T cells altered by CRISPR may be safe to use in cancer patients

Schematic representation of CRISPR-Cas9 NYCE T cells. (Source: Stadtmauer et al., 2020)

Schematic representation of CRISPR-Cas9 NYCE T cells. (Source: Stadtmauer et al., 2020)

Discovery of CRISPR (clustered regularly interspaced short palindromic re- peats) in E.coli in 1987, and the subsequent development of CRISPR-Cas9 -(CRISPR associated with Cas9 endonuclease- in 2012 (in “parallel” by Gasiunas et al., 2012 & Jinek et al., 2012) has sparked interest in the utility of gene-editing as immunotherapy. [Read more about CRISPR Timeline and listen to Freakonomics Podcast of Jennifer Doudna]. Advances in CRISPR-Cas 9 technology has enabled modification of immune cells to improve cancer immunotherapy. Where cancer-patients’ own cells are genetically engineered at single cell levels to target cancer-immunogens, resulting in direct killing of cancer cells. However, this can be challenging as “engineered cells” in the case of T cells can become exhausted and dysfunctional, resulting in unwanted and potentially detrimental effects.

Scientists from USA have recently reported on the first human phase I clinical trial that tested the safety of using CRISPR edited immune cells in patients with advanced cancer. CRISPR-Cas9 gene editing was used to enhance the natural ability of human T cells to fight cancer in three patients. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRα (TRAC) and TCRβ (TRBC) were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding PD-1 (PDCD1), was performed to improve anti-tumor immunity by limiting T cell exhaustion.

Bloodwork from the patients showed the CRISPR-edited T cells circulated in the body for at least nine months. The editing did have some “off-target” effects, in which the wrong DNA was unintentionally edited. However the number of cells with unintended changes were minimal and these cells were short-lived.

Overall the clinical trial was a success, showing CRISPR gene-editing is safe and can be used at clinical scale for cancer immunotherapy. A follow-up study on a larger cohort and longer follow-up will be needed to determine safety before scaling up the trial to determine potential efficacy.

Journal Article: Stadtmauer et al., 2020. CRISPR-engineered T cells in patients with refractory cancer. Science 

Article by Bonamy Holtak

International Union of Immunological SocietiesUniversity of South AfricaInstitute of Infectious Disease and Molecular MedicineScience Education PrizesElizabeth Glazer Pediatric Aids Foundation