- A method of improving the potency of T cells against cancer was developed by a research team from Memorial Sloan Kettering Cancer Center.
- The chimeric antigen receptor T cells were altered using the CRISPR/Cas9 system
- The immune response mediated by the T cells aided in better tumor rejection
A research team from Memorial Sloan Kettering Cancer Center (MSK) has utilized the benefits offered by the CRISPR/Cas9 gene editing tool
to develop potent chimeric antigen receptor (CAR) T cells which increase tumor rejection. The study was published in the journal Nature and will aid in identifying CAR immunobiology and highlight the importance of CRISPR/Cas9 system in cancer immunotherapy
In the current study, the CRISPR gene editing tool was used to deliver the CAR gene to a particular location in the T cell genome which would aid in producing CAR T cells with increased stamina. These cells are then found to kill tumor cells and are less likely to wear out. This technique is expected to lead to improved immunotherapy strategies among cancer patients.
‘Improving T cell Immune response using CRISPR would aid in better defense against Cancer’
The Director of the Center for Cell Engineering and 'the Gene Transfer and Gene Expression Laboratory' at MSK, Dr. Michel Sadelain, who is the senior author of the study said that cancer cells evade treatment through various mechanisms and that there was a need for CAR T cells to overpower them. The current study provides support to the theory that these genome editing tools may be used to develop 'living therapies' that boost treatment for cancer. The scientists' claim that they are 'eager' to identify how such genome-editing technology could be used to develop the next generation of CAR T cell therapy.
Clinical Trials of CRISPR
The clinical trials that use CRISPR are in the initial stages of planning but Dr. Sadelain and his colleagues state that work is on to identify the safety in using CRISPR for developing altered CAR T cell. The current method of delivering CAR gene into T cells is by using lentiviral or retroviral technology. This gene editing tool can be used to deliver the CAR gene at random locations on the genome, which is a limitation as it can lead to unnecessary mutations.
CRISPR is short for Clustered Regularly Interspaced Short Palindromic Repeat. It is a unique arrangement of short, semi-palindromic repeated DNA sequences that are present in micro-oganisms like bacteria. Though they seem innocuous, these sequences of DNA are a vital part of the immune system.
Bacterial cells are affected by infectious viruses that invade the bacterial genome. However, the host cells have developed a defense mechanism where the CRISPR/Cas9 system splices the viral genome. The host cell, therefore, is protected from a viral infection.
In between these CRISPR sequences are certain sequences of DNA that are called spacers, which are where the 'memory' of the viral DNA that entered the bacterial cell is stored. Any repeat attack by the same type of virus will elicit a faster response by the CRISPR system.
The CRISPR/Cas9 system is now utilized by scientists to replace certain sequences of DNA. The Cas 9 system acts like a pair of molecular scissors which cut the DNA at specific sites. Pre-determined sequences of DNA are then added to these sites. This gene editing tool is considered to be an important tool in building a defense against many genetic disorders as well as infections.
CRISPR used for HIV Treatment
Studies conducted using CRISPR identified a key gene in the cell, called C-C chemokine receptor type 5, which was important for binding the HIV to T cells. When inhibitors for this gene were utilized, it led to side effects.
Further studies that were conducted aided in identifying two genes which were found to modify the CCR5 molecule, making HIV binding easier.
- TPST2 (Tyrosylprotein Sulfotransferase 2)
- SLC35B2 (Solute Carrier Family 35 Member B2)
Another gene that was identified was ALCAM that is required for cell-to-cell adhesion. An exposure of CD4 cells to small amount of virus results in protection against the viral infection, when there is a loss of function of the gene.
First Human Trial of CRISPR Cas 9 system
The CRISPR/Cas9 system was trialed for the first time on critical lung cancer patients. The immune cell of the patients were isolated and treated with the CRISPR/Cas9 system, where genes that code for the protein PD-1 were silenced. The initial findings of the study pointed towards control over the spread of cancer. Though this human trial was conducted on patients at advanced stage of the disease and where there were no further treatment options that were available, it could soon be adopted as an earlier line of protection.
The current study that focuses on increasing the cancer fighting ability of T cells using the CRISPR/Cas9 system promises better immunotherapy against cancer. The body's own immune cells will be strengthened to fight against the tumor growth, which could limit side effects associated with regular cancer therapy.
- What is CRISPR? - (http://sitn.hms.harvard.edu/flash/2014/crispr-a-game-changing-genetic-engineering-technique/)