The successful delivery of CRISPR/Cas9 modified immune cells to cancer patients represents the first U.S. clinical trial to test the gene editing approach in humans.
Researchers from the Abramson Cancer Center of the University of Pennsylvania have published data suggesting that immune cells modified using the gene editing tool CRISPR/Cas9 are able to survive and function for months following delivery to cancer patients .
The research team demonstrated that T cells taken from patients and modified ex vivo (outside the body) can be safely returned to the patient and continue to survive and fight cancer. The cells were successfully edited in three ways: by deleting the TRAC, TRBC, and PDCD1 genes. In addition to these edits, a cancer-specific T cell receptor was inserted to target the NY-ESO-1 antigen to help improve the T cells’ ability to detect tumors.
The study builds on the researchers’ previous work from last year, when they used CRISPR/Cas9 to successfully edit cells from three cancer patients and demonstrated that it was plausible to move into human trials using the approach.
It should be noted that this initial phase 1 trial had enrolled only three patients, but it does demonstrate two key things. First, it is possible to perform multiple gene edits with accuracy during ex vivo modification, and the resulting immune cells survive in the body longer than other previous published data suggests. Second, the edited cells demonstrate an increased ability to seek and destroy tumors once delivered to the patient.
The approach used in this study is similar to the immunotherapy known as CAR-T, in which patients receive engineered T cells to help them fight cancer. However, there are some key differences between CAR-T and this approach. Unlike CAR-T, which gives the T cells a receptor for a protein such as CD19, this approach removes the TRAC, TRBC, and PDCD1 genes using CRISPR/Cas9. The TRAC and TRBC edits serve to remove the T cell’s regular receptors so they can be reprogrammed to express a new synthetic T cell receptor, which then improves how well the cells can detect and destroy tumors. The PDCD1 edit removes a built-in checkpoint that can sometimes disrupt the T cells and prevent them from destroying cancer.
With these three genes silenced, the final modification was achieved by using a lentivirus to insert a cancer-specific T cell receptor, which then instructs the modified T cells to target an antigen known as NY-ESO-1.
Previous studies have shown that these cells often survive for a week or less; however, in this study, the researchers show that the edited cells were able to survive for far longer, with the last check-up nine months later. The researchers even collected some of the edited cells that had been living in the patients months later, which still demonstrated that they were able to destroy tumors.
The modified T cells in the study do, however, require the presence of a molecule called HLA-A*0201, which is only expressed in some people, and the three patients in the study were screened to ensure they were suitable for the particular approach. Once the modified cells were prepared, they were delivered in a single infusion following a short chemotherapy course. Blood analysis confirmed that the delivered T cells were surviving and thriving in the patients, and while none of the patients responded to the single therapy, there were no serious side effects observed, which is good news, as this was a phase 1 trial to establish safety.
The next step will be to move to larger-scale safety studies and tests of the efficacy of this approach, which could have implications beyond just treating cancer.
CRISPR-Cas9 is a revolutionary gene-editing technology that offers the potential to treat diseases such as cancer, but the effects of CRISPR in patients are currently unknown. Stadtmauer et al. report a phase 1 clinical trial to assess the safety and feasibility of CRISPR-Cas9 gene editing in three patients with advanced cancer (see the Perspective by Hamilton and Doudna). They removed immune cells called T lymphocytes from patients and used CRISPR-Cas9 to disrupt three genes (TRAC, TRBC, and PDCD1) with the goal of improving antitumor immunity. A cancer-targeting transgene, NY-ESO-1, was also introduced to recognize tumors. The engineered cells were administered to patients and were well tolerated, with durable engraftment observed for the study duration. These encouraging observations pave the way for future trials to study CRISPR-engineered cancer immunotherapies.
This is significant progress given that previous immunotherapy attempts using similar approaches have typically seen the T cells failing and losing function in a matter of days; the fact that these modified cells continued to persist and function properly months later following a single dose is encouraging.
Ex vivo therapies at this early point in time are the wise choice, as modified cells are far easier to sort and monitor in isolation prior to transplant to the patient. This presents a far lesser challenge than would result from attempting to modify immune cells in situ in the body.
 Stadtmauer, E. A., Fraietta, J. A., Davis, M. M., Cohen, A. D., Weber, K. L., Lancaster, E., … & Tian, L. (2020). CRISPR-engineered T cells in patients with refractory cancer. Science.