Employing CRISPR to expose ‘hiding’ cancer cells to immunotherapy

Immunotherapy employs the patient’s immune system against cancer.  There are various types of immunotherapy including adoptive cell therapy, cancer vaccines and checkpoint blockade that are used in the clinic.  Their unprecedented success is attributed to the specificity of the immune system to find and attack the patient’s unique tumour.  However, current regiments frequently fail to provide sustained clinical responses in cancer patients highlighting the need for advancement and innovation in the field. 

Another hot topic has been the development of a genome-editing technology mediated by CRISPR.  It works by using CRISPR-RNA sequences to guide the Cas9 enzyme to specific parts of the DNA.  Cas9 then binds and cuts the DNA sequence allowing for a new piece of DNA to be inserted.  CRISPR made it much simpler and faster to modify multiple DNA sequences simultaneously and with high precision.  Among its many applications, CRISPR has been used to create cancer models and identify new therapeutic targets. 

A recent research article combines CRISPR technology with immunotherapy and provides a promising new system termed multiplexed activation of endogenous genes as an immunotherapy (MAEGI).  

Immune cells can identify cancer cells on the basis of the aberrantly expressed proteins (or tumour-associated antigens, TAAs) that characterise them.  The researchers considered that cancer cells can ‘hide’ from the immune cells when TAAs are not presented in high amounts or, during the progression of the cancer, are not presented at all.  MAEGI uses CRISPR to activate numerous cancer-related genes, therefore dramatically increasing the abundance of TAAs in the tumour.  As Dr Chen, the principal researcher in this study described it, “It is the molecular equivalent of dressing tumor cells in orange jump suits, allowing the immune system police to quickly find and eradicate the deadly cells”.  

MAEGI showed therapeutic efficacy across different tumour types (triple-negative breast cancer, pancreatic cancer and melanoma) in mice.  Dr Chen believes the new system shows promise in tackling cancers that are resistant to current immunotherapy and plans to further develop MAEGI with the aim to evaluate it in the clinic.  Careful evaluation of the effect of each target gene will be required to mitigate potential toxicity issues that could arise from CRISPR activation.  Like CRISPR, MAEGI is very versatile; it can be designed to activate multiple cancer-related genes and genes that are likely to mutate during the progression of the disease.  MAEGI therefore has the potential to have long-lasting effects.  Future success in animal models and clinical trials could lead to a new type of therapy involving MAEGI alone or in combination with other anti-tumour agents.