CAR+ and CAR- T cells share a differentiation trajectory into an NK-like subset after CD19 CAR T cell infusion in patients with B cell malignancies

Raymond Hall Yip Louie; Curtis Cai; Jerome Samir; Mandeep Singh; Ira W Deveson; James M Ferguson; Timothy G Amos; Helen Marie McGuire; Kavitha Gowrishankar; Thiruni Adikari; Robert Balderas; Martina Bonomi; Marco Ruella; David Bishop; David Gottlieb; Emily Blyth; Kenneth Micklethwaite; Fabio Luciani

doi:10.1038/s41467-023-43656-7

CAR⁺ and CAR^- T cells share a differentiation trajectory into an NK-like subset after CD19 CAR T cell infusion in patients with B cell malignancies

Nat Commun. 2023 Nov 27;14(1):7767. doi: 10.1038/s41467-023-43656-7.

Authors

Raymond Hall Yip Louie^#^{1

2

3}, Curtis Cai^#^{2

3}, Jerome Samir^#^{2

3}, Mandeep Singh⁴, Ira W Deveson⁴, James M Ferguson⁴, Timothy G Amos⁴, Helen Marie McGuire^{5

6

7}, Kavitha Gowrishankar^{8

9}, Thiruni Adikari^{2

3}, Robert Balderas¹⁰, Martina Bonomi^{2

11}, Marco Ruella¹², David Bishop^{8

9

13}, David Gottlieb^{8

9

13}, Emily Blyth^{8

9

13}, Kenneth Micklethwaite^{8

9

13

14}, Fabio Luciani^{15

16

17}

Affiliations

¹ School of Computer Science and Engineering, UNSW Sydney, Sydney, NSW, Australia.
² Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW, Australia.
³ School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia.
⁴ Garvan Institute for Medical Research, Sydney, NSW, Australia.
⁵ Ramaciotti Facility for Human Systems Biology, The University of Sydney, Sydney, NSW, Australia.
⁶ Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
⁷ Infection, Immunity and Inflammation Theme, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
⁸ Blood Transplant and Cell Therapies Program, Department of Haematology, Westmead Hospital, Sydney, NSW, Australia.
⁹ Westmead Institute for Medical Research, Sydney, NSW, Australia.
¹⁰ Becton Dickinson, San Jose, CA, USA.
¹¹ Department of Physics, University of Bologna, Bologna, Italy.
¹² Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA.
¹³ Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
¹⁴ NSW Health Pathology Blood Transplant and Cell Therapies Laboratory - ICPMR Westmead, Sydney, NSW, Australia.
¹⁵ Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW, Australia. luciani@unsw.edu.au.
¹⁶ School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia. luciani@unsw.edu.au.
¹⁷ Garvan Institute for Medical Research, Sydney, NSW, Australia. luciani@unsw.edu.au.

^# Contributed equally.

Abstract

Chimeric antigen receptor (CAR) T cell therapy is effective in treating B cell malignancies, but factors influencing the persistence of functional CAR⁺ T cells, such as product composition, patients' lymphodepletion, and immune reconstitution, are not well understood. To shed light on this issue, here we conduct a single-cell multi-omics analysis of transcriptional, clonal, and phenotypic profiles from pre- to 1-month post-infusion of CAR⁺ and CAR^- T cells from patients from a CARTELL study (ACTRN12617001579381) who received a donor-derived 4-1BB CAR product targeting CD19. Following infusion, CAR⁺ T cells and CAR^- T cells shows similar differentiation profiles with clonally expanded populations across heterogeneous phenotypes, demonstrating clonal lineages and phenotypic plasticity. We validate these findings in 31 patients with large B cell lymphoma treated with CD19 CAR T therapy. For these patients, we identify using longitudinal mass-cytometry data an association between NK-like subsets and clinical outcomes at 6 months with both CAR⁺ and CAR^- T cells. These results suggest that non-CAR-derived signals can provide information about patients' immune recovery and be used as correlate of clinically relevant parameters.

MeSH terms

B-Lymphocytes
Humans
Immunotherapy, Adoptive / methods
Lymphoma, Large B-Cell, Diffuse* / pathology
Receptors, Antigen, T-Cell*
T-Lymphocytes

Substances

Receptors, Antigen, T-Cell

Abstract

MeSH terms

Substances

Grants and funding