| Title: |
Comparison of axicabtagene ciloleucel and tisagenlecleucel patient CAR-T cell products by single-cell RNA sequencing |
| Authors: |
Yu, Xiaoqing; Jain, Michael D; Menges, Meghan A; Cen, Ling; Noble, Jerald D; Atkins, Reginald; Mohammad, Turab J; Bachmeier, Christina A; Naderinezhad, Samira; Reid, Kayla; Corallo, Salvatore; Yoder, Sean J; Zhang, Chaomei; Zhang, Lanmin; Miranda, Julieta Abraham; Shah, Bijal; Chavez, Julio C; Hesterberg, Rebecca S; Delgado, Luis Cuadrado; Savid-Frontera, Constanza; Rodriguez, Paulo C; Cleveland, John L; Wang, Xuefeng; Davila, Marco L; Locke, Frederick L |
| Contributors: |
Leukemia and Lymphoma Society; Division of Cancer Prevention, National Cancer Institute; NIH; Mark Foundation For Cancer Research; Florida Department of Health |
| Source: |
Journal for ImmunoTherapy of Cancer ; volume 13, issue 7, page e011807 ; ISSN 2051-1426 |
| Publisher Information: |
BMJ |
| Publication Year: |
2025 |
| Description: |
Background Autologous CD19 chimeric antigen receptor (CAR) T-cell therapy leads to durable responses and improved survival in patients with relapsed or refractory large B-cell lymphoma (R/R LBCL). Among approved CAR T-cell products, axicabtagene ciloleucel (axi-cel; CD19/CD28) has greater real-world efficacy and cytokine-associated toxicity than tisagenlecleucel (tisa-cel; CD19/4-1BB), for reasons that are poorly understood. Methods Here we report single-cell RNA sequencing (scRNA-seq) of 57 pre-infusion CAR T-cell products from axi-cel (n=39) and tisa-cel (n=18) patients treated as standard-of-care for R/R LBCL, and their biological associations with clinical outcomes. In vitro CAR manufacturing conditions mimicking those known for axi-cel and tisa-cel were performed using CD19/CD28z or CD19/4-1BBz constructs. Results ScRNA-seq revealed that axi-cel and tisa-cel are markedly different products. Axi-cel is comprised of more CD4 central memory, CD8 central memory, and CD8 effectors, whereas tisa-cel is comprised of more proliferative CD4 and CD8 cells. Across multiple T-cell subsets, axi-cel had greater expression of immune response pathways and protein synthesis and trafficking pathways versus tisa-cel. On comparison of infusion product CAR transgene-positive (CAR+) cells to CAR transgene-negative (CAR−) T cells, axi-cel CAR+ cells had vastly different gene expression than axi-cel CAR− cells. Unexpectedly, tisa-cel CAR+ cells were highly similar to tisa-cel CAR− cells. Under recapitulated CAR-T manufacturing conditions known to be used for axi-cel and tisa-cel, we found that CAR+ cells differed from CAR− cells early after manufacturing yet became more similar to CAR− cells after prolonged expansion. Prolonged time in expansion culture, as used during tisa-cel manufacturing, greatly decreased naïve and central memory T-cell subsets. Conclusions Following manufacture, axi-cel is less differentiated and has greater immune activation compared with tisa-cel, potentially accounting for its greater efficacy and ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1136/jitc-2025-011807 |
| Availability: |
https://doi.org/10.1136/jitc-2025-011807; https://syndication.highwire.org/content/doi/10.1136/jitc-2025-011807 |
| Rights: |
http://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.5FF44002 |
| Database: |
BASE |