Clinical Update: CRISPR-Edited Checkpoint Cell Therapy for Gastrointestinal Cancer

New York-based Intima Bioscience is sponsoring a first-of-a kind trial that explores gene-edited immune checkpoint therapy for Stage IV metastatic gastrointestinal cancers. The principle investigator is gastrointestinal oncologist Emil Lou at the Masonic Cancer Center at the University of Minnesota (UMN).

The trial, which is still recruiting, is open to adults with Stage IV metastatic gastrointestinal epithelial cancer who have had at least one first line standard therapy and who are in reasonably good health. So far, two patients have been treated without evidence of acute toxicity related to the CRISPR-edited TILS (see Abstract 208), and a total of 20 adult participants are expected to be enrolled and treated by October 2022.

CISH inactivation boosts the activity of tumour-fighting immune cells

The trial was initiated following groundbreaking research by scientists at National Cancer Institute (NCI) and UMN last year, who found that CRISPR-Cas9-mediated inactivation of the cytokine-inducible SH2 (CISH) gene in tumour infiltrating lymphocytes (TILs), increased their capability to fight solid tumours. We previously described these findings in detail in an interview with Douglas Palmer (NCI), Beau Webber and Branden Moriarity (both UMN).

TILs are a naturally occurring subset of immune cells that migrate from blood into tumours. The idea behind the new therapy, which combines CRISPR and the principle of CAR T-cell therapy, is that CISH inactivation in TILs and other T cells will augment their natural ability to target and destroy solid tumours, opening up a new treatment avenue for solid tumours, which often respond poorly to CAR-T cell therapies.

Clinical-scale GMP manufacturing of CISH-disrupted primary human TILs

The new therapy is developed from autologous (patients’ own) cells, which are isolated from patient tumour tissue. From this, TILS are isolated and then edited with CRISPR to remove the CISH gene. The edited cells are expanded in the lab with the help of the interleukin 2 (IL-2) cytokine, before being infused back into the patient following lymphodepletion, as depicted in the schematic below. Lymphodepletion is a treatment that reduces the patient’s own T cell numbers, so they will not antagonise the proliferation of the infused engineered T cells.