Optimization of T-cell Receptor-Modified T Cells for Cancer Therapy

Area of Science:

• Immunology
• Oncology
• Gene Therapy

Background:

• T-cell receptor (TCR)-modified T-cell gene therapy shows limited clinical success against tumors.
• A key factor may be insufficient T-cell activation in vivo.
• Enhancing T-cell activation is crucial for improving therapeutic efficacy.

Purpose of the Study:

• To investigate the potential of expressing proinflammatory cytokines within TCR-modified T cells to enhance anti-tumor efficacy.
• To compare the efficacy of interleukin 18 (IL18) versus interleukin 12 (IL12) in boosting T-cell activation and anti-tumor responses.

Main Methods:

• Engineered T cells expressing IL18 or IL12 were generated.
• The anti-tumor effects and survival of mice were evaluated in syngeneic and xenograft tumor models.
• T-cell persistence, functionality, and the tumor microenvironment were analyzed.

Main Results:

• IL18 secretion by tumor-directed TCR-modified T cells induced a superior proinflammatory signal compared to IL12.
• IL18-secreting T cells promoted persistent, functional effector T cells and a proinflammatory tumor microenvironment, augmenting survival in mice.
• Combined IL18-secreting T cells and sublethal irradiation eradicated tumors; IL12-secreting T cells caused toxicity.
• IL18 enhanced persistence and efficacy of human T cells in a xenograft model.

Conclusions:

• Expression of IL18 in TCR-modified T cells enhances T-cell persistence, functionality, and anti-tumor efficacy.
• IL18 represents a promising strategy for optimizing TCR-modified T-cell cancer therapy.
• IL18 offers a safer alternative to IL12, avoiding excessive cytokine-induced toxicity.