Chimeric Antigen Receptor T Cell Therapy: Challenges to Bench-to-Bedside Efficacy

Abstract

Immunotherapy with T cells genetically modified to express chimeric Ag receptors (CARs) that target tumor-associated molecules have impressive efficacy in hematological malignancies. The field has now embraced the challenge of applying this approach to treat common epithelial malignancies, which make up the majority of cancer cases but evade immunologic attack by a variety of subversive mechanisms. In this study, we review the principles that have guided CAR T cell design and the extraordinary clinical results being achieved in B cell malignancies targeting CD19 with a single infusion of engineered T cells. This success has raised expectations that CAR T cells can be applied to solid tumors, but numerous obstacles must be overcome to achieve the success observed in hematologic cancers. Potential solutions driven by advances in genetic engineering, synthetic biology, T cell biology, and improved tumor models that recapitulate the obstacles in human tumors are discussed.

Figure 1. Adoptive cell therapy with chimeric antigen receptor (CAR)-modified T cells

Figure 2. Barriers to CAR T cell therapy for solid tumors

Bottom left: CAR T cell trafficking depends on expression of receptors for chemokines secreted by the tumor. CAR T cells endogenously express chemokine receptors like CXCR3 and CCR5, but their cognate ligands are often not highly expressed by solid tumors. CAR T cells can be engineered to express receptors (e.g. CCR2, CCR4) for chemokines naturally secreted by the tumor to improve trafficking to tumors. Bottom right: Antigen-activated CAR T cells in the tumor microenvironment up-regulate expression of inhibitory receptors which can lead to T cell dysfunction. Upper left: Tumor microenvironments are rich in factors like adenosine, extracellular potassium, and reactive oxygen species (ROS), which can inhibit T cells directly or indirectly. Upper right: Immunosuppressive cells like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) can promote tumor growth and inhibit T cell activity both directly and indirectly. Cancer-associated fibroblasts (CAF) deposit extracellular matrix to limit T cell penetration and can recruit other immunosuppressive cells.

Figure 3. Comparison of mouse models for human solid tumors