Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy

Abstract

Chimaeric antigen receptor (CAR) T-cells are T-cells that have been genetically modified to express an artificial construct consisting of a synthetic T-cell receptor (TCR) targeted to a predetermined antigen expressed on a tumour. Coupling the T-cell receptor to a CD3ζ signalling domain paved the way for first generation CAR T-cells that were efficacious against cluster of differentiation (CD)19-expressing B-cell malignancies. Optimization with additional signalling domains such as CD28 or 4-1BB in addition to CD3ζ provided T-cell activation signal 2 and further improved the efficacy and persistence of these second generation CAR T-cells. Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported. In this review, we discuss a different approach to optimization of CAR T-cells. Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence. The choice of the ‘armor’ agent is based on knowledge of the tumour microenvironment and the roles of other elements of the innate and adaptive immune system. Although there are several variants of armored CAR T-cells under investigation, here we focus on three unique approaches using interleukin-12 (IL-12), CD40L and 4-1BBL. These agents have been shown to further enhance CAR T-cell efficacy and persistence in the face of a hostile tumour microenvironment via different mechanisms.

The Role of Checkpoint Inhibitors and Cytokines in Adoptive Cell-Based Cancer Immunotherapy with Genetically Modified T Cells

“…IL 15 belongs to the gamma chain cytokine superfamily and is produced by monocytes, dendritic cells, macrophages, and stromal cells [77]. Similar to IL 2, IL 15 stimulates cell proliferation, pro motes cell viability, and influences effector functions of natural killer and T cells.…”

Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to date, current limitations and perspectives

“…Researchers at Memorial Sloan Kettering Cancer Center are investigating the armoring of CAR T-cells with agents to make them more potent. For example, CAR T-cells can be engineered to constitutively secrete IL-12, express CD40L or 4-1BB, depending on the type of tumor targeted [62].…”

CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases

“…So-called armored CARs include the 4-1BB ligand in addition to the CAR in order to provide increased costimulation through the 4-1BB pathway [29]. Recently described examples are TRUCKs that co-express catalase to protect T cells from oxidative stress-mediated repression [30] and heparanase to improve T cell penetration through tumor stroma [31].…”