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

ABSTRACT: The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers^1-7. 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 leukaemia^1-4 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.

SUBMITTER: Melenhorst JJ

PROVIDER: S-EPMC9166916 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Melenhorst J Joseph JJ Chen Gregory M GM Wang Meng M Porter David L DL Chen Changya C Collins McKensie A MA Gao Peng P Bandyopadhyay Shovik S Sun Hongxing H Zhao Ziran Z Lundh Stefan S Pruteanu-Malinici Iulian I Nobles Christopher L CL Maji Sayantan S Frey Noelle V NV Gill Saar I SI Loren Alison W AW Tian Lifeng L Kulikovskaya Irina I Gupta Minnal M Ambrose David E DE Davis Megan M MM Fraietta Joseph A JA Brogdon Jennifer L JL Young Regina M RM Chew Anne A Levine Bruce L BL Siegel Donald L DL Alanio Cécile C Wherry E John EJ Bushman Frederic D FD Lacey Simon F SF Tan Kai K June Carl H CH

Nature 20220202 7897

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 i ...[more]

PMID: 35110735

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Project description:Theiler's murine encephalomyelitis virus (TMEV) is the causative agent of TMEV-induced demyelinating disease (TMEV-IDD); a well-established animal model for the chronic progressive form of human multiple sclerosis (MS). In susceptible mice with an inadequate immune response, TMEV-IDD is triggered by virus persistence and maintained by a T cell mediated immunopathology. OT-mice are bred on a TMEV-resistant C57BL/6 background and own predominantly chicken ovalbumin (OVA)-specific populations of CD8+ T cells (OT-I) or CD4+ T cells (OT-II), respectively. It is hypothesized that the lack of antigen specific T cell populations increases susceptibility for a TMEV-infection in OT-mice on a TMEV-resistant C57BL/6 background. OT-I, OT-II, and C57BL/6 control mice were infected intracerebrally with the TMEV-BeAn strain. Mice were scored weekly for clinical disease and after necropsy, histological and immunohistochemical evaluation was performed. OT-I mice started to develop progressive motor dysfunction between 7 and 21 days post infection (dpi), leading up to hind limb paresis and critical weight loss, which resulted in euthanasia for humane reasons between 14 and 35 dpi. OT-I mice displayed a high cerebral virus load, an almost complete absence of CD8+ T cells from the central nervous system (CNS) and a significantly diminished CD4+ T cell response. Contrarily, only 60% (12 of 20) of infected OT-II mice developed clinical disease characterized by mild ataxia. 25% of clinically affected OT-II mice (3 of 12) made a full recovery. 5 of 12 OT-II mice with clinical disease developed severe motor dysfunction similar to OT-I mice and were euthanized for humane reasons between 13 and 37 dpi. OT-II mice displayed only low virus-immunoreactivity, but clinical disease correlated well with severely reduced infiltration of CD8+ T cells and the increased presence of CD4+ T cells in the brains of OT-II mice. Though further studies are needed to reveal the underlying pathomechanisms following TMEV infection in OT mice, findings indicate an immunopathological process as a main contributor to clinical disease in OT-II mice, while a direct virus-associated pathology may be the main contributor to clinical disease in TMEV-infected OT-I mice.

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

Publications

Decade-long leukaemia remissions with persistence of CD4<sup>+</sup> CAR T cells.

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