CRISPR/Cas9 technology was used to engineer donor T cells to treat children with pediatric B-cell acute lymphoblastic leukemia (B-ALL) who had exhausted all other available therapies, according to a phase I trial.
The results, published in Science Translational Medicine, represent “the first use of universal CRISPR-edited cells in humans and are a significant step forward in the use of gene-edited cells for cancer treatment,” according to the investigators, led by Giorgio Ottaviano, MD, of the Great Ormond Street Hospital for Children National Health Service (NHS) Trust.
The phase I, open-label, non-randomized clinical trial enrolled six children aged 14 months to 11 years with relapsed/refractory CD19-positive B-ALL.
The published results, covering a period up to February 2022, showed that four of the first six children treated entered remission within 28 days, which allowed them to receive a stem cell transplant. Of those four children, two remain in ongoing remission nine months and 18 months after treatment, respectively, while two relapsed following their hematopoietic stem cell transplant (HSCT).
The genome editing approach promises to make chimeric antigen receptor (CAR) T-cell treatments more accessible by allowing donated cells to be pre-manufactured and used in multiple patients.
“Whilst there are challenges to overcome, this study is a promising demonstration of how emerging genome-editing technologies can be used to tackle unmet health needs in some of the sickest children we see,” said senior author Waseem Qasim, PhD, of the Great Ormond Street Hospital for Children NHS Trust.
Dr. Ottaviano and colleagues used CRISPR to make a cut in the donor T cells’ DNA and insert a piece of genetic code that allows the cells to express a CAR that can recognize a marker on the surface of cancerous B cells and destroy them. The CAR T cells were also gene edited to disrupt the TRAC (T-cell receptor αlpha chain) gene to prevent graft-versus-host disease (GVHD) and enable “off the shelf” use of the cells without donor matching. The CD52 gene was also removed to confer a survival advantage in the presence of alemtuzumab.
The investigators generated three cell banks of the engineered donor cells, which they called “TT52CAR19 T cells” and cryopreserved them for use in the trial.
Four of the six patients infused with the TT52CAR19 T cells exhibited cell expansion, achieved flow cytometric remission, and then proceeded to receive allogeneic HSCT, the investigators reported. Two patients required biological intervention for grade 2 cytokine release syndrome, one patient developed transient grade 4 neurotoxicity, and one patient developed skin GVHD, which resolved after transplant conditioning.
“This study provides a demonstration of the feasibility, safety, and therapeutic potential of CRISPR-engineered immunotherapy,” the investigators wrote.
Ottaviano G, Georgiadis C, Gkazi SA; TT52 CRISPR-CAR group. Phase 1 clinical trial of CRISPR-engineered CAR19 universal T cells for treatment of children with refractory B cell leukemia. Sci Transl Med. 2022;14(668):eabq3010. doi:10.1126/scitranslmed.abq3010