The diagram above represents the process of chimeric antigen receptor T-cell therapy (CAR), this is a method of immunotherapy, which is a growing practice in the treatment of cancer. The final result should be a production of equipped T-cells that can recognize and fight the infected cancer cells in the body.
T-cells (represented by objects labeled as 't') are removed from the patient's blood.
Then in a lab setting the gene that encodes for the specific antigen receptors are incorporated into the T-cells.
Thus producing the CAR receptors (labeled as c) on the surface of the cells.
The newly modified T-cells are then further harvested and grown in the lab.
After a certain time period, the engineered T-cells are infused back into the patient.
Immunotherapy orbiological therapy is the treatment ofdisease by activating or suppressing theimmune system. Immunotherapies designed to elicit or amplify an immune response are classified asactivation immunotherapies, while immunotherapies that reduce or suppress are classified assuppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms ofcancer.[1][2][3][4]
Cell-based immunotherapies are effective for some cancers.[5][6] Immune effector cells such aslymphocytes,macrophages,dendritic cells,natural killer cells, andcytotoxic T lymphocytes work together to defend the body against cancer by targeting abnormal antigens expressed on the surface of tumor cells. Vaccine-induced immunity to COVID-19 relies mostly on an immunomodulatory T-cell response.[7]
Cancer treatment used to be focused on killing or removing cancer cells and tumours, with chemotherapy or surgery or radiation. In 2018 theNobel Prize in Physiology or Medicine was awarded toJames P. Allison andTasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation." Cancer immunotherapy attempts to stimulate theimmune system to destroy tumours. A variety of strategies are in use or are undergoing research and testing. Randomized controlled studies in different cancers resulting in significant increase in survival and disease free period have been reported[2] and its efficacy is enhanced by 20–30% when cell-based immunotherapy is combined with conventional treatment methods.[2]
One of the oldest forms of cancer immunotherapy is the use ofBCG vaccine, which was originally to vaccinate againsttuberculosis and later was found to be useful in the treatment ofbladder cancer.[13] BCG immunotherapy induces both local and systemic immune responses. The mechanisms by which BCG immunotherapy mediates tumor immunity have been widely studied, but they are still not completely understood.[14]
The use ofmonoclonal antibodies in cancer therapy was first introduced in 1997 withrituximab, an anti-CD20 antibody for treatment of B cell lymphoma.[15] Since then several monoclonal antibodies have been approved for treatment of various haematological malignancies as well as for solid tumours.[16][17]
Dendritic cells (DC) can be stimulated to activate acytotoxic response towards anantigen. Dendritic cells, a type ofantigen-presenting cell, are harvested from the person needing the immunotherapy. These cells are then either pulsed with an antigen or tumour lysate ortransfected with aviral vector, causing them to display the antigen. Upon transfusion into the person, these activated cells present the antigen to the effector lymphocytes (CD4+ helper T cells, cytotoxicCD8+ T cells andB cells). This initiates a cytotoxic response against tumour cells expressing the antigen (against which the adaptive response has now been primed). The first FDA-approved cell-based immunotherapy,[28] thecancer vaccineSipuleucel-T is one example of this approach.[29] The Immune Response Corporation[30] (IRC) developed this immunotherapy and licensed the technology to Dendreon, which obtained FDA clearance.
The current approaches forDC-based vaccination are mainly based on antigen loading onin vitro-generated DCs frommonocytes orCD34+ cells, activating them with differentTLR ligands,cytokine combinations, and injecting them back to the patients. Thein vivo targeting approaches comprise administering specific cytokines (e.g.,Flt3L,GM-CSF) and targeting the DCs with antibodies to C-type lectin receptors or agonistic antibodies (e.g., anti-CD40) that are conjugated with antigen of interest. Multiple, next-generation anti-CD40 platforms are being actively developed.[31] Future approach may target DC subsets based on their specifically expressedC-type lectin receptors orchemokine receptors. Another potential approach is the generation of genetically engineered DCs frominduced pluripotent stem cells and use ofneoantigen-loaded DCs for inducing better clinical outcome.[32]
Alternatively,Genetically engineered T cells are created by harvesting T cells and then infecting the T cells with aretrovirus that contains a copy of aT cell receptor (TCR) gene that is specialised to recognise tumour antigens. The virus integrates the receptor into the T cells'genome. The cells are expanded non-specifically and/or stimulated. The cells are then reinfused and produce an immune response against the tumour cells.[34] The technique has been tested on refractory stage IV metastatic melanomas[33] and advancedskin cancer.[35][36][37] The first FDA-approved CAR-T drug, Kymriah, used this approach. To obtain the clinical and commercial supply of this CAR-T, Novartis purchased the manufacturing plant, the distribution system and hired the production team that produced Sipuleucel-T developed by Dendreon and the Immune Response Corporation.[38]
Whether T cells are genetically engineered or not, before re-infusion, lympho-depletion of the recipient is required to eliminate regulatory T cells as well as unmodified, endogenous lymphocytes that compete with the transferred cells for homeostatic cytokines.[33][39][40][41] Lymphodepletion may be achieved bymyeloablative chemotherapy, to which total body irradiation may be added for greater effect.[42] Transferred cells multipliedin vivo and persisted in peripheral blood in many people, sometimes representing levels of 75% of all CD8+ T cells at 6–12 months after infusion.[43] As of 2012[update], clinical trials for metastatic melanoma were ongoing at multiple sites.[44] Clinical responses to adoptive transfer of T cells were observed in patients with metastatic melanoma resistant to multiple immunotherapies.[45]
Anti-PD-1/PD-L1 and anti-CTLA-4 antibodies are the two types of checkpoint inhibitors currently available to patients. The approval of anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) antibodies for human use has already resulted in significant improvements in disease outcomes for various cancers.[46]
Although these molecules were originally discovered as molecules playing a role inT cell activation orapoptosis, subsequent preclinical research showed their important role in the maintenance of peripheral immune tolerance.[47]
These therapies have revolutionizedcancer immunotherapy as they showed for the first time in many years of research in metastaticmelanoma, which is considered one of the mostimmunogenic human cancers, an improvement in overall survival, with an increasing group of patients benefiting long-term from these treatments, although caution remains needed for specific subgroups.[47][50][51]
The next generation of checkpoint inhibitors targets other receptors such as lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). Antibodies against these receptors have been evaluated in clinical studies, but have not yet been approved for widespread use.[52]
Immunosuppressive drugs can be used to control the immune system with organ transplantation and with autoimmune disease. Immune responses depend on lymphocyte proliferation. Lymphocyte proliferation is the multiplication of lymphocyte cells used to fight and remember foreign invaders.[60] Cytostatic drugs are a type of immunosuppressive drug that aids in slowing down the growth of rapidly dividing cells. Another example of an immunosuppressive drug is Glucocorticoids which are more specific inhibitors of lymphocyte activation. Glucocorticoids work by emulating actions of natural actions of the body's adrenal glands to help suppress the immune system, which is helpful with autoimmune diseases|,[61] Alternatively, inhibitors of immunophilins more specifically target T lymphocyte activation, the process by which T-lymphocytes stimulate and begin to respond to a specific antigen,[62] There is also Immunosuppressive antibodies which target steps in the immune response to prevent the body from attacking its tissues, which is a problem with autoimmune diseases,[63] There are various other drugs that modulate immune responses and can be used to induce immune regulation. It was observed in a preclinical trial that regulation of the immune system by small immunosuppressive molecules such as vitamin D, dexamethasone, and curcumin could be helpful in preventing or treating chronic inflation. Given that the molecules are administered under a low-dose regimen and subcutaneously. A study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Valrubicin-loaded immunoliposomes (Val-ILs) as a novel nanoparticle technology to target immunosuppressive cells. Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death of immunosuppressive cells.[64]
The body naturally does not launch an immune system attack on its own tissues. Models generally identifyCD4+ T-cells at the centre of theautoimmune response. Loss of T-cell tolerance then unleashes B-cells and other immune effector cells on to the target tissue. The idealtolerogenic therapy would target the specific T-cell clones co-ordinating the autoimmune attack.[65]
Immune tolerance therapies seek to reset the immune system so that the body stops mistakenly attacking its own organs or cells inautoimmune disease or accepts foreign tissue inorgan transplantation.[66] A recent[when?] therapeutic approach is the infusion ofregulatory immune cells into transplant recipients. The transfer of regulatory immune cells has the potential to inhibit the activity of effector.[67][68]
Creatingimmune tolerance reduces or eliminates the need for lifelong immunosuppression and attendant side effects. It has been tested on transplantations,rheumatoid arthritis,type 1 diabetes and other autoimmune disorders.
Approaches to therapeutic tolerance induction[65][69][70]
Immunotherapy can also be used to treatallergies. While allergy treatments (such asantihistamines orcorticosteroids) treat allergic symptoms, immunotherapy can reduce sensitivity toallergens, lessening its severity. Allergen immunotherapy can also be referred to as allergen desensitization or hypo-sensitization.[71] Immunotherapy may produce long-term benefits.[72] Immunotherapy is partly effective in some people and ineffective in others, but it offers people with allergies a chance to reduce or stop their symptoms.[citation needed]
Subcutaneous allergen immunotherapy was first introduced in 1911 through the hypothesis that people with hay fever were sensitive to pollen from grass. A process was developed to create an extract by drawing out timothy pollen in distilled water and then boiling it. This was injected into patients in increasing doses to help alleviate symptoms.[73]
Allergen Immunotherapy is indicated for people who are extremely allergic or who cannot avoid specificallergens and when there is evidence of an IgE-mediated reaction that correlates with allergen symptoms. These IgE-mediated reactions can be identified via a blood IgE test or skin testing. If a specific IgE antibody is negative, there is no evidence that allergen immunotherapy will be effective for that patient.
However, there are risks associated with allergen immunotherapy as it is the administration of an agent the patient is known to be highly allergic to. Patients are at increased risk of fatalanaphylaxis, local reaction at the site of injection, or life-threatening systemic allergic reactions.[71]
A promising approach to treat food allergies is the use oforal immunotherapy (OIT). OIT consists in a gradual exposure to increasing amounts of allergen can lead to the majority of subjects tolerating doses of food sufficient to prevent reaction on accidental exposure.[74] Dosages increase over time, as the person becomes desensitized. This technique has been tested on infants to prevent peanut allergies.[75]
Whipwormova (Trichuris suis) andhookworm (Necator americanus) have been tested for immunological diseases and allergies, and have proved beneficial on multiple fronts, yet it is not entirely understood. Scientists have found that the immune response triggered by the burrowing of hookworm larvae to pass through the lungs and blood so the production of mast cells and specific antibodies are now present. They also reduce inflammation or responses ties to autoimmune diseases, but despite this, the hookworm's effects are considered to be negative typically.[76]Helminthic therapy has been investigated as a treatment for relapsing remittingmultiple sclerosis,[77]Crohn's,[78][79][80] allergies and asthma.[81] While there is much to be learned about this, many researchers think that the change in the immune response is thanks to the parasites shifting to a more anti-inflammatory or regulatory system, which would in turn decrease inflammation and self inflicted immune damage as seen in Crohn's and multiple sclerosis. Specifically, MS patients saw lower relapse rates and calmer symptoms in some cases when experimenting with helminthic therapy.[82] Hypothesized mechanisms include re-polarisation of theTh1 / Th2 response[83] and modulation of dendritic cell function.[84][85] The helminths downregulate the pro-inflammatory Th1 cytokines,interleukin-12 (IL-12),interferon-gamma (IFN-γ) andtumor necrosis factor-alpha (TNF-α), while promoting the production of regulatory Th2 cytokines such asIL-10,IL-4,IL-5 andIL-13.[83][86]
Co-evolution with helminths has shaped some of the genes associated withinterleukin expression and immunological disorders, suchCrohn's,ulcerative colitis andceliac disease. Helminths' relationship to humans as hosts should be classified as mutualistic orsymbiotic.[87] In some ways, the relationship is symbiotic because the worms themselves need the host (humans) for survival, because this body supplies them with nutrients and a home. From another perspective, it could be reasoned that it is mutualistic, being that the above information about benefits in autoimmune disorders continues to remain true and supported. Also, some say that the worms can regulate gut bacteria.[88] Another possibility is one of this being a parasitic relationship, arguing that the possible risks of anemia and other disorders outweighs the benefits, yet this is significantly less supported, with the research alluding to the mutualistic and symbiotic approach being much more likely.
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