The future of engineered immune cell therapies

Abstract

Immune cells are being engineered to recognize and respond to disease states, acting as a "living drug" when transferred into patients. Therapies based on engineered immune cells are now a clinical reality, with multiple engineered T cell therapies approved for treatment of hematologic malignancies. Ongoing preclinical and clinical studies are testing diverse strategies to modify the fate and function of immune cells for applications in cancer, infectious disease, and beyond. Here, we discuss current progress in treating human disease with immune cell therapeutics, emerging strategies for immune cell engineering, and challenges facing the field, with a particular emphasis on the treatment of cancer, where the most effort has been applied to date.

Figure 1:. Ex vivo immune cell engineering.

A Major ex vivo immune cell engineering approaches and their key attributes. B Example systems of various engineering approach. Logic circuit: Synthetic notch, SynNotch, receptor is composed of an extracellular binding domain, a notch core transmembrane domain, and a transcription factor (TF). The binding of the extracellular binding domain to a target antigen on another cell leads to the cleavage of the TF, which subsequently induces the expression of a CAR. The CAR is designed to bind to another antigen on the same target cell, forming a IF-THEN AND logic. Switch: A lenalidomide regulatable CAR is composed of a conventional CAR fused to a degron IKZF3. The binding of IKZF3 to lenalidomide recruits the endogenous ubiquitin ligase, leading to CAR degradation. Therapeutic protein delivery: Immune cells can be engineered to locally produce and secrete therapeutic proteins. Knockin: The specific integration of the CAR sequence into the T-cell receptor α constant (TRAC) locus enables more uniformed CAR expression and better CAR T cell efficacy. Knockout: PD-1 is an inhibitory receptor that can limit immune cell therapy efficacy. PD-1 knockout can potentially lead to more potent immune cell therapy.

Figure 2:. Barriers to the effectiveness of engineered T cells in solid tumors.

Figure 3.. In vivo immune cell engineering approaches.

Cell transfer can be aided by biomaterial delivery vehicles that localize immune cells to specific anatomic sites and provide biochemical cues (e.g., cytokines) or mechanical properties that promote desirable cell phenotypes. Transferred cells can also be manipulated via externally applied signals such as ultrasound or magnetic fields. Alternatively, host or transferred immune cells may be genetically altered in situ, via viral or non-viral strategies, bypassing ex vivo cell manipulation and transfer.