CAR-T Cell Therapy for Lymphoma

Abstract

Lymphomas arise from clonal expansions of B, T, or NK cells at different stages of differentiation. Because they occur in the immunocyte-rich lymphoid tissues, they are easily accessible to antibodies and cell-based immunotherapy. Expressing chimeric antigen receptors (CARs) on T cells is a means of combining the antigen-binding site of a monoclonal antibody with the activating machinery of a T cell, enabling antigen recognition independent of major histocompatibility complex restriction, while retaining the desirable antitumor properties of a T cell. Here, we discuss the basic design of CARs and their potential advantages and disadvantages over other immune therapies for lymphomas. We review current clinical trials in the field and consider strategies to improve the in vivo function and safety of immune cells expressing CARs. The ultimate driver of CAR development and implementation for lymphoma will be the demonstration of their ability to safely and cost-effectively cure these malignancies.

Keywords: CD19; CD20; CD30; adoptive T cell therapy; immunotherapy; kappa light chain.

Figures

Figure 1

The basic structure of first-generation chimeric antigen receptors (CARs). The most common CARs combine the extracellular antigen-recognition site of a monoclonal antibody and the intracellular domains of a T cell receptor (TCR) complex molecule. Clustering of CARs induced by antigen binding on the surface of tumor cells initiates signal transduction that leads to T cell activation and killing of tumor cells.

Figure 2

Three generations of chimeric antigen receptors (CARs). First-generation CARs include an extracellular domain (ectodomain), usually derived from a single-chain variable fragment (scFv), composed of the antigen-binding regions of both heavy and light chains of a monoclonal antibody; a transmembrane domain; and an intracellular domain (endodomain) with a cell-signaling component derived from the T cell receptor, usually the ζ chain. Most subsequent CARs have followed this same structural pattern, with incorporation of one (second-generation CARs) or more (third-generation CARs) accessory or costimulatory signaling components, such as CD28, CD137 (4-1BB), and CD134 (OX40). These additional costimulatory endodomains improve T cell activation and proliferation, and thus may promote killing of target tumor cells.

Figure 3

Tumor strategies for immune evasion. Malignant cells and their supporting stroma secrete immunosuppressive cytokines, such as transforming growth factor β (TGFβ); attract immunosuppressive cells, such T regulatory cells (Tregs) and myeloid-derived suppressive cells (MDSCs); inhibit dendritic cell (DC) maturation; express immunosuppressive molecules on their surface, including Fas ligand and PD-L1 (programmed death 1 ligand); and create a metabolic environment that is immunosuppressive, including high lactate levels, low tryptophan levels, and high kynurenine levels [through the activity of indoleamine 2,3-dioxygenase (IDO) in tumor cells and immature DCs], as well as low arginine levels (through the activity of arginase in MDSCs). Malignant cells and stroma also secrete vascular endothelial growth factor (VEGF), which promotes tumor vascularization and growth via recruitment of endothelial cells. Possible countermeasure strategies include increasing the level of CAR-T cell activation or decreasing physiological downregulation (e.g., by autocrine production of IL-15 or inclusion of additional costimulatory domains); engineering the CAR-T cells to be resistant to tumor immune evasion strategies (such as expressing a dominant negative receptor for TGFβ in CAR-T cells); and targeting the cellular components of tumor stroma [cancer-associated fibroblasts (CAFs) and endothelial cells] using an additional CAR.