CARs Take Leukemia Patients Closer to a Cure With Decade-Long Remissions

Take-aways:

• Two adults who received infusions of the anti-CD19 CAR T-cell therapy tisagenlecleucel were in remission at 9- and 10-year follow-up.
• Analyses revealed two distinct phases of the anti-leukemia response: an initial phase characterized by CD8+ or CD4−CD8− CAR T cells, followed by the predominance of a proliferative CD4+ CAR T-cell population.
• Single-cell profiling demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics and ongoing functional activation and proliferation.

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A study published in Nature provides the longest documented persistence of chimeric antigen receptor (CAR)T-cell therapy to date, describing 2 adults with chronic lymphocytic leukemia (CLL) whose disease remained in remission and who had detectable levels of CAR T cells 10 years after initial infusion. The findings were reported by Jan Joseph Melenhorst, PhD, Research Professor of Pathology and Laboratory Medicine in at the University of Pennsylvania’s Perelman School of Medicine, and coauthors.

“This long-term remission is remarkable and witnessing patients living cancer-free is a testament to the tremendous potency of this ‘living drug’ that works effectively against cancer cells,” said Dr. Melenhorst. “Witnessing our patients respond well to this innovative cellular therapy makes all of our efforts so worthwhile, being able to give them more time to live and to spend it with loved ones.”

CLL was the first disease for which CAR T cells were studied and developed at Penn and the Children’s Hospital of Philadelphia more than a decade ago. The two patients included in this study had been diagnosed with CLL in 1996 and 2000. They received infusions of CTL019 (later FDA approved as tisagenlecleucel) in 2010, by which time their disease had proven resistant to standard therapies.

Each patient experienced a complete remission, and the authors reported that peak CAR T-cell expansion occurred on day 3 post-infusion in patient 1, and day 31 in patient 2. The delay is “a possible reflection of the almost 78-fold lower infusion dose in patient 2,” they noted.

CAR T cells were detectable by flow cytometry across time points, including the most recent phlebotomy (10 years post-infusion for patient 1 and 9 years post-infusion for patient 2).

The persistence of CAR T cells in these complete responders allowed researchers to interrogate molecular and functional attributes of highly effective anti-CLL T cells. Their analyses revealed two distinct phases of the anti-leukemia response: an initial phase characterized by CD8+ or CD4−CD8− CAR T cells, followed by the predominance of a proliferative CD4+ CAR T-cell population in the ensuing years.

For example, the CAR T cells detected in patient 1 at year 9.3 were exclusively CD4+, “a surprising finding that led us to rethink the possibility that CD4+ T cells may be primarily responsible for cytotoxicity against CD19-expressing cells at these time points.”

Based on the ongoing proliferation, cytokine expression, and metabolic activity of these CAR T cells, the researchers postulated that proliferation was likely driven by ongoing antigenic signaling through the CAR rather than clonotype-specific features or systemically circulating cytokines.

“The apparent clonal selection in these 2 patients was an intriguing observation, with possible contributors including disruption of nearby genes, integration into genomic regions associated with more robust expression of the CAR construct, and genetic drift,” Dr. Melenhorst and coauthors wrote. “These findings offer intriguing new insights into the nature of long-term CAR T-cell signaling and persistence in these unique patients.”

Disclosures: This research was supported in part by the Novartis Institute for Biomedical Research. Study authors report financial relationships with Novartis, the manufacturer of tisagenlecleucel, and report holding patents related to CAR T-cell manufacturing and biomarker discovery.

Reference

Melenhorst JJ, Chen GM, Wang M, et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature. 2022;602:503-509.