The Details Of CAR-T Explained

Scientists can genetically engineer cells to alter their characteristics by introducing foreign DNA or by replacing mutated genes with functional copies. Great success in recent clinical trials for patients with B-cell lymphoma has sparked enormous interest in genetically engineering T cells to combat cancer. Scientists have engineered T cells by inserting foreign DNA that code for a Chimeric Antigen Receptor (CAR). This receptor  recognizes antigens only present on tumor cells and initiates signals that lead to massive tumor death.

The use of genetic engineering to treat cancer exploded after the FDA approved Kite Pharmaceuticals to treat B-cell lymphoma in clinical trials. Introducing foreign DNA to genetically engineer T cells boosts the body’s immune system to decimate cancerous cells. This fabricated stimulation of the immune system, immunotherapy, is being called the “fifth pillar” of treatment by leading scientists.

Companies such as Novartis and Kite Pharmaceuticals are among the leaders in immunotherapy, and have been granted breakthrough status by the FDA for their various therapeutic strategies to combat cancer.  

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Figure 1: a T cell after it has been genetically engineered to express a Chimeric Antigen Receptor (CAR). It will now recognize a cancer antigen, a protein found on the surface of a tumor cell

The newest generation of engineered CAR-T cells are effective at recognizing and destroying tumor cells. The single chain Fusion variant (scFv) is the portion of the CAR that is responsible for recognizing a cancerous cell. Different cancers express unique antigens, but with a CAR any cancer antigen can be recognized by an engineered T cell. Other chimeric antigens include the targeting of genes such as: EGFR and HER2. This opens the possibility of CAR-T therapy to expand to treating both solid and liquid tumors. As long as the T cells can recognize the tumor, the therapy can work. Once they recognize a tumor, a signal is sent to the costimulatory domains of the T cell.

The costimulatory domains on CAR-T cells are responsible for the activation and proliferation of T cells. Once the scFv has recognized a tumor antigen, it will send downstream signals to cause the T cells to activate and proliferate. This increases the number of genetically engineered T cells that can recognize and kill tumor cells.

Source: Juno Therapeutics
 Figure 2: CAR in T cells– Figure 2 is a protein CAR that is present in between the membrane of the T cell. Scientists first need to synthesize DNA that codes for the various domains listed. The DNA is then inserted into the cell

The process of inserting foreign DNA into a cell explained

After the DNA is inserted into the cells, the cells use their own machinery to produce the RNA and Protein. The proteins activate the T cell when the scFv recognizes the antigen on a tumor cell and trigger reactions to kill the tumor. Scientists at Kite have a successful therapy, KTE-C19, in phase II clinical trials treating patients with B cell lymphomas and leukemias. Their therapy uses a scFv that recognizes the CD-19 antigen, a cell-membrane protein that is ubiquitous on B cells.

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