Designing chimeric antigen receptors to effectively and safely target tumors

Abstract

The adoptive transfer of T cells engineered to express artificial chimeric antigen receptors CARs) that target a tumor cell surface molecule has emerged as an exciting new approach for cancer immunotherapy. Clinical trials in patients with advanced B cell malignancies treated with CD19-specific CAR-modified T cells (CAR-T) have shown impressive antitumor efficacy, leading to optimism that this approach will be useful for treating common solid tumors. Because CAR-T cells recognize tumor cells independent of their expression of human leukocyte antigen (HLA) molecules, tumors that escape conventional T cells by downregulating HLA and/or mutating components of the antigen processing machinery can be eliminated. The ability to introduce or delete additional genes in T cells has the potential to provide therapeutic cell products with novel attributes that overcome impediments to immune mediated tumor elimination in immunosuppressive tumor microenvironments. This review will discuss recent concepts in the development of effective and safe synthetic CARs for adoptive T cell therapy (ACT).

Figure 1. Structural Elements of Chimeric Antigen Receptors

Biophysical components of chimeric antigen receptors work in concert to affect qualitative and quantitative signaling outputs to the T cell. Signal output tuning based on scFv binding affinity, extracellular spacer size adapted to the target epitope location, and cytoplasmic costimulatory and ITAM elements are interdependent. The net effect of any combination of components is to tune the CAR to be compatible with effector T cell physiology between thresholds that enforce hypoactivity (anergy) and hyperactivity (activation induced cell death).

Figure 2. Formulating Engineered T Cell Products of Defined Composition

The composition of T cells present in peripheral blood is heterogeneous and prone to fluctuations based on patient age, disease status and prior therapies. Without formulation of T cell products of defined composition, each patient will receive a different product with potentially significant bariance in potency and safety. CAR trials are now underway that are examining the impact of formulating products of defined ratios of CD4 and CD8 T cells derived from different precursors (T_N= naïve, T_CM= central memory), as well as, purifying CAR T cells based on purity and expression level of the CAR.