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John Gordon: CART cells vs B cells Deliver a ‘Killer Punch’ to CAR-ve Onlookers

Photo taken from John Gordon/LinkedIn

Apr 21, 2024, 23:39

John Gordon: CART cells vs B cells Deliver a ‘Killer Punch’ to CAR-ve Onlookers

John Gordon, Vice president of

“CART cells vs B cells Deliver a ‘Killer Punch’ to CAR-ve Onlookers |
CART cell Therapy activates CD8+ Cytotoxic CARneg bystander Tcells in non-Human Primates and Patients | New Study by Ulrike Gerdemann and Co. |

CAR-T cells hold promise as a therapy for B-cell-derived malignancies, yet despite their impressive initial response rates, a significant proportion of patients ultimately experience relapse. While 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-Seq (scRNA-Seq) on non-human 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.

Here* utilising a highly translatable CD20 CAR NHP model, the authors 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 NK-cell markers (KIR3DL2, CD160, KLRD1), chemokines and chemokine receptors (CCL5, XCL1, CCR9), and downregulation of naive T-cell-associated genes (SELL, CD28).

A transcriptionally similar population was identified in patients following Tisagenlecleucel infusion. Mechanistic studies revealed that 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 the bystander phenotype efficiently killed leukemic cells through a TCR-independent mechanism.

Collectively, this dataset provides the first comprehensive identification and profiling of CARneg bystander CD8+ T-cells following B-cell targeting CAR-T cell therapy and suggests a novel mechanism through which CAR-T cell infusion might trigger enhanced anti-leukemic responses.

OPEN ACCESS preprint can be found at bioRxiv and medRxiv.” John Gordon

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Source: John Gordon/LinkedIn

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