Nature: First use of CRISPR to replace gene therapy for cancer patients

For the first time, scientists have used CRISPR technology to insert genes that allow immune cells to focus on attacking cancer cells, potentially leaving normal cells unharmed and improving the effectiveness of
immunotherapy.
The new approach was presented at the Society for Cancer Immunotherapy (SITC) 2022 and published in the journal Nature
.
The study was co-led
by Antoni Ribas, MD, and UCLA Professor of Medicine at the UCLA Jonsson Comprehensive Cancer Center.

CRISPR technology has previously been used to remove specific genes in humans, making the immune system more active in fighting cancer
.
In the new study, researchers at PACT Pharmaceuticals report that they were not only able to use CRISPR to remove specific genes, but also insert new genes into immune cells, effectively redirecting immune cells to recognize mutations
in patients' own cancer cells.
When infused back into the patient, these CRISPR-engineered immune cells preferentially flow to the cancer cells and become the most representative immune cells
there.

The human immune system has specific receptors on immune cells that can specifically recognize cancer cells and distinguish them from normal cells
.
Every patient's situation is different, so finding an effective way to isolate them and insert them into immune cells to produce a personalized cell therapy to treat cancer is key
to making this approach feasible at scale.

The new study reports an effective way to isolate immune receptors from a patient's own blood, using a new technique originally developed by Dr.
Ribas in collaboration with James Heath, Ph.
D.
, director of the Institute for Systems Biology in Seattle, Dr.
David Baltimore, Nobel laureate, professor emeritus at Caltech, and members of the UCLA Jonsson Comprehensive Cancer Center, and further developed into the clinic
by PACT Pharmaceuticals.
After isolation, using CRISPR gene editing, immune receptors are used to redirect immune cells to recognize cancer
.

"This is a leap forward in developing personalized treatments for cancer, in which immune receptors that specifically recognize a patient's own cancer mutations are used to treat cancer
.
" Dr Ribas, the corresponding author of the article, said
.
"Without the newly developed CRISPR technology's ability to replace immune receptors in clinical-grade cell formulations in one step, it would not be possible to generate personalized cell therapies
for cancer.
"

The researchers reported that they treated 16 patients with a variety of solid cancers, including colon, breast and lung cancers
.
Based on the binding, immune cells were isolated from the patient's blood to capture agents that showed 350 mutations from the patient's own cancer, targeting a total of more than 5,000 mutations
across 34 HLA subtypes of the immune system.
Genes that allow immune cells to specifically recognize immune receptors for cancer mutations were sequenced, resulting in a total of 175 newly isolated cancer-specific immune receptors
.
Then, through one-step CRISPR editing, they are inserted into the patient's own immune cells, which involves knocking out existing immune cell receptors and knock-in immune receptors
that can redirect those cells to specifically recognize cancer mutations.

After giving conditioned chemotherapy, up to three of these gene-edited immune cells were injected back into patients, and the 16 patients involved in the study were infused with a total of 37 immune receptors
.
The patients experienced the expected side effects of chemotherapy, two developed potential side effects of gene-edited cells, one developed fever and chills, the other developed insanity, and both recovered
quickly.
Gene-edited immune cells are preferentially recovered from biopsies after the patient's infusion and typically represent the top 20 percent of immune cells
in cancer.

"This study demonstrates the feasibility of isolating and cloning multiple immune cell receptors that recognize mutations in cancer cells, the feasibility of using single-step, non-viral precision genome editing to knock out both endogenous immune receptors and knock in redirected immune receptors, the safety of manufacturing clinical-grade CRISPR-engineered T cells, the safety of injecting up to three gene-edited immune cell products, and the ability of gene-edited immune cells to deliver to patients' tumors," said Dr
.
Ribas.