T cell engineering for adoptive T cell therapy: safety and receptor avidity

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Adoptive T cell therapy (ACT) has evolved significantly over 80 years, becoming a potent treatment for infections and cancers.
• Genetic engineering allows for the creation of highly specific T cell products using antigen-specific receptors like T cell receptors (TCRs) and chimeric antigen receptors (CARs).
• While engineered T cells offer high efficacy, they also pose risks of severe off-target toxicities, necessitating robust safety strategies.

Purpose of the Study:

• To review the critical role of receptor avidity in balancing the safety and efficacy of engineered T cell therapies.
• To discuss strategies for optimizing T cell receptor (TCR)/chimeric antigen receptor (CAR) affinity to enhance therapeutic outcomes.
• To explore the potential of combining high and low avidity receptors for improved safety and efficacy in ACT.

Main Methods:

• Review of existing literature on adoptive T cell therapy (ACT) and engineered T cells.
• Analysis of the impact of T cell receptor (TCR)/chimeric antigen receptor (CAR) avidity on T cell function and toxicity.
• Discussion of safety strategies, including cell removal, activity control, and target selectivity.

Main Results:

• High avidity TCRs/CARs demonstrate faster responses but risk over-activation, T cell exhaustion, and cytokine-related side effects.
• Low avidity TCRs/CARs are less prone to over-activation and may offer better selectivity for tumors with shared antigens, though complete eradication is not guaranteed.
• Optimal avidity is key to maximizing the safety/efficacy balance in engineered T cell therapy.

Conclusions:

• Achieving an 'optimal' T cell receptor (TCR)/chimeric antigen receptor (CAR) affinity is crucial for enhancing the safety and efficacy of engineered T cell therapies.
• Simultaneous or sequential infusion of high and low avidity receptors presents a promising approach for developing efficacious yet safe ACT.
• Further research into avidity modulation can lead to safer and more effective treatments for cancer and infectious diseases.