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

Abstract

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. Non-specific 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.

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

“…Based on the modular composition of the prototype CAR, the intracellular activating domain can be exchanged by a moiety which delivers inhibitory signals to the T cell, including PD-1, CTLA-4, or CD45 [63]. Such an inhibitory CAR (iCAR) represses T cell activation upon binding to cognate antigen (Figure 1).…”

Putting on the brakes

“…A group at the Memorial Sloan-Kettering Cancer Center thinks it has solved the problem with T cells expressing two antigenspecific receptors to distinguish on-target cancer cells from off-target normal cells. 1 Chimeric antigen receptor (CAR) T cells currently in the clinic are made up of an antigen-specific single-chain variable fragment (scFv) fused to T cell-activating and -co-stimulatory domains. The CAR is designed to bind to an extracellular, tumor-associated antigen, and the stimulatory domains cause T cells to activate and proliferate, thus eliminating tumor cells.…”

Masked Chimeric Antigen Receptor for Tumor-Specific Activation

“…However, when they traffic to the tumor environment with availability of only aCAR, but not iCAR antigen, CAR-T cells can be fully activated to elicit antitumor immunity. 41 Other elegantly designed logic-gate T cells have also been reported and some of them also require dual antigen recognition for CAR-T activation. 36,37 Our mCAR method offers one more strategy to create conditionally active CARs for enhancing tumor-specificity of CAR-T cells with less structural complexity.…”

“…[36][37][38][39][40][41] One elegant strategy exploits dual targeting with two CARs to achieve selective recognition of tumor, but not normal cells. Sadelain and co-workers 38 demonstrated that T cells expressing two CARs targeting two different antigens could operate as logic gates to control full T cell activation.…”