Use of CRISPR to Create Cancer Fighting T-Cells
Researchers at the Perelman School of Medicine at the University of Pennsylvania investigated a new treatment approach for devastating cancers such as multiple melanoma. Making use of novel gene editing technology, the researchers engineered T-cells to target and kill cancer cells.
However, this isn't the first form of cancer immunotherapy. For example, in CAR T-Cell therapy-- a treatment that has already received FDA approval in the US -- T-cells are extracted from the patient's blood and genetically modified to express chimeric antigen receptors. This in turn enables the T-cells to identify and target cancer cell antigens. This approach has several limitations, including T-cell exhaustion which results in reduced efficacy of the treatment. Previous studies have attributed this to programmed cell death protein 1 (PD-1) -- a protein found on T-cells that is responsible for regulating immune responses to self-antigens. Inhibiting PD-1 in T-cells has been found to significantly improve efficacy of CAR T-cell therapy.
Another issue with this treatment is that the therapeutic T-cell receptors tend to mis-pair with the alpha and beta chains of the endogenous therapeutic T-cell receptors. This can reduce the expression of the T-cell receptors and thus the efficacy of the treatment.
The purpose of the current study was to investigate the effect of using CRISPR to silence certain genes in the T-cells to combat these limitations and potentially increase the efficacy of the treatment. Specifically, the researchers silenced the genes TCRα and TCRβ which code for the endogenous T-cell receptor alpha and beta chains, respectively. They also deleted a gene that encodes for PD-1. Finally, a gene for a receptor for NY-ESO-1 was added, allowing the modified T-cells to target tumors which produce those proteins on their surface.
Patients enrolled in this study were monitored intensively following T-cell infusion. Clinical outcomes were modest, with only one patient displaying regression of tumor and two others displaying stable disease. However, the transgenic T-cells displayed durable engrafement that persisted for more than 9 months. This is significantly longer than in other CAR T-cell studies that observed a persistence of around 2 months.
Antoni Ribas, an oncologist not involved in the study states that there are several reasons for the modest results observed by the researchers.
"It wasn’t like you turned off those genes and those T cells started doing things that were amazing” Says Ribas. "What June’s group offers is 'a needed start' for giving patients CRISPR-edited T cells. From now on, It’s going to be easier—because they did it first.”