Engineered T cells: the promise and challenges of cancer immunotherapy

• Published in: Nature reviews. Cancer Vol. 16; no. 9; pp. 566 - 581
• Main Authors: Fesnak, Andrew D., June, Carl H., Levine, Bruce L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2016; Nature Publishing Group
• Subjects: 631/154/51/201; 631/67/1059/2325; 692/700/565/545/576/1955; Antigen Presentation; Antigens, CD19 - immunology; Antigens, Neoplasm - immunology; Biomedicine; Cancer Research; Cancer treatment; Clinical Trials as Topic; Costimulatory and Inhibitory T-Cell Receptors - genetics; Costimulatory and Inhibitory T-Cell Receptors - immunology; Cytokines - metabolism; Forecasting; Gene Editing; Gene Transfer Techniques; Genetic Engineering; Hematologic Neoplasms - immunology; Hematologic Neoplasms - therapy; HLA Antigens - immunology; Humans; Immune response regulation; Immunotherapy; Immunotherapy, Adoptive - adverse effects; Immunotherapy, Adoptive - methods; Immunotherapy, Adoptive - trends; Innovations; Models, Immunological; Neoplasms - immunology; Neoplasms - therapy; Observations; Properties; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; review-article; Syndrome; T cells; T-Cell Antigen Receptor Specificity; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - transplantation; Tumor Escape; Tumor Microenvironment - immunology
• ISSN: 1474-175X; 1474-1768
• DOI: 10.1038/nrc.2016.97

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. This Review assesses what we have learnt about adoptive cell transfer of engineered T cells for the treatment of patients with B cell malignancies and discusses how this therapy can be improved and applied to other malignancies, including solid tumours. 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.