Generation of T cell responses against broad KRAS hotspot neoantigens for cell therapy or TCR discovery

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Adoptive cell therapy (ACT) shows promise for anti-tumor immunity by targeting neoantigens.
• Current ACT approaches for KRAS neoantigens are limited to a small subset of known targets.

Purpose of the Study:

• To develop a universal ex vivo process for priming and expanding T cell responses to any KRAS neoantigen, tailored to individual human leukocyte antigen (HLA) profiles.
• To generate and characterize T cell receptors (TCRs) with potent anti-tumor activity against KRAS neoantigens.

Main Methods:

• A novel single process was developed starting from peripheral blood to prime and expand T cells ex vivo.
• T cell responses were evaluated against 47 KRAS neoantigens in 20 healthy donors.
• Over 150 KRAS-specific T cell receptors (TCRs) were identified and cloned.

Main Results:

• The process successfully generated T cell responses to 46 out of 47 evaluated KRAS neoantigens.
• The most potent TCRs exhibited efficacy comparable to clinically validated benchmark TCRs.
• Generated T cells demonstrated the ability to inhibit tumor growth in both in vitro and in vivo models.

Conclusions:

• The developed ex vivo process provides a versatile platform for generating personalized T cell therapies against KRAS neoantigens.
• This approach can be utilized for developing novel ex vivo primed therapeutics or for discovering a comprehensive library of TCRs targeting diverse KRAS neoantigens.