CRISPR technology to improve the efficacy of immunotherapy

Using CRISPR technology for the first time, researchers have inserted genes that enable immune cells to concentrate their attack on cancer cells, potentially sparing healthy cells and boosting the effectiveness of immunotherapy.

Image Credit: elenabsl/Shutterstock.com

The innovative strategy was recently published in the journal Nature and was introduced on November 10^th, 2022 at the Society for Immunotherapy of Cancer (SITC) 2022. Professor of medicine at UCLA and director of the UCLA Jonsson Comprehensive Cancer Center Antoni Ribas, MD, PhD, is co-leading it.

Humans have previously used the CRISPR technique to delete particular genes to boost the immune system’s ability to fight cancer. In this new study, researchers at PACT Pharma describe using CRISPR to effectively reroute immune cells so they can detect mutations in the patient’s cancer cells in addition to eliminating specific genes and inserting new ones.

These CRISPR-engineered immune cells are infused back into patients, where they preferentially move to cancer and become the immune cells that are most prevalent there.

Immune cells in the human body have particular receptors that can recognize and distinguish cancer cells from healthy cells. The key to making the method work on a large scale is figuring out an effective way to isolate them and put them back into immune cells to create personalized cell therapy to treat cancer.

In the new study, new technologies were created initially through a collaboration between Dr Ribas and James Heath, PhD, president of the Institute for Systems Biology in Seattle, and Nobel Prize winner David Baltimore, PhD, emeritus professor at Caltech and member of the UCLA Jonsson Comprehensive Cancer Center.

PACT Pharma further developed these technologies for use in the clinic. Using CRISPR gene editing, immune cells are redirected to recognize cancer after being isolated using immune receptors.

This is a leap forward in developing a personalized treatment for cancer, where the isolation of immune receptors that specifically recognize mutations in the patient’s own cancer are used to treat the cancer.”

Dr Antoni Ribas, Study Corresponding Author and Professor, Medicine, University of California-Los Angeles Health Sciences

Dr Ribas added, “The generation of a personalized cell treatment for cancer would not have been feasible without the newly developed ability to use the CRISPR technique to replace the immune receptors in clinical-grade cell preparations in a single step.”

A total number of 16 patients were treated by the researchers for a range of solid cancers, including colon, breast, and lung cancers. Immune cells from the patient’s blood were isolated based on their ability to bind to reagents showing up to 350 mutations from their own cancer, for a total of over 5000 mutations being targeted across 34 different HLA subtypes.

Following this, the genes of the immune receptors that enabled immune cells to recognize cancer mutations specifically were sequenced, resulting in the isolation of 175 new cancer-specific immune receptors.

The patient’s immune cells were then used to re-insert them using a one-step CRISPR editing process that involved knocking out the immune cell receptors that were already present and introducing immune receptors that could direct those cells to specifically recognize cancerous mutations.

After receiving conditioning chemotherapy, up to three of these preparations of gene-edited immune cells were infused back into the patients, giving the 16 study participants a total of 37 immune receptors. Patients experienced the typical side effects of chemotherapy, and two patients also experienced two possible side effects from the gene-edited cells: one patient experienced fever and chills, and the other experienced confusion.

Both patients quickly recovered. The top 20% of immune cells in cancers were frequently the gene-edited immune cells, which were preferentially recovered from biopsies of patients after infusion.

“This study demonstrates the feasibility of isolating and cloning multiple immune cell receptors recognizing mutations in cancer cells, the simultaneous knock-out of the endogenous immune receptor and knock-in of the redirecting immune receptor using single-step, non-viral precision genome editing, the manufacturing of CRISPR engineered T cells at clinical grade, the safety of infusing up to three gene edited immune cell products, and the ability of the gene edited immune cells to traffic to the patients’ tumors,” Dr Ribas further stated.