B-cell-directed CAR T-cell therapy activates CD8+ cytotoxic CARneg bystander T cells in patients and nonhuman primates.

Autor:	Kaminski J; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA., Fleming RA; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA., Alvarez-Calderon F; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Winschel MB; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA., McGuckin C; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA., Ho EE; 2seventy bio, Cambridge, MA., Eng F; 2seventy bio, Cambridge, MA., Rui X; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA., Keskula P; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA., Cagnin L; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA., Charles J; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA., Zavistaski J; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA., Margossian SP; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Kapadia MA; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Rottman JB; 2seventy bio, Cambridge, MA., Lane J; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.; Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA., Baumeister SHC; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Tkachev V; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.; Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA., Shalek AK; Broad Institute of MIT and Harvard, Cambridge, MA.; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA.; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA.; Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge, MA., Kean LS; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Gerdemann U; Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Jul 04; Vol. 144 (1), pp. 46-60.
DOI:	10.1182/blood.2023022717
Abstrakt:	Abstract: Chimeric antigen receptor (CAR) T cells hold promise as a therapy for B-cell-derived malignancies, and despite their impressive initial response rates, a significant proportion of patients ultimately experience relapse. Although recent studies have explored the mechanisms of in vivo CAR T-cell function, little is understood about the activation of surrounding CARneg bystander T cells and their potential to enhance tumor responses. We performed single-cell RNA sequencing on nonhuman primate (NHP) and patient-derived T cells to identify the phenotypic and transcriptomic hallmarks of bystander activation of CARneg T cells following B-cell-targeted CAR T-cell therapy. Using a highly translatable CD20 CAR NHP model, we observed a distinct population of activated CD8+ CARneg T cells emerging during CAR T-cell expansion. These bystander CD8+ CARneg T cells exhibited a unique transcriptional signature with upregulation of natural killer-cell markers (KIR3DL2, CD160, and KLRD1), chemokines, and chemokine receptors (CCL5, XCL1, and CCR9), and downregulation of naïve T-cell-associated genes (SELL and CD28). A transcriptionally similar population was identified in patients after a tisagenlecleucel infusion. Mechanistic studies revealed that interleukin-2 (IL-2) and IL-15 exposure induced bystander-like CD8+ T cells in a dose-dependent manner. In vitro activated and patient-derived T cells with a bystander phenotype efficiently killed leukemic cells through a T-cell receptor-independent mechanism. Collectively, to our knowledge, these data provide the first comprehensive identification and profiling of CARneg bystander CD8+ T cells following B-cell-targeting CAR T-cell therapy and suggest a novel mechanism through which CAR T-cell infusion might trigger enhanced antileukemic responses. Patient samples were obtained from the trial #NCT03369353, registered at www.ClinicalTrials.gov. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
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