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A Nonviral Approach to Generate Transient Chimeric Antigen Receptor T Cells Using mRNA for Cancer Immunotherapy

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Published on: February 21, 2025

A Costimulatory CAR Improves TCR-based Cancer Immunotherapy.

Bilal Omer^1,2, Mara G Cardenas¹, Thomas Pfeiffer^1,2

¹Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas.

Cancer Immunology Research

|February 17, 2022

Summary

Engineered T cells with a costimulatory chimeric antigen receptor (CoCAR) demonstrated enhanced antitumor activity. This approach overcomes the lack of costimulatory signals, improving T-cell persistence and tumor control in preclinical models.

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Manufacturing Chimeric Antigen Receptor CAR T Cells for Adoptive Immunotherapy

Manufacturing Chimeric Antigen Receptor CAR T Cells for Adoptive Immunotherapy

Published on: December 17, 2019

Area of Science:

Immunology
Cancer Biology
Cell Therapy

Background:

T-cell receptors (TCRs) are crucial for T-cell activation against cancer antigens.
T-cell responses require TCR signaling (signal 1), costimulatory signals (signal 2), and cytokines (signal 3).
Tumor cells often lack costimulatory molecules, leading to incomplete T-cell activation and limited antitumor effects.

Purpose of the Study:

To engineer T cells with a costimulatory chimeric antigen receptor (CoCAR) to overcome the deficiency of costimulatory signals in the tumor microenvironment.
To evaluate the efficacy of CoCAR-modified T cells in enhancing antitumor responses against cancer antigens.
To assess the safety profile of CoCARs by omitting the cytotoxic CD3ζ chain.

Main Methods:

Genetic modification of tumor-specific T cells with a costimulatory chimeric antigen receptor (CoCAR).
CoCARs were designed to provide signal 2 upon antigen recognition, independent of the cytotoxic CD3ζ chain.
Testing in co-culture systems and murine tumor models using T cells engineered with a survivin-specific transgenic TCR (sTCR) or Epstein-Barr virus-specific TCR (EBVST).

Main Results:

CoCAR-modified T cells (sTCR+CoCAR+) demonstrated enhanced killing of leukemia cells, overcoming antigen heterogeneity.
In vivo studies showed improved tumor control and prolonged survival in mice treated with sTCR+CoCAR+ T cells compared to sTCR+ T cells alone.
CoCAR-expressing EBVSTs exhibited enhanced expansion and delayed tumor progression in a murine lymphoma model.

Conclusions:

The costimulatory chimeric antigen receptor (CoCAR) effectively enhances the antitumor activity of T cells expressing both native and transgenic TCRs.
CoCAR technology provides a promising strategy to improve T-cell-based cancer immunotherapies by supplying essential costimulatory signals.
The CoCAR design, lacking the CD3ζ chain, offers a potential approach to mitigate CAR-related toxicities while maintaining therapeutic efficacy.