Researchers at Washington University School of Medicine in St. Louis have spearheaded an international phase 1/2 clinical trial that demonstrates encouraging outcomes from a novel immunotherapy approach aimed at combating aggressive blood cancers, with side effects that remain largely controllable.
Evaluating a Specialized CAR-T Cell Therapy
This groundbreaking clinical study assessed both the safety profile and therapeutic effectiveness of a cutting-edge CAR-T cell immunotherapy engineered specifically to eliminate malignant T cells. The participants suffered from uncommon malignancies, including T cell acute lymphoblastic leukemia and T cell lymphoblastic lymphoma, conditions that had proven resistant to conventional treatments, leaving them without viable alternatives. Remarkably, the majority of individuals who received the complete dosage of these engineered cells experienced a total eradication of their cancer, achieving complete remission.
The findings from this trial were detailed in a publication released on May 30 in the esteemed journal Blood.
Senior author John F. DiPersio, MD, PhD, who holds the Virginia E. & Sam J. Golman Professor of Medicine position at WashU Medicine and pioneered this therapy in his own laboratory there, remarked, “For individuals battling these uncommon and fast-progressing cancers with no remaining treatment avenues, this innovation holds the potential to revolutionize the landscape of care.” He emphasized that the trial revealed a strong probability of positive responses, including full remissions. Furthermore, this CAR-T cell intervention appears poised to serve as a vital “bridge-to-transplant” option, enabling patients who were previously ineligible for stem cell transplantation—the sole potentially curative option for such blood disorders—to pursue it.
To ascertain if this therapy possesses standalone curative capabilities, investigators stress the need for expanded trials involving greater numbers of participants and extended observation periods.
Patient Demographics and Disease Context
The study enrolled 28 patients, encompassing both adults and adolescents, diagnosed with relapsed or refractory T cell acute lymphoblastic leukemia and T cell lymphoblastic lymphoma. These conditions affect approximately 1,000 individuals each year across the United States. When standard therapies fail or the disease recurs post-initial treatment, the prognosis is grim: average survival stands at just six months, with fewer than 7% of patients surviving five years.
Development and Implementation of WU-CART-007
Known as WU-CART-007, this therapy emerged from Wugen, a biotechnology startup launched in 2018 by DiPersio alongside other WashU Medicine experts, such as Matthew Cooper, PhD. Cooper, a former faculty member at WashU Medicine and now Wugen’s chief scientific officer, played a key role in co-founding the company. The initiative received support from WashU’s Office of Technology Management. The multicenter trial spanned sites in Australia, Europe, and various locations in the U.S., including the St. Louis hub at Siteman Cancer Center, affiliated with Barnes-Jewish Hospital and WashU Medicine.
Trial Structure: Dose Escalation and Lymphodepletion
The protocol featured a dose-escalation stage to pinpoint the optimal dosage for the subsequent efficacy phase. This methodical approach identifies the highest tolerable dose of CAR-T cells while ensuring side effects stay within manageable bounds. Thirteen participants underwent lymphodepletion—a preparatory regimen that depletes the patient’s existing immune cells—to create space for the incoming therapeutic T cells to proliferate effectively. They then received the full regimen of 900 million CAR-T cells. Unfortunately, two of these patients succumbed to disease progression or complications like infections during the observation window.
Among the 11 evaluable patients post-treatment, the therapy yielded an impressive overall response rate of 91%. This encompassed 10 individuals who either exhibited no detectable cancer or experienced a substantial decrease in cancer burden. Notably, 72.7%—or eight out of 11—attained complete remission. As of the data cutoff, six patients who proceeded to transplantation continued in remission, showing no disease evidence between six and 12 months afterward.
Lead author and corresponding author Armin Ghobadi, MD, a professor of medicine and clinical director of the Center for Gene and Cellular Immunotherapy at WashU Medicine, highlighted, “Achieving remission rates of 70% to 90% far surpasses the typical 20% to 40% seen with standard treatments for this malignancy.” He added that these results are particularly striking given the participants’ dire circumstances: their aggressive cancers had recurred despite multiple prior therapies, including relapses post-stem cell transplant in several cases.
Managing Side Effects Effectively
A significant portion of patients—88.5%—developed cytokine release syndrome, a frequent consequence of CAR-T therapies where activated immune cells unleash inflammatory cytokines systemically. Fortunately, most instances were mild to moderate in severity. Around 19% encountered more intense episodes. Infrequently, other complications arose, including neurotoxicity syndrome and mild graft-versus-host disease, all of which were addressed successfully through supplementary interventions.
Advantages of Off-the-Shelf Universal CAR-T Therapy
What sets this immunotherapy apart is its classification as a “universal” CAR-T product. Leveraging advanced CRISPR gene-editing techniques, it utilizes T cells from any healthy donor, rendering it suitable for any patient with T cell malignancies. Traditional approved CAR-T therapies, by comparison, rely on autologous cells extracted from the patient, processed off-site over three to six weeks, and returned. This new off-the-shelf variant can be pre-manufactured, cryopreserved, and deployed immediately, slashing delays dramatically.
CRISPR editing excises the T cell receptor from donor cells, minimizing graft-versus-host disease risks where donor cells assault host tissues. It also eliminates a critical antigen to avert self-destruction among CAR-T cells (fratricide). This is especially pertinent here, as both therapeutic and malignant cells are T lineage, unlike B cell-targeted therapies that avoid such issues. Post-editing, the cells are programmed to hone in on the CD7 protein adorning cancerous T cells, facilitating precise tumor destruction.
DiPersio noted, “An expanded international trial is now in progress. While we await its completion, optimism surrounds the prospect of this universal CAR-T therapy gaining approval as a frontline option against these lethal T cell cancers.”
