CRISPR/Cas9 is an experimental gene editing technique that potentially could be used in the treatment of a wide range of disorders caused by DNA mutations. It also is currently being investigated as a potential cancer immunotherapy by a range of research groups worldwide.

How CRISPR/Cas9 works

Gene editing involves introducing a change to genes, which provide instructions to make proteins. Genes are made of a specific sequence of DNA bases.

The CRISPR/Cas9 technique is based on a natural system that bacteria use to “remember” and quickly remove viral infections before they can cause damage. Once bacteria have defeated a virus, they incorporate small sections of the virus’ genetic material into their own genome, separated by CRISPR, which stands for clustered regularly interspaced short palindromic repeats. If the same virus attacks again, the bacteria respond by producing pieces of guide RNA (a molecule similar to DNA) from the CRISPR array, which bind to the matching sequences in the virus genome and direct the enzyme Cas9 to cut and deactivate it.

Researchers can now use this technique to introduce specific changes to the DNA in cells to disable or change the function of a gene. For the approach, cells are provided with three key components:

  • The enzyme Cas9, to cut the DNA.
  • Guide RNA, to direct Cas9 to cut only at a specific site.
  • A DNA template, with the changes that will be made to the gene.

In immuno-oncology, CRISPR is being explored to genetically alter T-cells, a type of immune cell, to increase their ability to recognize and kill cancer cells. The T-cells are filtered out of a patient’s blood and modified using CRISPR in the laboratory. They are then reintroduced into the patient’s body via injection to target cancerous cells and reduce tumor growth.

CRISPR/Cas9 in clinical trials for cancer treatment

Researchers at Sichuan University in China were the first to inject a cancer patient with cells that contained CRISPR-edited genes, in October 2016 as part of an ongoing open-label Phase 1 clinical trial (NCT02793856). The trial continues to recruit patients with advanced non-small cell lung cancer (NSCLC) in China.

T-cells removed from the patient’s blood were modified using CRISPR to disable a gene called PD-1, which is part of an immune checkpoint. PD-1 normally acts as an “off switch” to stop T-cells from damaging healthy tissues, but many types of cancer cells hijack this system to evade detection by the immune system and grow unchecked. During the trial, the edited “PD-1 knockout” T-cells are injected back into the patient and should be able to identify and attack the cancer.

The trial aims to determine the safety of varying doses of T-cells edited through the CRISPR technique. The patients will be followed for six months to check for any adverse events and to receive a preliminary assessment for anti-cancer activity. Researchers reported that the first injection was successful. The trial is expected to be completed in 2018.

Two further clinical trials using CRISPR as a cancer immunotherapy also are ongoing in China. A Phase 2 clinical trial (NCT03081715) is investigating PD-1 knockout T-cells in an estimated 21 esophageal cancer patients. A Phase 1/2 trial (NCT03166878) is investigating UCART019 in up to 80 patients with B-cell lymphoma and leukemia. UCART019 is a type of CAR T-cell therapy that uses CRISPR to introduce a protein that enables T-cells to effectively recognize and kill cells expressing a protein called CD19, which is common in B-cell lymphoma and leukemia.

Further clinical trials using CRISPR-edited cells in a variety of cancer types are being planned worldwide. For example, CRISPR Therapeutics aims to start clinical trials with their immuno-oncology candidate CTX101 in 2018. Editas Medicine and Intellia Therapeutics also are developing potential CRISPR-based cancer therapies.


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