Editors' ChoiceCancer

Special delivery by “armored” CAR-T

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Science Translational Medicine  05 Sep 2018:
Vol. 10, Issue 457, eaav0334
DOI: 10.1126/scitranslmed.aav0334

Abstract

The integration of immune checkpoint blockade with CAR-T cell therapy improves antitumor efficacy with potential for reduced side effects.

The last decade has seen crucial advances in understanding of T cell immunobiology with respect to cancer, ushering in a new era in therapeutic development. Starting in 2011, the U.S. Food and Drug Administration (FDA) has approved several immune checkpoint inhibitor molecules that enhance antitumor activity of T cells. Additionally, in 2017, the FDA issued its first approvals of chimeric antigen receptor (CAR)–T cell therapies, which specifically target tumor cells for destruction by T cells via engineered receptors. Although both approaches have shown bona fide clinical results, each has its own shortcomings. Immune checkpoint blockade can have systemic autoimmune-like side effects, and the effectiveness of CAR-T therapy has so far mostly been limited to B cell acute lymphoblastic leukemia patients.

To overcome these limitations, researchers have attempted to exploit the potential mechanistic synergy between immune checkpoint inhibitors and CAR-T cells in combination therapy, with impressive preclinical results. Rafiq et al. took this concept a step further in their recent publication, leveraging their research group’s previous development of an “armored” CAR-T cell approach that endows these cells with the ability to secrete cytokines to enhance their function. In their study, the authors created CAR-T cells that secrete immunoglobulin domain fusion proteins, known as single-chain variable fragments (scFv), that block binding of the T cell inhibitor receptor programmed cell death 1 (PD-1) by its ligand programmed death ligand 1 (PD-L1), which can be expressed by cancer cells and suppress T cell function. This modification enhanced CAR-T cell efficacy in both syngeneic and xenogeneic PD-L1+ tumor-bearing mice. Critically, since CAR-T cells localize to tumor cells based on affinity interactions, this approach enabled more specific delivery of checkpoint inhibitors, potentially reducing the incidence of immune-related adverse events that can be associated with systemic checkpoint blockade therapy.

The encouraging results in mice reported in this study remain to be validated in additional models prior to clinical trials. Further, the effects of delivery by “armored” CAR-T cells on immune checkpoint inhibitor biodistribution should be specifically quantified to better assess the potential for reduced side effects using this approach. Overall, however, the reported results provide a foundation for translation of the next generation of CAR-T cell therapeutics with the potential to expand the impact of this approach to a wide variety of cancer patients.

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