Decade-long leukaemia remissions with persistence of CD4+ CAR T cells

J. Joseph Melenhorst (), Gregory M. Chen, Meng Wang, David L. Porter, Changya Chen, McKensie A. Collins, Peng Gao, Shovik Bandyopadhyay, Hongxing Sun, Ziran Zhao, Stefan Lundh, Iulian Pruteanu-Malinici, Christopher L. Nobles, Sayantan Maji, Noelle V. Frey, Saar I. Gill, Alison W. Loren, Lifeng Tian, Irina Kulikovskaya, Minnal Gupta, David E. Ambrose, Megan M. Davis, Joseph A. Fraietta, Jennifer L. Brogdon, Regina M. Young, Anne Chew, Bruce L. Levine, Donald L. Siegel, Cécile Alanio, E. John Wherry, Frederic D. Bushman, Simon F. Lacey, Kai Tan () and Carl H. June ()
Additional contact information
J. Joseph Melenhorst: University of Pennsylvania
Gregory M. Chen: University of Pennsylvania
Meng Wang: University of Pennsylvania
David L. Porter: University of Pennsylvania
Changya Chen: Center for Childhood Cancer Research, The Children’s Hospital of Philadelphia
McKensie A. Collins: University of Pennsylvania
Peng Gao: Center for Childhood Cancer Research, The Children’s Hospital of Philadelphia
Shovik Bandyopadhyay: University of Pennsylvania
Hongxing Sun: University of Pennsylvania
Ziran Zhao: University of Pennsylvania
Stefan Lundh: University of Pennsylvania
Iulian Pruteanu-Malinici: Novartis Institute for Biomedical Research
Christopher L. Nobles: University of Pennsylvania
Sayantan Maji: University of Pennsylvania
Noelle V. Frey: University of Pennsylvania
Saar I. Gill: University of Pennsylvania
Alison W. Loren: University of Pennsylvania
Lifeng Tian: University of Pennsylvania
Irina Kulikovskaya: University of Pennsylvania
Minnal Gupta: University of Pennsylvania
David E. Ambrose: University of Pennsylvania
Megan M. Davis: University of Pennsylvania
Joseph A. Fraietta: University of Pennsylvania
Jennifer L. Brogdon: Novartis Institute for Biomedical Research
Regina M. Young: University of Pennsylvania
Anne Chew: University of Pennsylvania
Bruce L. Levine: University of Pennsylvania
Donald L. Siegel: University of Pennsylvania
Cécile Alanio: University of Pennsylvania
E. John Wherry: University of Pennsylvania
Frederic D. Bushman: University of Pennsylvania
Simon F. Lacey: University of Pennsylvania
Kai Tan: University of Pennsylvania
Carl H. June: University of Pennsylvania

Nature, 2022, vol. 602, issue 7897, 503-509

Abstract: Abstract The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers1–7. However, little is known about the long-term potential and clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia1–4 who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4+ population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8+ CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia.

Date: 2022
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DOI: 10.1038/s41586-021-04390-6

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