibodies are chimeric, humanized or human; as long as it contains IgG1 Fc region. Complement may cause cell death by the activation of complex membrane attacks, known as complementary cytotoxicity; increased antibody-mediated cell cytotoxicity; and cellular cytotoxicity that depend on CR3. Complicated cytotoxicity occurs when the antibodies bind to the surface of cancer cells, the C1 complex binds to these antibodies and subsequently protein pores are formed in the cancer cell membrane.
FDA approved antibody
Alemtuzumab
Alemtuzumab (Campeth-1H) is an anti-CD52 anti-CD52 monoclonal antibody indicated for the treatment of chronic lymphocytic leukemia (CLL) flusinabin-refractory, cutaneous T cell lymphoma, peripheral T cell lymphoma and T-prolymphosytic leukemia. CD52 found on & gt; 95% of peripheral blood lymphocytes (both T-cells and B-cells) and monocytes, but their function in lymphocytes is unknown. It binds to CD52 and initiates its cytotoxic effect with complementary fixation and ADCC mechanisms. Because the targeted antibodies (immune system cells) common complications of alemtuzumab therapy are infection, toxicity and myelosuppression.
Atezolizumab
Durvalumab
Durvalumab (Imfinzi) is a monoclonal antibody of human G1 kappa (IgG1?) Immunoglobulin that blocks the ligand 1 (PD-L1) cell interactions with programmable PD-1 and CD80 (B7.1) molecules. Durvalumab is approved for the treatment of patients with local urothelial carcinoma or advanced metastasis which:
- has a disease progression during or after platinum-containing chemotherapy.
- have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Ipilimumab
Ipilimumab (Yervoy) is a human IgG1 antibody that binds to the surface protein of CTLA4. In normal physiology, the T-cell is activated by two signals: the T-cell receptor binding to the MHC-antigen complex and the T-CD28 cell surface receptor binding to the CD80 or CD86 protein. CTLA4 binds to CD80 or CD86, preventing the binding of CD28 to this surface protein and therefore negatively regulates T-cell activation.
Active cytotoxic T-cells are needed for the immune system to attack melanoma cells. Typically cytotoxic T-specific cells inhibited melanoma can produce an effective anti-tumor response. Ipilumumab may cause a shift in the ratio of regulation of T-cells to cytotoxic T cells to improve anti-tumor response. T-cell regulation inhibits other T cells, which may benefit tumors.
Nivolumab
Ofatumumab
Ofatumumab is a second generation IgG1 antibody binding to CD20. It is used in the treatment of chronic lymphocytic leukemia (CLL) because CLL cancer cells are usually CD20-expressing B-cells. Unlike rituximab, which binds a large loop of CD20 protein, ofatumumab binds to a separate small circle. This may explain their different characteristics. Compared with rituximab, ofatumumab induces cytotoxicity depending on the lower dose with less immunogenicity.
Pembrolizumab
Pembrolizumab is approved for first-line treatment of patients with metastatic non-small cell lung cancer whose tumors have high PD-L1 expression as determined by FDA-approved tests.
Rituximab
Rituximab is a specific chimeric IgG1 monoclonal antibody for CD20, developed from its parent Ibritumomab antibody. Like ibritumomab, rituximab targets CD20, making it effective in treating malignant B-cells. These include aggressive and sluggish lymphomas such as spreading large B-cell lymphomas and follicular lymphomas and leukemia such as chronic lymphocytic leukemia of B. Although CD20 function is relatively unknown, CD20 may be the calcium channel involved in B-cell activation. The mode of action of antibodies is primarily through ADCC induction and complement-mediated cytotoxicity. Other mechanisms include apoptosis and cell growth capture. Rituximab also increases the sensitivity of B cancer cells to chemotherapy.
Cytokine therapy
Cytokines are proteins produced by many types of cells present in the tumor. They can modulate the immune response. Tumors often employ them to allow it to grow and reduce the immune response. This immune-modulating effect allows them to be used as a drug to induce an immune response. Two commonly used cytokines are interferon and interleukin.
Interferon
Interferon is produced by the immune system. They are usually involved in an anti-viral response, but also have a use for cancer. They fall in three groups: type I (IFN and IFN?), Type II (IFN?) And type III (IFN?). IFN? has been approved for use in hair-celled leukemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukemia and melanoma. Type I and II IFN have been studied extensively and although both types promote the effects of the anti-tumor immune system, only type I IFN has been shown to be clinically effective. IFN? showing promise for its anti-tumor effect on animal models.
Unlike type I IFNs, gamma interferon has not been approved for the treatment of any cancer. However, increased survival was observed when gamma interferon was administered in patients with bladder carcinoma and melanoma cancer. The most promising results are achieved in patients with stage 2 and 3 ovarian carcinoma. In vitro studies of IFN-gamma in cancer cells are broader and the results show prominent IFN-gamma anti-proliferation activity. for inhibition of cell growth or death, commonly caused by apoptosis but occasionally by autophagy.
Interleukin
Interleukin has a series of immune system effects. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma. In normal physiology, it promotes effector T cells and T-regulatory cells, but the exact mechanism of action is unknown.
Immunotherapy combination
Combining various immunotherapies such as PD1 and CTLA4 inhibitors can improve the anti-tumor response leading to a long-lasting response.
Combining tumor ablation therapy with immunotherapy enhances the immunostimulation response and has a synergistic effect for curative metastatic cancer treatment.
Combining immunotherapy checkpoints with pharmaceutical agents have the potential to improve response, and such combination therapy is a highly investigated field of clinical investigation. Immunostimulant drugs such as CSF-1R inhibitors and TLR agonists are very effective in this setting.
Polysaccharide-K
Japan's Ministry of Health, Labor and Welfare approved the use of K-polysaccharides extracted from the fungus Coriolus versicolor in the 1980s to stimulate the immune system of patients undergoing chemotherapy. This is a dietary supplement in the US and other jurisdictions.
Research
Adoptive T Cell Therapy
Adoptive T cell therapy is a passive immune form by transfusion of T cells (transfer cell lift). They are found in blood and tissue and are usually active when they encounter an alien pathogen. In particular they activate when T-cell surface receptors encounter cells that feature foreign protein parts on the surface of their antigen. It can be either an infected cell, or an antigen-presenting cell (APCs). They are found in normal tissues and in tumor tissue, where they are known as lymphocyte infiltration tumors (TILs). They are activated by the presence of APC such as dendritic cells that present tumor antigens. Although these cells can attack the tumor, the environment in the tumor is very immunosuppressive, preventing immune-mediated tumor death.
A variety of ways to produce and obtain targeted tumor T cells have been developed. Special cells for tumor antigens can be removed from the tumor sample (TIL) or filtered from the blood. Activation and subsequent cultures are done ex vivo, with reinfused results. Activation can occur through gene therapy, or by exposing T cells to tumor antigens.
In 2014, several ACT clinical trials are underway. Importantly, one study from 2018 showed that clinical responses could be obtained in patients with metastatic melanoma resistant to some previous immunotherapy.
2 first-use T cell therapy, tisagenlecleucel and axicabtagene ciloleucel, were approved by the FDA in 2017.
Another approach is adaptive transfer from haploidentical ?? T cells or NK cells from healthy donors. The main advantage of this approach is that these cells do not cause GVHD. The disadvantage is the frequent disruption of the function of the removed cell.
Anti-CD47 Therapy
Many overexpress CD47 tumor cells to escape immune system of host immunosurveillance. CD47 binds to alpha regulatory regulatory protein (SIRP?) And lowers the regulation of tumor cell phagocytosis. Therefore, anti-CD47 therapy aims to restore the clearance of tumor cells. In addition, more and more evidence supports the use of T cell antigen-specific tumor responses in response to anti-CD47 therapy. A number of therapies are being developed, including anti-CD47 antibodies, engineered decoy receptors, anti-SIRP? antibodies and bispecific agents. In 2017, a variety of dense and hematologic malignancies are being clinically tested.
Anti-GD2 antibodies
Carbohydrate antigens on the cell surface can be used as targets for immunotherapy. GD2 is a ganglioside found on the surface of various types of cancer cells including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumor, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas. Usually not expressed on the surface of normal tissue, making it a good target for immunotherapy. In 2014, clinical trials are underway.
Immune checkpoint
Immune checkpoints affect the functioning of the immune system. Immune checkpoints may be stimulated or inhibited. Tumors can use these checkpoints to protect themselves against immune system attacks. The currently approved checkpoint therapies block the receptor checkpoint receptors. A negative feedback blockade that signals the immune cells resulting in an increased immune response to the tumor.
One ligand-receptor interaction under investigation was the interaction between transmembrane programmed cell death 1 protein (PDCD1, PD-1, also known as CD279) and its ligand, PD-1 ligand 1 (PD-L1, CD274). PD-L1 on the cell surface binds to PD1 on the surface of immune cells, which inhibits immune cell activity. Among the functions of PD-L1 is a major regulatory role in T-cell activity. It appears that cancer-mediated upregulation of PD-L1 on the cell surface can inhibit T cells that may attack. PD-L1 in cancer cells also inhibits FAS and interferon-dependent apoptosis, protecting cells from cytotoxic molecules produced by T cells. Antibodies that bind either PD-1 or PD-L1 and therefore block the interactions allow T-cells to attack the tumor.
CTLA-4 blockade
The first FDA-approved checkpoint antibody is ipilimumab, approved in 2011 for melanoma treatment. This blocks the CTLA-4 immune-checking molecule. Clinical trials also show some of the benefits of anti-CTLA-4 therapy in lung cancer or pancreatic cancer, especially in combination with other drugs. In an ongoing trial, a combination of CTLA-4 blockade with PD-1 or PD-L1 inhibitors was tested on various cancers.
However, patients treated with blocked check-points (especially CTLA-4 blocking antibodies), or combination of check-point blocking antibodies, are at high risk for immune-related side effects such as dermatology, gastrointestinal, endocrine, or autoimmune liver reactions. This is most likely due to the extent of T cell activation induced when anti-CTLA-4 antibodies are administered by injection in the bloodstream.
Using bladder cancer mouse models, researchers have found that local injections of low doses of anti-CTLA-4 in the tumor area have the same tumor-inhibitory capacity as when the antibodies were delivered in the blood. At the same time the circulating antibody level is lower, indicating that local administration of anti-CTLA-4 therapies may produce fewer side effects.
PD-1 inhibitor
Early clinical trials with IgG4 PD1 antibody Nivolumab were published in 2010. It was approved in 2014. Nivolumab was approved to treat melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin's lymphoma. A 2016 clinical trial for non-small cell lung cancer failed to meet its main end point for treatment in a first-line setting, but FDA-approved for subsequent therapy.
Pembrolizumab is another PD1 inhibitor approved by the FDA in 2014. Keytruda (Pembrolizumab) is approved to treat melanoma and lung cancer.
BGB-A317 antibody is a PD-1 inhibitor (designed not to bind to Fc gamma receptor I) in initial clinical trials.
PD-L1 inhibitors
In May 2016, a PD-L1 atezolizumab inhibitor was approved to treat bladder cancer.
Anti-PD-L1 antibodies currently under development include avelumab and durvalumab, in addition to biotherapeutic afimer.
More
Other ways to improve adoptive immunotherapy include targeting block blocks of intrinsic blocks such as CISH.
Oncolytic virus
Oncolytic virus is a virus that exclusively infects and kills cancer cells. Because infected cancer cells are destroyed by oncolysis, they release new viral infection particles or virions to help destroy the remaining tumors. The oncolytic virus is thought to not only cause direct damage to tumor cells, but also to stimulate the host anti-tumor immune response for long-term immunotherapy.
The viral potential as an anti-cancer agent was first realized in the early twentieth century, although coordinated research efforts did not begin until the 1960s. A number of viruses including adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia have now been clinically tested as oncolytic agents. T-Vec is the first oncolytic virus approved by the FDA for the treatment of melanoma. A number of other oncolytic viruses are in phase II-III.
Polysaccharide
Certain compounds found in fungi, especially polysaccharides, can regulate the immune system and may have anti-cancer properties. For example, beta-glucans such as lentinan have been shown in laboratory studies to stimulate macrophages, NK cells, T cells and immune system cytokines and have been investigated in clinical trials as immunological adjuvants.
Neoantigens
Many tumors express mutations. These mutations have the potential to create new, targetable antigens (neoantigens) for use in T cell immunotherapy. The presence of CD8 T cells in cancer lesions, as identified using RNA sequencing data, is higher in tumors with high mutation loads. The transcript rate associated with the sitolytic activity of natural killer cells and T cells is positively correlated with mutation loads in many human tumors. In patients with non-small cell lung cancer treated with lambrolizumab, mutation loads show a strong correlation with clinical response. In ipilimumab-treated melanoma patients, long-term benefits are also associated with higher mutation loads, although less significant. The predicted MHC-binding neoantigens in patients with long-term clinical benefit are enriched for a series of tetrapeptide motifs not found in patient tumors without minimal or minimal clinical benefit. However, the human neoantigen identified in other studies showed no bias against signs of tetrapeptide.
See also
- Cancer vaccine
- Antigen 5T4
- Coley Poison
- Combinatorial and combinations of immunotherapy
- Cryoimmunotherapy
- Photoimmunotherapy
References
External links
- Immunotherapy - Using Immune System to Treat Cancer
- Cancer Research Institute - What is Cancer Immunotherapy
- Association for Cancer Immunotherapy
- Society for Cancer Immunotherapy
- "And then there are Five". Economist .
- "Discover Immunology-Oncology". Bristol-Myers Squibb . Retrieved March 13 2014 .
- Eggermont A, Finn O. "Progress in immuno-oncology". Oxford University Press . Retrieved March 13, 2014 .
- "Immuno-Oncology: Investigating Cancer Therapy Supported by the Immune System". Merck Serono . Retrieved March 13 2014 . Source of the article : Wikipedia
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