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CAR T cells for infection, autoimmunity and allotransplantation

Nature Reviews Immunology volume 18, pages 605–616 (2018)Cite this article

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Abstract

Chimeric antigen receptors (CARs) have shown remarkable ability to re-direct T cells to target CD19-expressing tumours, resulting in remission rates of up to 90% in individuals with paediatric acute lymphoblastic lymphoma. Lessons learned from these clinical trials of adoptive T cell therapy for cancer, as well as investments made in manufacturing T cells at commercial scale, have inspired researchers to develop CARs for additional applications. Here, we explore the challenges and opportunities of using this technology to target infectious diseases such as with HIV and undesired immune responses such as autoimmunity and transplant rejection. Despite substantial obstacles, the potential of CAR T cells to enable cures for a wide array of disease settings could be transformational for the medical field.

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Fig. 1: CD4-based CARs for HIV-1.
Fig. 2: Engineering CAR T cells to traffic to B cell follicles.

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Acknowledgements

The authors thank members of the Riley laboratory for their thoughtful comments and support and members of the Center of Cellular Immunotherapies at the University of Pennsylvania for providing an exciting environment in which to study chimeric antigen receptor T cell therapy.

Reviewer information

Nature Reviews Immunology thanks S. Kitchen and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Author notes

  1. These authors contributed equally: Colby R. Maldini, Gavin I. Ellis.

Authors and Affiliations

  1. Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Colby R. Maldini, Gavin I. Ellis & James L. Riley

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  1. Colby R. Maldini
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  2. Gavin I. Ellis
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All authors researched data for the article, discussed its content and wrote, reviewed and edited it before submission.

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Correspondence to James L. Riley.

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Glossary

Chimeric antigen receptor

(CAR). A synthetic receptor engineered to be expressed on the surface of T cells or other immune cells to redirect cellular specificity.

HIV reservoir

Persistent HIV that remains transcriptionally silent as inactive provirus within infected CD4+ T cells despite effective combination antiretroviral therapy.

Combination antiretroviral therapy

(cART). Therapy that consists of two or more active drugs with different mechanisms of action that are used to subdue HIV replication.

Exhaustion

A state of T cell dysfunction that develops over time with repeated exposure to cognate antigen, for example, during chronic infection with a virus such as HIV.

Broadly neutralizing antibodies

(bNAbs). Antibodies that have the unique ability to neutralize and prevent infection with multiple and diverse strains of HIV.

Homology-directed repair

(HDR). A mechanism in cells to repair double-stranded DNA breaks using a DNA donor template with homologous sequences flanking the break site.

MegaTAL nuclease

A sequence-specific endonuclease with a DNA-binding domain that promotes efficient cleavage of genomic DNA with a high degree of fidelity.

Good manufacturing practice

(GMP). A series of guidelines enforced by the Food and Drug Administration in the United States, and other similar bodies elsewhere, regarding the manufacturing of safe biological therapeutic agents.

Tonic signalling

Low-level signalling caused by antigen-independent clustering of receptor molecules in the basal state of a cell.

Latency-reversing agents

(LRAs). Pharmacological agents that induce HIV transcription from cells harbouring HIV provirus.

T follicular helper cells

(TFH cells). A specialized CD4+ T cell subset that primarily resides in the B cell follicles of lymphoid tissue to aid the development of the humoral immune response.

Elite controller

A rare population of HIV-infected individuals who can spontaneously control HIV replication in the absence of combination antiretroviral therapy.

Cytokine storm

The excessive production of pro-inflammatory cytokines often induced by the over-activation of immune cells.

Chimeric autoantibody receptors

(CAARs). Chimeric antigen receptor-like receptors whose extracellular domain consists of the protein target of a B cell-mediated autoimmune response.

Pemphigus vulgaris

An antibody-mediated autoimmune disease that causes blistering of the skin.

Desmogleins

Components of cell–cell adhesion complexes that form desmosomes under antibody-mediated attack in patients with pemphigus vulgaris.

Bystander suppression

The ability of a regulatory T (Treg) cell to suppress effector T cell responses directed at an antigen distinct from the antigen that stimulated the Treg cell.

Treg cell-specific demethylated region

A conserved region of intron 1 of FOXP3 that is demethylated in cells that are stably committed to the regulatory T (Treg) cell lineage.

Suicide switches

Engineered logic gates used as a safety mechanism that cause cells to undergo apoptosis when certain conditions are met. Many suicide switches activate in response to exogenous drugs.

Infectious tolerance

A phenomenon by which regulatory T cell activation can impart suppressive activity to effector T cells.

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Maldini, C.R., Ellis, G. & Riley, J.L. CAR T cells for infection, autoimmunity and allotransplantation. Nat Rev Immunol 18, 605–616 (2018). https://doi.org/10.1038/s41577-018-0042-2

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