Decade-long remissions of leukemia sustained by the persistence of activated CD4+ CAR T-cells
Abstract
The adoptive transfer of T lymphocytes reprogrammed to target tumor cells has demonstrated significant potential in various malignancies. However, little is known about the long-term potential and the clonal stability of the infused cells. Here, we studied the longest persisting CD19-redirected chimeric antigen receptor (CAR) T cells to date in two chronic lymphocytic leukemia (CLL) patients who achieved a complete remission in 2010. CAR T-cells were still detectable up to 10+ years post-infusion, with sustained remission in both patients. Surprisingly, a prominent, highly activated CD4+ population developed in both patients during the years post-infusion, dominating the CAR T-cell population at the late time points. This transition was reflected in the stabilization of the clonal make-up of CAR T-cells with a repertoire dominated by few clones. Single cell multi-omics profiling via Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) with TCR sequencing of CAR T-cells obtained 9.3 years post-infusion demonstrated that these long-persisting CD4+ CAR T-cells exhibited cytotoxic characteristics along with strong evidence of ongoing functional activation and proliferation. Our data provide novel insight into the CAR T-cell characteristics associated with long-term remission in leukemia.
Competing Interest Statement
JJM, DLP, JAF, SFL, CHJ hold patents related to CAR T-cell manufacturing and biomarker discovery. IPM and JN are employees of Novartis. The remaining authors declare that they have no competing interests.
Footnotes
↵# These authors jointly supervised this work: J. Joseph Melenhorst (mej{at}pennmedicine.upenn.edu), Kai Tan (tank1{at}chop.edu), Carl H. June (cjune{at}upenn.edu)
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