Is Transplant Tolerance the Next Frontier in Kidney Care? With Joseph Leventhal, MD, PhD

Limits of Long-Term Immunosuppression

Long-term limitations imposed by current immunosuppression options after kidney transplantation have led investigators to evaluate the potential of cellular therapies in early-phase clinical trials.1,2

While consistent immunosuppression is essential to prevent graft rejection, the long-term efficacy, pill burden, and graft survival remain crucial issues that clinicians have yet to tackle with this patient population.1

“With current drug-based immunosuppression, the best we can do—with a living donor transplant—is around 20 years,” said Joseph Leventhal, MD, PhD, a Professor of Surgery and Director of the Kidney and Pancreas Transplant Programs within the Comprehensive Transplant Center of the Northwestern University Feinberg School of Medicine, in an interview with HCPLive. “If you're someone in your 20s or 30s, that means you're going to need at least 2, maybe 3 transplants during your lifetime.”

Exploring Tolerance Induction

Against this backdrop, investigators are exploring immune tolerance strategies designed to retrain the immune system to accept transplanted organs without recognizing them as foreign, while preserving normal immune function.

“That’s why tolerance induction is so important—whether it's getting someone entirely off of immunosuppression, full tolerance, or reducing the need and minimizing the need for drug-based immunosuppression to a low dose of a single agent, what we call drug minimization,” said Leventhal. “We’re looking to develop strategies that can safely do this in the large majority of patients. Where drug-based approaches have failed to allow us to establish tolerance, we are increasingly looking at cellular therapies to do this.”

Several early-phase clinical trials are currently underway, including a phase 1b study evaluating hematopoietic stem cell transplantation combined with regulatory T-cell therapy in living donor kidney transplant recipients, as well as a randomized phase 2 trial assessing whether patients can be safely transitioned to single-agent immunosuppression. Additional investigational approaches are exploring novel induction strategies using modified donor immune cells.2

Across these studies, investigators are closely monitoring immunologic markers to better understand how tolerance may be achieved in practice. This includes assessing donor-specific hyporesponsiveness over time and combining these findings with biomarkers of immune quiescence.

“We want to show evidence of immune regulation that supports reducing immunosuppression,” the investigator said. “More than 95% of patients require multiple drugs today, so achieving monotherapy would be a major advance.”

Reducing exposure to multi-drug regimens may also help mitigate long-term toxicity and potentially improve graft durability. For some investigators, the long-term goal is to move closer to a model in which a single transplant can last a patient’s lifetime.

Looking ahead, the adoption of cellular therapies could require a shift in how transplant care is delivered, with Leventhal describing the potential for a “paradigm shift” towards increasingly personalized approaches.

While these strategies remain investigational, they reflect ongoing efforts to address persistent limitations in transplant care and improve long-term outcomes for patients.

Editor’s Note: Leventhal has reported relevant disclosures with Talaris Therapeutics.

References

1. Kamila Szumilas, Wilk A, Piotr Wiśniewski, et al. Current Status Regarding Immunosuppressive Treatment in Patients after Renal Transplantation. International Journal of Molecular Sciences. 2023;24(12):10301-10301. doi:https://doi.org/10.3390/ijms241210301

2. Clinicaltrials.gov. Published 2026. Accessed April 23, 2026. https://clinicaltrials.gov/study/NCT07083830?tab=researcher

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