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T Cell Activation and Clonal Selection

T Cell Activation and Clonal Selection

T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...

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Updated: Jun 19, 2026

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PTPN2-KO CAR-T Cells Demonstrate Enhanced Effector Function, CNS Infiltration, and Toxicity in a Non-Human Primate

Francesca Alvarez Calderon, Ryan A Fleming, Marlana Winschel

Biorxiv : the Preprint Server for Biology

|September 26, 2025

Summary

Deleting PTPN2 in chimeric antigen receptor T (CAR-T) cells enhances their ability to fight cancer. However, this modification also increases the risk of severe toxicities, particularly neurotoxicity, in preclinical models.

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Area of Science:

Immunology
Cell Therapy
Cancer Research

Background:

Chimeric antigen receptor T (CAR-T) cell therapies show promise for B-cell malignancies but often lack durable responses.
Enhancing CAR-T cell efficacy by deleting negative regulators like PTPN2 is a potential strategy.
The impact of PTPN2 knockout (KO) on human CAR-T cells and associated in vivo toxicity is not well understood.

Purpose of the Study:

To evaluate the in vitro and in vivo efficacy and toxicity of PTPN2-KO human CD19 CAR-T cells.
To assess the impact of PTPN2 deletion on CAR-T cell function, expansion, and potential adverse effects in an immunocompetent model.

Main Methods:

Generated PTPN2-KO human CD19 CAR-T cells and assessed their in vitro effector functions.
Conducted a dose-escalation study using PTPN2-KO and wild-type (WT) CD20 CAR-T cells in a non-human primate (NHP) model.
Analyzed CAR-T cell expansion, B-cell depletion, CNS infiltration, and toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS).

Main Results:

PTPN2-KO CAR-T cells demonstrated enhanced cytokine production, cytotoxicity, and signaling in vitro, leading to superior leukemic cell killing.
In vivo, PTPN2-KO CD20 CAR-T cells showed dose-dependent superior expansion and B-cell depletion in NHPs.
Higher doses of PTPN2-KO CAR-T cells were associated with increased toxicities, including ICANS, driven by enhanced CNS infiltration of CD8+ T cells.

Conclusions:

PTPN2 deletion enhances the on-target functionality of human CAR-T cells.
While PTPN2-KO CAR-T cells exhibit improved efficacy, they also carry increased risks of severe toxicity, particularly ICANS.
Rigorous preclinical evaluation is crucial for potent genetic modifications in CAR-T therapy to balance efficacy and safety.