Beyond CAR T Cells: Other Cell-Based Immunotherapeutic Strategies Against Cancer

Abstract

Background: Chimeric antigen receptor (CAR)-modified T cells have successfully harnessed T cell immunity against malignancies, but they are by no means the only cell therapies in development for cancer. Main Text Summary: Systemic immunity is thought to play a key role in combatting neoplastic disease; in this vein, genetic modifications meant to explore other components of T cell immunity are being evaluated. In addition, other immune cells-from both the innate and adaptive compartments-are in various stages of clinical application. In this review, we focus on these non-CAR T cell immunotherapeutic approaches for malignancy. The first section describes engineering T cells to express non-CAR constructs, and the second section describes other gene-modified cells used to target malignancy. Conclusions: CAR T cell therapies have demonstrated the clinical benefits of harnessing our body's own defenses to combat tumor cells. Similar research is being conducted on lesser known modifications and gene-modified immune cells, which we highlight in this review.

Keywords: NK cells; NKT cells; cell therapy; dendritic cells; gamma delta T cells; gene modified cells; immunotherapy.

Figure 1

Schematic of a T cell (purple) and various modification - clockwise from left: forcibly expressed chemokine receptors (blue star) that help the cell migrate down the relevant chemokine gradient secreted by the tumor, secreted checkpoint inhibitors (green Ys) that bind to the checkpoint receptors on T cells (blue diamonds), abrogating their inhibitory function, a dominant negative receptor (black no sign) that helps block immune suppressive effects of cytokines like TGF-beta, and cytokines (yellow) that help stimulate the T cells in an autocrine function.

Figure 2

Schematic of various other cells and their effects on the tumor – clockwise from left: (A) natural killer (NK) cells, which lyse tumors without the need for identifying a known antigen, working through a balance of inhibitory and activating receptors (and also amenable to transduction with chimeric antigen receptors), as well as secrete cytokines that activate other components of the immune response, (B) natural killer T (NKT cells, which recognize lipid antigens and also help orchestrate the immune response, (C) dendritic cells (DC) which present antigen to T cells and help jump start immune responses like a vaccine.