Review Article | Published:

Engineered T cells: the promise and challenges of cancer immunotherapy

Nature Reviews Cancer volume 16, pages 566581 (2016) | Download Citation

Abstract

The immune system evolved to distinguish non-self from self to protect the organism. As cancer is derived from our own cells, immune responses to dysregulated cell growth present a unique challenge. This is compounded by mechanisms of immune evasion and immunosuppression that develop in the tumour microenvironment. The modern genetic toolbox enables the adoptive transfer of engineered T cells to create enhanced anticancer immune functions where natural cancer-specific immune responses have failed. Genetically engineered T cells, so-called 'living drugs', represent a new paradigm in anticancer therapy. Recent clinical trials using T cells engineered to express chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) have produced stunning results in patients with relapsed or refractory haematological malignancies. In this Review we describe some of the most recent and promising advances in engineered T cell therapy with a particular emphasis on what the next generation of T cell therapy is likely to entail.

Key points

  • Adoptive immunotherapy has rapidly evolved to harness modern genetic techniques to create T cells with enhanced specificity, efficacy and safety. Artificial expression of chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) in autologous T cells has enabled a new generation of targeted cellular therapeutics.

  • Early clinical trials targeting B cell malignancies have shown great promise, generating unprecedented response rates to treatment of patients with relapsed and refractory B cell acute lymphoblastic leukaemia (B-ALL). As more patients with different B cell malignancies are treated, areas for further optimization are brought to light.

  • Engineered T cell therapy has been adapted to treat non-B cell malignancies, including multiple myeloma and myeloid malignancies as well as solid tumours. To date, target selection has proved challenging as many tumour-conserved markers are also expressed on benign tissues (for example, mesothelin) and other tumour-specific markers are less uniformly expressed (for example, epidermal growth factor receptor variant III (EGFRvIII)).

  • More precise targeting of tumour cell subsets, such as cancer stem cells, or targeting of portions of intracellular tumour markers in the context of the major histocompatibility complex (MHC), may enhance specificity and limit off-tumour effects. Combining non-specific and specific immune responses (for example, T cells redirected for universal cytokine killing (TRUCKs), fluorescein isothiocyanate (FITC)–folate plus FITC-CAR T cell) could further enhance antitumour immune response, while minimizing off-tumour effects.

  • Although lentiviral and retroviral transduction are still the most common approaches to ex vivo T cell gene modification, DNA and RNA transfection have some advantages. In particular, RNA transfection of short guide RNAs enables CRISPR–Cas9 modification of T cells. This targeted gene disruption approach could help to create engineered T cells with supraphysiological antitumour capabilities.

  • In addition to specificity-enhancing artificial receptor expression, the next generation of engineered T cells may include modifications to overcome tumour-mediated immune suppression, additional receptors to enable Boolean gating of signal transduction or safety switches to enhance precision control of in vivo engineered T cell activity.

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Acknowledgements

A.D.F. is supported by National Institutes of Health (NIH) grant 5T32HL007775-22; B.L.L. is supported by NIH grants 1RO1CA165206 and P30-CA016520-35. C.H.J. is supported by NIH grants 1RO1CA165206 and 5R01CA120409, by the Leukemia and Lymphoma Society and the Parker Foundation. The authors would like to acknowledge research assistance from K. Lamontagne, and the inspiration and support of their patients and their professional colleagues.

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  1. Department of Pathology and Laboratory Medicine and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-5156, USA.

    • Andrew D. Fesnak
    • , Carl H. June
    •  & Bruce L. Levine

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  2. Search for Carl H. June in:

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Competing interests

The University of Pennsylvania has entered into a partnership with Novartis for the development of chimeric antigen receptors. This partnership is managed in accordance with the University of Pennsylvania's conflict of interest policy. The authors are in compliance with this policy. B.L.L. and C.H.J.

Corresponding authors

Correspondence to Andrew D. Fesnak or Bruce L. Levine.

Glossary

B cell aplasia

The complete in vivo absence of B cells.

Response rates

Determinants of whether cancer patients progress, stay the same or improve following therapy.

Autologous

From the same organism.

Plasma cells

B cell derivatives that produce immunoglobulin and are generally CD38+CD138+.

Cytokine release syndrome

(CRS). A serious and in some cases potentially life-threatening toxicity that has been observed after administration of natural and bispecific antibodies and, more recently, following adoptive T cell therapies for cancer. CRS is associated with elevated circulating levels of several cytokines including interleukin-6 (IL-6) and interferon-γ (IFNγ).

Minimal residual disease

Small amount of disease remaining, typically after treatment.

Immune privileged sites

Body sites that resist immune infiltration and activation.

Immune activation threshold

The sum of minimum signals necessary for immune cell activation; specifically for T cell activation, effector function and proliferation.

Lymphodepletive preconditioning

Treatment regimen, usually chemotherapeutic, that results in lymphopenia and disruption in homeostasis resulting in the in vivo production of lymphocyte growth factors that can assist with engraftment following adoptive cellular immunotherapy.

Neoantigens

Tumour-specific antigens that have not previously been seen by the immune system.

Central tolerance

Mechanism for developing lymphocytes in the thymus and bone marrow to be rendered non-reactive to self antigens.

Antibody-dependent, cell-mediated cytotoxicity

(ADCC). Lysis of a target cell bound by antibodies, which is mediated by an immune cell binding to the Fc portion of the antibodies.

Graft-versus-host disease

(GVHD). Immune reaction of a donor graft containing immune cells against the recipient host that is a by-product of a mismatch in human leukocyte antigens (HLAs). GVHD is a major cause of morbidity following allogeneic haematopoietic stem cell transplantation.

Allogeneic

Genetically distinct but from the same species.

Immune checkpoints

System of immune suppression.

Primary signal

The antigen-specific signal delivered to a T cell through the T cell receptor, which is complemented by co-stimulatory signals to achieve full-function T cell activation and effector function.

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https://doi.org/10.1038/nrc.2016.97

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