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  • Review Article
  • Published:

Engineering lymphocyte subsets: tools, trials and tribulations

Nature Reviews Immunology volume 9, pages 704–716 (2009)Cite this article

Key Points

  • In principle, the goal of lymphocyte engineering is to pharmacologically enhance the function of the immune system, including specifying antigen recognition, improving lymphocyte survival, augmenting proliferative capacity, preventing apoptosis and/or inducing resistance to immune regulation.

  • Improved understanding of lymphocyte subsets has recently allowed adoptive transfer of CD4+ effector T cells, CD4+ regulatory T cells and CD8+ cytotoxic T cells. In addition to the previous clinical trials testing T cells expressing αβ T cell receptors, clinical protocols evaluating infusions of γδ T cells and invariant natural killer T cells have recently been completed.

  • For many years the only established method to engineer lymphocytes for clinical protocols used gammaretroviruses. Technological advances have produced lentiviral vectors and foamy virus vectors that have increased efficiency and potentially enhanced safety features, zinc-finger nucleases that allow site-specific modification and various other non-viral approaches such as transposons.

  • The most important questions currently facing the field are whether engineered lymphocytes are safe and, if so, under what conditions? Malignancies arising from retrovirally transduced haematopoietic stem cells have been reported in animal models and human gene therapy trials. Several hundred patients have been treated with engineered mature T cells for various indications including congenital immunodeficiency, cancer and AIDS following HIV infection. In contrast to stem cell engineering, to date there are no reported cases of transformation or leukaemia following engineered T cell transfer.

  • The first Phase III clinical study with engineered lymphocytes is currently testing whether allogeneic T cells can mediate immune reconstitution and antileukaemic effects and improve safety by triggering a conditional suicide gene comprised of herpes simplex virus thymidine kinase in the event of graft-versus-host disease.

Abstract

Cell-based therapies with various lymphocyte subsets hold promise for the treatment of several diseases, including cancer and disease resulting from inflammation and infection. The ability to genetically engineer lymphocyte subsets has the potential to improve the natural immune response and correct impaired immunity. In this Review we focus on the lymphocyte subsets that have been modified genetically or by other means for therapeutic benefit, on the technologies used to engineer lymphocytes and on the latest progress and hurdles in translating these technologies to the clinic.

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Figure 1: Cell culture approaches for adoptive transfer of lymphocyte subsets.

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Acknowledgements

C.H.J. is grateful for support by the US National Institutes of Health (NIH) (grants 5R01CA105216, 1R01CA120409, 5P01CA066726 and 1U19AI082628) and the Alliance for Cancer Gene Therapy. B.R.B. acknowledges direct support of this work by the US NIH (grants 2R01HL56067, R01AI34495, R01CA72669, P01CA142106 and P01AI056299) as well as a Leukemia and Lymphoma Translational Research Award. J.L.R. receives support from the US NIH (grants P30AI045008, R01AI057838, R01CA113783, R41CA130547, U19AI066290, U19AI082628 and P01AI080192) as well as from the JDRF Center on Cord Blood Therapies for Type 1 Diabetes.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Carl H. June & James L. Riley

  2. University of Minnesota Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, Minneapolis, 55455, Minnesota, USA

    Bruce R. Blazar

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Correspondence to Carl H. June.

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Carl H. June and James L. Riley receive research funding from Tmune Therapeutics, Inc. This is managed in compliance with the policies established at the University of Pennsylvania.

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Metabolic pathways that guide activation of human Vγ9Vδ2 T cells. (PDF 173 kb)

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Clinicaltrials.gov identifier NCT00842634

Phase III HSVtk engineered T Cell Trial (MolMed)

Target Product Profile

Glossary

Adoptive transfer

A form of immunotherapy in which effector lymphocytes are transfused. Allogeneic adoptive transfer is usually referred to as donor lymphocyte infusion and autologous lymphocyte adoptive transfer is referred to as adoptive transfer therapy.

Therapeutic window

The range of concentrations of a drug, or numbers of immune cells, that will achieve therapeutic effects in most patients with adverse effects in only a small percentage. In cell-based therapies, the condition of the host and the dose and schedule of administration can alter the therapeutic window.

Adeno-associated virus

(AAV). A replication-defective non-enveloped virus that is a member of the Parvovirus family. Vectors derived from AAV are useful because AAV does not cause disease and they can mediate long-term gene transfer in both dividing and non-dividing cells.

Gammaretrovirus

A genus of the retroviridae family. Vectors using gammaretroviruses were the first integrating vectors to be used clinically. Most vectors are derived from endogenous retroviruses isolated from mice such as the murine leukaemia virus.

Transposon

Mobile DNA elements that can relocate within the genome of their hosts. Transposons can be used for various applications, including insertional mutagenesis, gene identification, gene tagging and DNA sequencing.

Chimeric antigen receptor

Also known as chimeric immune receptor. Non-MHC-restricted chimeric antigen receptors combine antigen specificity and T cell-activating properties in a single fusion molecule. Most chimeric antigen receptors use an antibody-derived antigen-binding motif to recognize surface-expressed targets, in contrast to T cell receptors, which usually recognize peptide antigens presented by MHC molecules.

MicroRNAs

Single-stranded RNA molecules approximately 21–23 nucleotides in length that are thought to regulate the expression of other genes.

Epigenetic marks

Chemical modifications of chromatin that retain an intact DNA sequence and can modify gene expression. Examples are methylation of cytosine residues and histone modification by acetylation.

Regulatory T (TReg) cell

A specialized type of CD4+ T cell that can suppress the responses of other T cells. TReg cells provide a crucial mechanism for the maintenance of peripheral self tolerance and a subset of these cells is characterized by the expression of CD25 and FOXP3.

Protein transduction domains

(PTDs). Peptides derived from several viruses, such as the HIV Tat PTD, that can enhance cellular uptake of proteins or polynucleotides. In general, the PTD must be covalently attached to the protein.

Small interfering RNA

(siRNA). Synthetic RNA molecules of 19–23 nucleotides that are used to 'knock down' (that is, silence the expression of) a specific gene. This approach is known as RNA interference (RNAi) and is mediated by the sequence-specific degradation of mRNA.

Insertional mutagenesis

Genotoxicity from DNA-based engineering that can result in cellular transformation through various mechanisms. DNA insertion can result in mutations that lead to the activation of oncogenes or to the inactivation of tumour suppressor genes.

Zinc-finger nucleases

(ZFNs). Chimeric proteins comprised of engineered zinc-finger proteins fused to the catalytic domain of a restriction endonuclease that can bind and cleave DNA specifically at a unique and predetermined site in the human genome.

Target product profile

A prospective and dynamic summary of the ideal characteristics of a drug or biological product to ensure that the desired quality, and hence the safety and efficacy, of a drug product is achieved. The target product profile forms the basis of design for the development of the product.

T helper 17 (TH17) cells

A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves IL-23 and IL-21, as well as the transcription factors RORγt (retinoic acid receptor-related orphan receptor-γt) and STAT3 (signal transducer and activator of transcription 3).

Experimental autoimmune encephalomyelitis

An experimental model of multiple sclerosis that is induced by immunization of susceptible animals with myelin-derived antigens, such as myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein.

Central memory T (TCM) cells

Antigen-experienced T cells that express cell surface receptors required for homing to secondary lymphoid organs. These cells are generally thought to be long-lived and can serve as the precursors to effector T cells for recall responses.

Effector memory T (TEM) cells

Terminally differentiated T cells that lack lymph node-homing receptors but express receptors that enable them to home to inflamed tissues. TEM cells can exert immediate effector functions without the need for further differentiation.

Vγ9Vδ2+ T cells

Vγ9Vδ2+ T cell receptors are expressed by γδ T cells. Vγ9Vδ2+ T cells are unique to humans and primates and are a minor fraction of the leukocyte population in peripheral blood (0.5–5%).

SCID mouse

A naturally occurring mouse mutant with severe combined immune deficiency due to an inability to rearrange antigen receptor chain genes.

Natural killer T (NKT) cells

A subpopulation of T cells that expresses both NK cell and T cell markers. In the C57BL/6 mouse strain, NKT cells express the NK1.1 (NKRP1C) molecule and the T cell receptor (TCR). Some NKT cells recognize CD1d-associated lipid antigens and express a restricted repertoire of TCRs. After TCR stimulation of naive mice, NKT cells rapidly produce interleukin-4 and interferon-γ.

Replication-competent lentivirus

A lentivirus vector that produces infectious virions. Lentiviral vectors are designed to support only one infections cycle however mutations can induce replication competency.

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June, C., Blazar, B. & Riley, J. Engineering lymphocyte subsets: tools, trials and tribulations. Nat Rev Immunol 9, 704–716 (2009). https://doi.org/10.1038/nri2635

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