Discovery

UPenn researchers document decade-long CD19 CAR T cell persistence in Nature Medicine

Edited by Robert McTiernan··3 min read
UPenn researchers document decade-long CD19 CAR T cell persistence in Nature Medicine

Researchers at the University of Pennsylvania's Abramson Cancer Center have documented functional persistence of anti-CD19 CAR T cells for up to 10.1 years after a single infusion in patients with B cell non-Hodgkin lymphoma (B-NHL), providing the longest reported follow-up of engineered T cell persistence in humans, according to a study published August 10, 2026 in Nature Medicine. The findings provide new insight into the cellular biology underlying exceptionally durable responses to CAR T therapy.

The study was led by Luca Paruzzo, Stephen J. Schuster and Marco Ruella at Penn's Abramson Cancer Center and Center for Cellular Immunotherapies, with Schuster and Ruella jointly supervising the work. The study followed 38 patients with B-NHL — 24 with large B-cell lymphoma and 14 with follicular lymphoma — treated in a Phase IIa study with 4-1BB-costimulated, lentivirally transduced anti-CD19 CAR T cells, the construct that became tisagenlecleucel (Kymriah). Among 12 patients surviving beyond five years, eight had samples available for long-term persistence analysis. A separate cohort of eight patients treated with commercial tisagenlecleucel was used for validation.

CAR-positive cells remained detectable beyond five years in five of the eight evaluable long-term responders, with quantifiable CAR transgene copies detected in one patient 10.1 years after treatment. Sustained B cell aplasia at higher CAR transgene levels provided evidence that the persisting cells remained functionally active rather than representing residual genetic material alone.

Deep profiling of one patient 9.3 years after treatment found that the surviving CAR T cell population had evolved substantially from the cells present shortly after infusion. The late population was dominated by memory-like CD4−CD8− double-negative T cells and had become increasingly oligoclonal, with one clone accounting for approximately 70% of CAR-positive cells. That clone had been detectable at less than 0.1% frequency 14 days after infusion, suggesting that characteristics established early after treatment may contribute to exceptionally long persistence.

Comparison with published CAR T datasets from chronic lymphocytic leukemia and pediatric B-cell acute lymphoblastic leukemia also identified a late-persistence transcriptional signature shared across B cell malignancies, including FXYD2, HMOX1 and GPR183. The finding raises the possibility that common biological programs support long-term CAR T survival across different disease settings and could eventually provide biomarkers for identifying cells capable of durable engraftment.

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The results add mechanistic context to the long remissions already observed with autologous CD19 CAR T therapies. Tisagenlecleucel uses a 4-1BB costimulatory domain, which has been associated with memory-like T cell differentiation and persistence. Understanding which cellular states and clones survive for years could inform manufacturing and engineering strategies aimed at producing more durable cell therapies.

Long-term persistence is also relevant as the cell therapy field explores allogeneic and other off-the-shelf approaches, where achieving sufficient persistence without provoking immune rejection remains an important development challenge. The Penn findings do not establish that decade-long persistence is required for durable remission, but provide a benchmark for what autologous CAR T cells can achieve in a subset of patients.

The decade-long follow-up also provided additional safety information amid regulatory scrutiny of secondary T cell malignancies following CAR T therapy. Investigators found no concerning enrichment of lentiviral integrations near known proto-oncogenes and reported no secondary T cell malignancies during up to 10.1 years of follow-up.

The study remains limited by the small number of patients with samples available beyond five years, while detailed multiomics profiling was performed in only one long-term responder. The data therefore cannot establish which cellular characteristics cause long-term persistence or whether persistence itself is necessary for durable remission. Persistent B cell aplasia also illustrates a potential trade-off: CAR T cells capable of surveillance for years can continue eliminating normal CD19-positive B cells, reinforcing interest in approaches that could provide greater control over long-lived engineered cell populations.

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