PD-1– and CTLA-4–Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses

By V. D. Fedorov, M. Themeli, Michel Sadelain. Science Translational Medicine, 2013

719 citations recorded by the source corpus.

Human T cells that are reversibly inhibited upon contact with antigen protect bystander tissues from immune destruction. T Cells Switch Gears T cell immunotherapies are a rapidly expanding therapeutic approach for treating tumors, in part because of their ability to specifically target cancer over healthy tissue. This specificity depends on restricted expression on tumors of certain antigens, which activate the T cells. Such targets are hard to find, and even the best have some extratumor expression, which results in “on-target, off-tumor” toxicity of the T cell therapy. The only current way to block these side effects is nonspecific immunosuppression, but this also stops the T cells from attacking the tumor. Now, Fedorov et al. have designed antigen-specific inhibitory receptors to block these unwanted responses. The authors created inhibitory chimeric antigen receptors (iCARs) based on inhibitory molecules CTLA-4 or PD-1. They show that these iCARs block T cell responses from T cells activated by either their endogenous T cell receptor or an activating CAR. What’s more, this inhibiting effect is temporary. T cells that are shut off in the wrong tissue can switch back on again when they’re exposed to the activating signal in the absence of the inhibitory signal—the tumor. Incorporating iCARs may thus allow T cell therapies to target the tumor but not healthy tissue. T cell therapies have demonstrated long-term efficacy and curative potential for the treatment of some cancers. However, their use is limited by damage to bystander tissues, as seen in graft-versus-host disease after donor lymphocyte infusion, or “on-target, off-tumor” toxicities incurred in some engineered T cell therapies. Nonspecific immunosuppression and irreversible T cell elimination are currently the only means to control such deleterious responses, but at the cost of abrogating therapeutic benefits or causing secondary complications. On the basis of the physiological paradigm of immune inhibitory receptors, we designed antigen-specific inhibitory chimeric antigen receptors (iCARs) to preemptively constrain T cell responses. We demonstrate that CTLA-4– or PD-1–based iCARs can selectively limit cytokine secretion, cytotoxicity, and proliferation induced through the endogenous T cell receptor or an activating chimeric receptor. The initial effect of the iCAR is temporary, thus enabling T cells to function upon a subsequent encounter with the antigen recognized by their activating receptor. iCARs thus provide a dynamic, self-regulating safety switch to prevent, rather than treat, the consequences of inadequate T cell specificity.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/18b875fd3d3d6b652edcea9e109c319591f82edc

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Citations in the corpus

Precision Tumor Recognition by T Cells With Combinatorial Antigen Sensing Circuits (2016, positive): “6 Cell 164, 1–10, February 11, 2016 ª2016 Elsevier Inc. involve integrated signaling from multiple partially functional CARs that work cooperatively or antagonistically to control the activation of the T cell (Fedorov et al., 2013; Kloss et al., 2013; Wilkie et al., 2012).”
Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, background): “Instead of co-stimulatory domains, the inhibitory CARs contain inhibitory domains derived from immune-checkpoint proteins, such as cytotoxic lymphocyte protein 4 (CTLA-4) or programmed cell death 1 (PD-1), thereby co-opting the intrinsic immune-checkpoint signalling pathways of T cells 100 (Fig.”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “An elegant strategy for constructing this kind of NOT-gate circuit involves combining a CAR for one antigen (the killing antigen) with an inhibitory CAR (iCAR) for a second antigen, the overriding antigen (Fedorov et al., 2013).”