Naturally occurring T cell mutations enhance engineered T cell therapies

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Adoptive T cell therapy shows promise for cancer treatment but is limited by poor T cell persistence and function.
• Cancerous T cells evolve mutations that enhance their survival in challenging environments, offering potential insights for therapeutic improvement.

Purpose of the Study:

• To systematically screen mutations from T cell neoplasms for their potential to enhance therapeutic T cell function.
• To identify and characterize specific mutations that can improve T cell persistence and anti-tumor efficacy in adoptive T cell therapies.

Main Methods:

• Screened 71 mutations from T cell neoplasms to assess their impact on T cell signaling, cytokine production, and in vivo persistence.
• Identified and validated the CARD11-PIK3R3 gene fusion in a CD4+ cutaneous T cell lymphoma model.
• Evaluated the anti-tumor efficacy of CARD11-PIK3R3-expressing T cells in immunotherapy-refractory models.

Main Results:

• The CARD11-PIK3R3 gene fusion was identified and shown to augment CARD11-BCL10-MALT1 complex signaling.
• CARD11-PIK3R3 significantly enhanced the anti-tumor efficacy of therapeutic T cells in multiple refractory cancer models in an antigen-dependent manner.
• T cells expressing CARD11-PIK3R3 demonstrated safe in vivo persistence for up to 418 days without malignant transformation.

Conclusions:

• Exploiting naturally occurring mutations, such as CARD11-PIK3R3, is a viable strategy to enhance adoptive T cell therapies.
• This approach allows for the exploration of T cell biology extremes and the application of evolutionary solutions to improve cancer treatment.
• The CARD11-PIK3R3 fusion represents a promising candidate for improving the safety and efficacy of T cell-based cancer immunotherapies.