Louie et al. analyzed pre- to 1-month post- infusion PBMCs from eight patients with relapsed or refractory B-ALL or LBCL following HSCT and subsequent treatment with CD19-specific CAR T cells. After infusion, clonally expanded heterogeneous CD8+ T cell subsets predominated, and included CAR- NK-like or suppressive cells and CAR+ cells comprising primarily proliferative innate-like/effector cells. Analysis of published data from larger cohorts of patients with LBCL treated with two other CD19 CAR T cell therapies validated the post-treatment differentiation of innate-like cell subsets. Longitudinal analyses showed that CAR+ and CAR- NK-like T cell subsets were associated with clinical outcomes at 6 months.
Contributed by Paula Hochman
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.
Author Info: (1) School of Computer Science and Engineering, UNSW Sydney, Sydney, NSW, Australia. Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW, Australia. School of Medi
Author Info: (1) School of Computer Science and Engineering, UNSW Sydney, Sydney, NSW, Australia. Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW, Australia. School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia. (2) Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW, Australia. School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia. (3) Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW, Australia. School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia. (4) Garvan Institute for Medical Research, Sydney, NSW, Australia. (5) Garvan Institute for Medical Research, Sydney, NSW, Australia. (6) Garvan Institute for Medical Research, Sydney, NSW, Australia. (7) Garvan Institute for Medical Research, Sydney, NSW, Australia. (8) Ramaciotti Facility for Human Systems Biology, The University of Sydney, Sydney, NSW, Australia. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia. Infection, Immunity and Inflammation Theme, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia. (9) Blood Transplant and Cell Therapies Program, Department of Haematology, Westmead Hospital, Sydney, NSW, Australia. Westmead Institute for Medical Research, Sydney, NSW, Australia. (10) Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW, Australia. School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia. (11) Becton Dickinson, San Jose, CA, USA. (12) Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW, Australia. Department of Physics, University of Bologna, Bologna, Italy. (13) Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA. (14) Blood Transplant and Cell Therapies Program, Department of Haematology, Westmead Hospital, Sydney, NSW, Australia. Westmead Institute for Medical Research, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. (15) Blood Transplant and Cell Therapies Program, Department of Haematology, Westmead Hospital, Sydney, NSW, Australia. Westmead Institute for Medical Research, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. (16) Blood Transplant and Cell Therapies Program, Department of Haematology, Westmead Hospital, Sydney, NSW, Australia. Westmead Institute for Medical Research, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. (17) Blood Transplant and Cell Therapies Program, Department of Haematology, Westmead Hospital, Sydney, NSW, Australia. Westmead Institute for Medical Research, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. NSW Health Pathology Blood Transplant and Cell Therapies Laboratory - ICPMR Westmead, Sydney, NSW, Australia. (18) Kirby Institute for Infection and Immunity, UNSW Sydney, Sydney, NSW, Australia. luciani@unsw.edu.au. School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia. luciani@unsw.edu.au. Garvan Institute for Medical Research, Sydney, NSW, Australia. luciani@unsw.edu.au.
