CAR-T therapy for T-cell malignancies
An off-the-shelf, CRISPR-edited CAR-T therapy has shown promise for T-cell malignancies.
Researchers at Washington University School of Medicine (MO, USA) have led an international clinical trial investigating a novel CAR-T cell therapy specifically designed to target aggressive T-cell blood cancers, including T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.
Patients with T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma who fail to respond to standard therapies have an average survival of only six months and less than 7% surviving beyond five years. With approximately 1,000 new diagnoses annually in the US, these cancers represent a significant unmet medical need. CAR-T cell therapies have already shown remarkable success against B-cell cancers, but developing similar approaches for T-cell malignancies presents unique challenges, particularly the risk of “fratricide” where therapeutic T-cells might attack each other. This research aimed to overcome these obstacles through innovative CRISPR gene editing techniques, potentially offering hope to patients who previously had no viable treatment options after standard therapies failed.
The Phase I/II trial included 28 adult and adolescent patients with treatment-resistant or relapsed T-cell cancers across multiple sites in Australia, Europe and the United States. After determining optimal dosage through a dose-escalation phase, 13 patients received 900 million CAR-T cells following lymphodepletion, a procedure that clears patients’ immune cells to make room for the therapeutic cells.
The results demonstrated remarkable efficacy. Among the 11 evaluable patients, the therapy achieved a 91% overall response rate, with 72.7% achieving complete remission. Six patients who subsequently underwent stem cell transplantation remained in remission 6-12 months later. These response rates of 70-90% significantly exceeded the 20-40% typically expected with standard treatments.
The therapy, called WU-CART-007, represents a significant innovation as a universal CAR-T cell treatment created using CRISPR gene editing technology. Unlike traditional CAR-T therapies that require harvesting a patient’s own cells, this approach uses donor cells that can be prepared in advance as an “off-the-shelf” treatment, dramatically reducing wait times for critically ill patients.
What makes this therapy particularly groundbreaking is its novel approach to targeting T-cell cancers. The researchers used CRISPR gene editing to delete T-cell receptors from donor cells, reducing graft-versus-host disease risk, and removed specific antigens to prevent CAR-T cells from attacking each other. The cells were then engineered to target the CD7 protein on cancerous T cells. This overcomes the unique challenge of treating T-cell cancers with T-cell therapy, as previous CAR-T therapies only targeted B-cell cancers.
The treatment showed manageable side effects, with 88.5% of patients experiencing cytokine release syndrome, mostly mild to moderate. Some patients developed more severe cytokine release syndrome, neurotoxicity syndrome, or low-grade graft-versus-host disease, but all adverse events were manageable with additional therapies.
Senior author John F. DiPersio, who first developed the therapy in his lab, described it as potentially “a transformative advance in the field” that could serve as a “bridge-to-transplant” therapy for patients previously ineligible for stem cell transplantation.
The research team has launched a larger international clinical trial to further evaluate the therapy. Longer follow-up periods will help determine if the therapy could be curative on its own.
