Chimeric antigen receptor T cells (also known as CAR T cells) are T cells that have been genetically engineered to produce an artificial T-cell receptor.
Chimeric antigen receptors are bioengineered proteins that give T-cells the mechanism to neutralize a particular protein. The receptors are termed “chimeric” because they utilize both native T-cell functions and the new antigen-recognizing functions into one receptor.
CAR-T cell therapy uses T cells engineered with CARs for cancer therapy. The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to more effectively target and destroy them.
How does it work ?
Scientists harvest T cells from people, genetically alter them, then infuse the resulting CAR-T cells into patients to attack their tumors.
CAR-T cells can be either derived from T cells in a patient’s own blood (autologous) or derived from the T cells of another healthy donor (allogenic). Once isolated from a person, these T cells are genetically engineered to express a specific CAR, which programs them to target an antigen that is present on the surface of tumors. For safety, CAR-T cells are engineered to be specific to an antigen expressed on a tumor that is not expressed on healthy cells.
In theory, these T cells are not supposed to attack other non cancerous cells. .
After CAR-T cells are infused into a patient, they act as a “living drug” against cancer cells. When they come in contact with their targeted antigen on a cell, CAR-T cells bind to it and become activated, then proceed to proliferate and become cytotoxic.
CAR-T cells destroy cells through several mechanisms, including extensive stimulated cell proliferation, increasing the degree to which they are toxic to other living cells (cytotoxicity), and by causing the increased secretion of factors that can affect other cells such as cytokines, interleukins, and growth factors.
- 2Cancer treatment
- 2.1Clinical studies and FDA approvals
- 2.2Safety concerns
- 3Receptor structure
- 3.2Transmembrane domain
- 4.1Smart T cell
- 4.2SMDC adaptor technology
- 5See also
- 7External links
The first step in the production of CAR-T cells is the isolation of T cells from human blood. CAR-T cells may be manufactured either from the patient’s own blood, known as an autologous treatment, or from the blood of a healthy donor, known as an allogenic treatment. The manufacturing process is the same in both cases; only the choice of initial blood donor is different.
First, leukocytes are isolated using a blood cell separator in a process known as leukocyte apheresis. Peripheral blood mononuclear cells (PBMC) are then separated and collected. The products of leukocyte apheresis are then transferred into a cell processing center. In the cell processing center, specific T cells are stimulated so that they will actively proliferate and expand to large numbers. To drive their expansion, T cells are typically treated with the cytokine Interleukin 2 (IL-2) and anti-CD3antibodies.
The expanded T cells are purified and then transduced with a gene encoding the engineered CAR via a retroviral vector, typically either an integrating gammaretrovirus (RV) or a lentiviral (LV) vector. These vectors are very safe in modern times due to a partial deletion of the U3 region.
The patient undergoes lymphodepletion chemotherapy prior to the introduction of the engineered CAR-T cells. The depletion of the number of circulating leukocytes in the patient upregulates the number of cytokines that are produced and reduces competition for resources, which help to promote the expansion of the engineered CAR-T cells.
T cells are genetically engineered to express chimeric antigen receptors specifically directed toward antigens on a patient’s tumor cells, then infused into the patient where they attack and kill the cancer cells. Adoptive transfer of T cells expressing CARs is a promising anti-cancer therapeutic, because CAR-modified T cells can be engineered to target virtually any tumor associated antigen. There is great potential for this approach to improve patient-specific cancer therapy in a profound way.
Early CAR-T cell research has focused on blood cancers. The first approved treatments use CARs that target the antigen CD19, present in B-cell-derived cancers such as acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). There are also efforts underway to engineer CARs targeting many other blood cancer antigens, including CD30 in refractory Hodgkin’s lymphoma; CD33, CD123, and FLT3 in acute myeloid leukemia (AML); and BCMA in multiple myeloma.
Solid tumors have presented a more difficult target. Identification of good antigens has been challenging: such antigens must be highly expressed on the majority of cancer cells, but largely absent on normal tissues. CAR-T cells are also not trafficked efficiently into the center of solid tumor masses, and the hostile tumor microenvironment suppresses T cell activity.
Many Clinical Trials
As of August 2017, there were around 200 clinical trials happening globally involving CAR-T cells. Around 65% of those trials targeted blood cancers, and 80% of them involved CD19 CAR-T cells targeting B-cell cancers. In 2016, studies began to explore the viability of other antigens, such as CD20.
The first two FDA approved CAR-T therapies both target the CD19 antigen, which is found on many types of B-cell cancers.Tisagenlecleucel (Kymriah) is approved to treat relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), while axicabtagene ciloleucel (Yescarta) is approved to treat relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Although the initial clinical remission rates after CAR-T cell therapy in ALL patients are as high as 90%, long term survival rates are much lower. The cause is typically the emergence of leukemia cells that do not express CD19 and so evade recognition by the CD19–CAR T cells, a phenomenon known as antigen escape. Preclinical studies developing CAR-T cells with dual targeting of CD19 plus CD22 or CD19 plus CD20 have demonstrated promise, and trials studying bispecific targeting to circumvent CD19 down-regulation are ongoing.
CAR-T cells are undoubtedly a major breakthrough in cancer treatment. However, there are serious side effects that result from CAR-T cells being introduced into the body, including cytokine release syndrome and neurological toxicity. Because it is a relatively new treatment, there is little data about the long-term effects of CAR-T cell therapy. There are still concerns about long-term patient survival, as well as pregnancy complications in female patients treated with CAR-T cells.
The most common issue after treatment with CAR-T cells is cytokine release syndrome (CRS), a condition in which the immune system is activated and releases an increased number of inflammatory cytokines. The clinical manifestation of this syndrome resembles sepsis with high fever, fatigue, myalgia, nausea, capillary leakages, tachycardia and other cardiac dysfunction, liver failure, and kidney impairment. CRS occurs in almost all patients treated with CAR-T cell therapy; in fact, the presence of CRS is a diagnostic marker that indicates the CAR-T cells are working as intended to kill the cancer cells. Note, however, that a higher grade of CRS severity does not correlate with an increased response to the treatment, but rather higher disease burden.
Neurological toxicity is also often associated with CAR-T cell treatment. The underlying mechanism is poorly understood, and may or may not be related to CRS. Clinical manifestations include delirium, the partial loss of the ability to speak a coherent language while still having the ability to interpret language (expressive aphasia), lowered alertness (obtundation), and seizures. During some clinical trials deaths caused by neurotoxicity have occurred. The main cause of death from neurotoxicity is cerebral edema. In a study carried out by Juno Therapeutics, Inc., five patients enrolled in the trial died as a result of cerebral edema. Two of the patients were treated with cyclophosphamide alone and the remaining three were treated with a combination of cyclophosphamide and fludarabine. In another clinical trial sponsored by the Fred Hutchinson Cancer Research Center, there was one reported case of irreversible and fatal neurological toxicity 122 days after the administration of CAR-T cells.
Anaphylaxis is an expected side effect, as the CAR is made with a foreign monoclonal antibody and as a result, provokes an immune response.
On-target/off-tumor recognition occurs when the CAR-T cell recognizes the correct antigen, but the antigen is expressed on healthy, non-pathogenic tissue. This results in the CAR-T cells attacking non-tumor tissue, such as healthy B cells that express CD19. The severity of this adverse effect can vary from B-cell aplasia, which can be treated with supporting infusions, to extreme toxicity leading to death.
There is also the unlikely possibility that the engineered CAR-T cells will themselves become transformed into cancerous cells through insertional mutagenesis, due to the viral vector inserting the CAR gene into a tumor suppressor or oncogene in the host T cell’s genome. Lentiviral (LV) vectors carry a lower risk than retroviral (RV) vectors. However, both have the potential to be oncogenic.
Chimeric antigen receptors combine many facets of normal T cell activation into a single protein. They link an extracellular antigen recognition domain to intracellular signalling domains, which activates the T cell when an antigen is bound. CARs are composed of three regions: the ectodomain, the transmembrane domain, and the endodomain.
The ectodomain is the region of the receptor that is exposed to the outside of the cell and so interacts with potential target molecules. It consists of 3 major components: an antigen recognition region that binds the target molecule, a signal peptide that directs the nascent protein into the endoplasmic reticulum, and a spacer that makes the receptor more available for binding.
The antigen recognition region is responsible for targeting the CAR-T cell to cells expressing a particular molecule, and typically consists of a single-chain variable fragment (scFv). An scFv is a chimeric protein made up of the light (VL) and heavy (VH) chains of immunoglobins, connected with a short linker peptide. These VL and VH regions are selected in advance for their binding ability to the target antigen (such as CD19). The linker between the two chains consists of hydrophilic residues with stretches of glycine and serine in it for flexibility as well as stretches of glutamate and lysine for added solubility.
The spacer is a small structural domain that sits between the antigen recognition region and the cell’s outer membrane. An ideal spacer enhances the flexibility of the scFv receptor head, reducing the spatial constraints between the CAR and its target antigen. This promotes antigen binding and synapse formation between the CAR-T cells and target cells. Spacers are often based on hinge domains from IgG or CD8.
The transmembrane domain is a structural component, consisting of a hydrophobic alpha helix that spans the cell membrane. This domain is essential for the stability of the receptor as a whole. Generally, the transmembrane domain from the most membrane-proximal component of the endodomain is used, but different transmembrane domains result in different receptor stability. The CD28 transmembrane domain is known to result in a highly expressed, stable receptor.
Using the CD3-zeta transmembrane domain is not recommended, as it can result in incorporation of the artificial TCR into the native TCR.
After an antigen is bound to the external antigen recognition region, CAR receptors cluster together and transmit an activation signal. The endodomain is the internal cytoplasmic end of the receptor that perpetuates signaling inside the T cell.
Normal T cell activation relies on the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) present in the cytoplasmic domain of CD3-zeta. To mimic this process, CD3-zeta’s cytoplasmic domain is commonly used as the primary CAR endodomain component. Other ITAM-containing domains have also been tried, but are not as effective.
T cells also require co-stimulatory molecules in addition to CD3 signaling in order to activate. For this reason, the endodomains of CAR receptors typically also include one or more chimeric domains from co-stimulatory proteins such as CD28, 4-1BB (CD127), or OX40.
The first CAR-T cells were developed in 1989 by Gideon Gross and Zelig Eshhar at Weizmann Institute, Israel. The sophistication of the engineered CAR receptors has grown over time, and are referred to as first, second, third, or fourth generation CARs depending on their composition.
First generation CARs are composed of an extracellular binding domain, a hinge region, a transmembrane domain, and one or more intracellular signaling domains. The extracellular binding domain contains a single‐chain variable fragment (scFv) derived from tumor antigen‐reactive antibodies that usually has a high specificity to a specific tumor antigen. All CARs contain the CD3ζ chain domain as the intracellular signaling domain, which is the primary transmitter of T cell activation signals.
Second generation CARs add a co‐stimulatory domain, like CD28 or 4‐1BB. The involvement of these intracellular signaling domains improve T cell proliferation, cytokine secretion, resistance to apoptosis, and in vivo persistence.
Third generation CARs combine multiple co-stimulatory domains, such as CD28-41BB or CD28-OX40, to augment T cell activity. Preclinical data show the third-generation CARs exhibit improved effector functions and better in vivo persistence as compared to second‐generation CARs.
Fourth generation CARs (also known as TRUCKs or armored CARs) further add factors that enhance T cell expansion, persistence, and anti‐tumoral activity. This can include cytokines, such is IL-2, IL-5, IL-12 and co‐stimulatory ligands.
Smart T cell is engineered with a suicide gene
Combined with exogenous molecules, some synthetic control devices have been implemented on CAR-T cells and alter the cell activity. The smart T cell is engineered with a suicide gene or other synthetic control panels to precisely control therapeutic function over the timing and dosage, there by alleviating cytotoxicity. Several strategies to improve safety and efficacy of CAR-T cells are:
Suicide gene engineering: engineered T cells are incorporated with suicide genes, which can be activated by extracellular molecule and then induce T cell apoptosis. Herpes simplex virus thymidine kinase (HSV-TK) and inducible caspase 9 (iCas9) are two types suicide genes have been integrated into CAR-T cells. In iCas9 system, the suicide gene is composed of the sequence of the mutated FK506-binding protein with high specificity to a small-molecule, AP1903 and a gene encoding human caspase 9 switch. When the release of cytokines by CAR-T cells becomes more pronounced than basic levels, the iCas9 can be dimerized and lead to rapid apoptosis of T cells. Although both suicide genes demonstrate a noticeable function of as a safety switch in clinical trials for cellular therapies, some hinder defects limit the application of this strategy. HSV-TK is derived from virus and may be immunogenic to humans. The suicide gene strategies may not act quickly enough to eliminate off-tumor cytotoxicity as well.
Dual-antigen receptor: T cells are engineered to express two tumor-associated antigen receptors at the same time. The dual-antigen receptor of engineered T cell module has been reported to have less intense side effects. The activation of CAR-T cell via TCR-CD3ζ signal transduction pathway is transient and a complementary signal pathway provided by co-stimulatory molecules on antigen presenting cells promotes survival of modified-T cell can ability in controlling tumor. An in vivo study in mice shows the dual-receptor T cells effectively eradicated prostate cancer and achieved complete long-term survival.
ON-switch: ON-switch CAR-T cell split synthetic receptors into two parts: the first part mainly contains an antigen binding domain towards and the other part features two different downstream signaling elements (e.g. CD3ζ and 4-1BB). Upon the presence of an exogenous molecule (rapamycin analogs for example), two physically separated signaling elements fuse together and CAR-T cells exert therapeutic functions. In this mechanism, the engineered T cell shows therapeutic function only in the presence of both tumor antigen and a benign exogenous molecule.
Bifunctional molecules as switches: The bispecific antibodies are developed as an efficacious bridge to target cytotoxic T cells to cancer cells and causes localized T cell activation. In this strategy, the bispecific antibody targets CD3 molecule of T cell and tumor-associated antigen presented on cancer cell surface. The anti-CD20/CD3 bispecific molecule shows high specificity to both malignant B cells and cancer cells in mice. FITC is another bifunctional molecule used in this strategy. FITC can redirect and regulate the activity of the FITC-specific CAR-T cells toward tumor cells with folate receptors.
History and Conclusion
SMDCs (small molecule drug conjugates) platform in immuno-oncology is a novel (currently experimental) approach that makes possible the engineering of a single universal CAR T cell, which binds with extraordinarily high affinity to a benign molecule designated as FITC. These cells are then used to treat various cancer types when co-administered with bispecific SMDC adaptor molecules. These unique bispecific adaptors are constructed with a FITC molecule and a tumor-homing molecule to precisely bridge the universal CAR T cell with the cancer cells, which causes localized T cell activation. Anti-tumor activity in mice is induced only when both the universal CAR T cells plus the correct antigen-specific adaptor molecules are present. Anti-tumor activity and toxicity can be controlled by adjusting the administered adaptor molecule dosing. Treatment of antigenically heterogeneous tumors can be achieved by administration of a mixture of the desired antigen-specific adaptors. Thus, several challenges of current CAR T cell therapies, such as: the inability to control the rate of cytokine release and tumor lysis, the absence of an “off switch” that can terminate cytotoxic activity when tumor eradication is complete, a requirement to generate a different CAR T cell for each unique tumor antigen, may be solved or mitigated using this approach.
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