Some types of immune cells — most notably T-cells — are able to kill cancer cells. However, cancers often evolve mechanisms that allow them to escape immune-mediated destruction.
The overarching goal of cancer immunotherapy is to increase the immune system’s ability to kill tumor cells. One such approach is engineering T-cells or other immune cells to make them more cells effective at killing cancer cells.
CAR T-cells, which are engineered to express cancer-targeted receptors, are an example of such a strategy. While such cell-based therapies have shown some promise in treating tumors in the blood, they are generally not effective at treating solid tumors.
Sponsored by Intima Bioscience, the trial will explore a new way of increasing the cancer-killing power of T-cells. Specifically, investigators will use CRISPR-Cas9 technology to delete the gene containing instructions to produce the cytokine-induced SH2 protein (CISH) protein, according to a university press release.
This protein normally acts to limit T-cell activity, so deleting it may increase activity. Conceptually, this is a similar strategy to checkpoint blockade — where medications are used to block signaling molecules such as PD-1, which normally limit immune activity.
“We believe that CISH is a key factor preventing T cells from recognizing and eliminating tumors, but because it resides inside the cell, we couldn’t block it in the same fashion as other checkpoint drugs like PD-1. Given the potential power of CISH to increase anti-cancer killing of solid tumors, we turned to CRISPR/Cas9 based genome engineering,” said Branden Moriarity, PhD, an assistant professor in the hematology/oncology division of the University of Minnesota Medical School.
Moriarity, alongside collaborators at the Masonic Cancer Center and National Cancer Institute’s Surgery Branch, conducted the groundbreaking research leading to the clinical trial.
They demonstrated that removing CISH from tumor-infiltrating cells — a subset of T-cells that enter tumors — increased their anti-tumor activity. Findings also suggested that these cells could function synergistically with an anti-PD-1 checkpoint blockade.
“Existing checkpoint therapies require repeated dosing and are often limited by the tumor environment that surrounds immune cells,” said Beau Webber, PhD, a trial investigator who also participated in the preclinical work.
“With our gene-editing approach, the checkpoint inhibition is accomplished in one step and is permanently hardwired into the T cells,” Webber added.
This Phase 1/2 clinical trial aims to enroll up to 20 adults, ages 18–70, with gastrointestinal epithelial cancer that has spread to distant locations (metastatic cancer). Eligible patients must have progressive disease following at least one standard first-line therapy.
Participants will be treated, via a 10- to 20-minute infusion, with patient-specific CRISPR-engineered T-cells, which will be made at the University of Minnesota’s Molecular and Cellular Therapeutics facility — one of five such gene and cell therapy manufacturing centers in the U.S.
The study’s main goals are to determine the highest dose of the experimental therapy that can be given without unacceptable toxicity, as well as to determine the therapy’s safety and effectiveness.
In the trial’s first phase, participants will be given ascending doses of engineered cells, in order to determine the highest tolerated dose. In its second phase, they will be treated with cells at the previously established optimal dose.
Over the week before the engineered T-cells are infused, patients will be treated with chemotherapies. Four days after the cells are administered, they will receive aldesleukin (interleukin-2), a medication that can increase the activity of T-cells.
Although the ongoing COVID-19 pandemic has challenged many clinical trials, this study has been actively recruiting since May and enrolled a number of patients.
“Given the potential importance of this novel cancer checkpoint, coupled with precision CRISPR engineered T cell therapy, we hope that we can start to recapitulate the success that T cell therapy and immuno-oncology have had in liquid tumors, to the much larger and significant unmet medical need in solid tumor cancer,” said Emil Lou, MD, PhD, who is leading the trial at the University of Minnesota.