CAR T cell manufacturing from naive/stem memory T lymphocytes enhances...

Paper

Abstract

Chimeric antigen receptor (CAR) T cell expansion and persistence represent key factors to achieve complete responses and prevent relapses. These features are typical of early memory T cells, which can be highly enriched through optimized manufacturing protocols. Here, we investigated the efficacy and safety profiles of CAR T cell products generated from preselected naive/stem memory T cells (TN/SCM), as compared with unselected T cells (TBULK). Notwithstanding their reduced effector signature in vitro, limiting CAR TN/SCM doses showed superior antitumor activity and the unique ability to counteract leukemia rechallenge in hematopoietic stem/precursor cell-humanized mice, featuring increased expansion rates and persistence together with an ameliorated exhaustion and memory phenotype. Most relevantly, CAR TN/SCM proved to be intrinsically less prone to inducing severe cytokine release syndrome, independently of the costimulatory endodomain employed. This safer profile was associated with milder T cell activation, which translated into reduced monocyte activation and cytokine release. These data suggest that CAR TN/SCM are endowed with a wider therapeutic index compared with CAR TBULK.

Analysis

Paper intelligence

Summary

Manufacturing CAR T cells from naive/stem memory T cells improves antitumor activity and persistence while reducing cytokine release syndrome compared to unselected T cells.

Key findings

CAR T cells from naive/stem memory T cells (TN/SCM) show superior antitumor activity and persistence in vivo.
CAR TN/SCM products are less prone to inducing severe cytokine release syndrome.
Reduced cytokine release syndrome is linked to milder T cell and monocyte activation.
CAR TN/SCM possess a wider therapeutic index than unselected T cells (TBULK).

Methods

Comparison of CAR T cell products generated from preselected naive/stem memory T cells (TN/SCM) versus unselected T cells (TBULK).
Evaluation of efficacy and safety profiles in hematopoietic stem/precursor cell-humanized mice.
Assessment of antitumor activity, leukemia rechallenge, expansion rates, persistence, and exhaustion/memory phenotype.
Analysis of T cell activation, monocyte activation, and cytokine release.

Limitations

The study was conducted in humanized mouse models, and direct translation to human patients may require further validation.
In vitro effector signature of CAR TN/SCM was reduced, though in vivo activity was superior.

Applications

Potential for improved CAR T cell therapy in hematologic malignancies.
Development of safer and more effective engineered T cell therapies.
Strategies to enhance CAR T cell persistence and reduce adverse events like CRS.

Confidence100%

Discovery

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Source record

Publication metadata

Authors: Silvia Arcangeli; Camilla Bove; Claudia Mezzanotte; Barbara Camisa; Laura Falcone; Francesco Manfredi; Eugenia Bezzecchi; Rita El Khoury; Rossana Norata; Francesca Sanvito; Maurilio Ponzoni; Beatrice Greco; Marta Angiola Moresco; Matteo G. Carrabba; Fabio Ciceri; Chiara Bonini; Attilio Bondanza; Monica Casucci
Published: May 3, 2022
Journal or venue: Journal of Clinical Investigation
DOI: 10.1172/jci150807
Paper type: journal article
Source: Openalex

DOI OpenAlex