CAR T cell Therapy: Over the course of time immunological research has been improved by the study of different receptor. The receptors ar...
Over
the course of time immunological research has been improved by the study of
different receptor. The receptors are studied on the basis of their structure
and their interaction with different other antigenic components like the
anti-immune components of different cancerous cells and some viruses and
microbes. These studies provided lot of help in the treatment of different
immunological diseases. One of the major approaches is CAR T Cell Therapy which
uses specific receptors for treatment of cancerous cells. These receptors are
modified in vitro and then utilized for treatment. This is process is a
categorized part of immunotherapy.
What
is CAR?
CAR
refers to “Chimeric Antigen Receptor” which is a protein made in laboratory
used to attach at T cell surface so that it act as receptor for antigens
present on cancerous cells. These CARs consist of Extracellular Chains which
single chained and are variable domains consisting of trans-membrane regions. The
intracellular region is also containing tyrosine based activation motifs which
functions for activation of its effector cells against antigens that it
recognizes. The single chain variable region functions for attachment to tumor
antigens present on tumor cell surfaces. The intracellular domain function for
activation of T cells, its proliferation.
Figure 1. Structure of CAR (Source:
Wikipedia )
The
Car structure is flexible in a sense that its single chain variable fragment
region can recognize a lot of different forms of antigens and is independent of
major histocompatibility complex (on which the receptors of T cells are
dependent).The CARs can recognize antigens with different types of functional
groups such as proteins, carbohydrates and gangliosides.
How
are CARs generated?
The
chimeric antigen receptors are generated in laboratory by using the clones of
specific gene responsible for single chain variable fragment specific for
carcino-embryonic antigen of a human carcino cell. The domain of gene was
cloned by its insertion into Jurkat cells which are immortalized lines human T
cells, by using pBi vectors (bidirectional vectors). The cDNA regions that are
cloned were obtained from hybridoma and modified by PCR processing to remove
the specified region coding for anti carcino-embryonic antigens.
Different
screening techniques were used to confirm the insertion in the clones and for T
cell activation confirmation, different T cell check assays were used like
cytokine production assay.
How
They Work?
When
the CAR T cells recognize the tumor antigens and bind to it, it causes the
activation of T cells by phosphorylation of the tyrosine based intracellular
motifs. This results in the secretions of different chemical signals like
cytokines which is followed by cytotoxic T cell activation and proliferation to
maintain a balanced attack against the specific tumor cells.
The
CAR T cells after antigen binding also causes the secretion of granzyme
granules and perforins and also interferon gamma IFN-γ. These also activate the cell death receptor indulging apoptosis
by using Fas-L and TNF-R. Thus this action of multi-immune agents causes the
destruction of tumor cells.
The
actions of CAR T cells are thought to be improved by using multiple signaling
receptors to activate the multiple components of immune system at a time to
efficiently destroy the tumor cells. TRUCK: T cell redirected for universal
cytokine killing, is a mechanism which was introduced to redirect CAR-T cells
so that it becomes able to release protein signals like IL-20 (Interleukin 20)
and others to activate innate immune system against tumor antigen alongside
adaptive immune activity to potentiate the process by co-activation of other
immune components like NK cells.
How
the therapy is performed?
During
this therapy the T cells of patient are taken from patients through apheresis
and then these T cells are modified by biotechnological modification using
techniques of PCR amplification and the product it then cloned and multiplied.
After genetic modification and cloning CAR T cells are produced which are then
injected back to the patient. Before the injection of CAR T cells the patients
are pre-tested by a short course of chemotherapy to check the effectiveness of
the patient for the process. Too weak immune patients are first aided to get
rid of some level of weakness and then treated.
Side
Effects of CAR T cell Therapy:
The
CAR T cell Therapy can also have some side effects and it require proper
handling as some patients have been died at its pre stages of treatments.
1.
Cytokine Release Syndrome CRS:
This is the excessive release of cytokines into the blood stream of
the patients. This causes due to excessive activation and proliferation of CAR
T cells soon after the injection of CAR-Ts into the patient blood. This can
result into lot of health problems like high fever, nausea, muscle aches etc.
Different drugs are used along side CAR infusion into patient to prevent the
CRS.
2.
Effects on Nervous system:
The improper infusion can also result in the causing of defects in
the brain the nervous system, which if not handled properly can be severely
dangerous. Researchers are working to still find the main reason of these
effects of CAR T cell therapy.
3.
B cell loss, B cell Aplasia:
This includes the destruction of normal B cells by CAR t cells
during its action of cancerous cells. This can then causes other immune
disabilities leading to slowness and even stopping of certain immune functions
against antigens.
4.
Tumor Lysis Syndrome TLS:
This is due to toxic effects caused by breakdown of the dying cells of
tumors which are destructed by immune components. This mainly is due to
metabolic mistakes durig action of CAR T cells on the cancerous cells and
usually starts after certain weeks of treatments. To handle this certain
medications and drugs are used after the therapy.
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