Therapeutic T cell engineering

Abstract

Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimaeric antigen receptors (CARs) are a class of synthetic receptors that reprogram lymphocyte specificity and function. CARs targeting CD19 have demonstrated remarkable potency in B cell malignancies. Engineered T cells are applicable in principle to many cancers, pending further progress to identify suitable target antigens, overcome immunosuppressive tumour microenvironments, reduce toxicities, and prevent antigen escape. Advances in the selection of optimal T cells, genetic engineering, and cell manufacturing are poised to broaden T-cell-based therapies and foster new applications in infectious diseases and autoimmunity.

Figure 1. Receptors for antigen

a, T cell receptor (TCR). Physiological antigen recognition is mediated by the TCR–CD3 complex, which comprises six independent gene products: the TCR α and β chains, which together bind to HLA–peptide complexes, and the CD3γ, δ, ε and ζ chains, which initiate T cell activation. b, Chimaeric antigen receptor (CAR). A prototypic second-generation CAR comprises three canonical domains for binding to antigen (unrestricted by HLA), T cell activation (commonly via the CD3ζ cytoplasmic domain) and co-stimulation (via the CD28 cytoplasmic domain in this example). The hinge and transmembrane domain also contribute to overall CAR function. c, Synthetic receptors in the extended CAR family: chimaeric co-stimulatory receptors (CCRs) provide co-stimulation in response to antigen or alternate ligands; chimaeric cytokine receptors (CyCRs) bind to one cytokine but transduce the signal of another; antigen-specific inhibitory receptors (iCARs) inhibit T cell activation in response to an antigen; synthetic Notch (synNotch) receptors induce CAR expression after antigen recognition by a chimaeric Notch receptor. The scissors indicate a cleavage site that releases a transcription factor (TF).

Figure 2. Where to apply CAR therapy

CARs are applicable in principle to any cancer for which suitable cell-surface target antigens are identified. CARs may be especially effective in cancers with low mutation burden that elude checkpoint blockade. Adapted from ref. (Nature Publishing Group), previously adapted from ref. (Nature Publishing Group).

Figure 3. Therapeutic T cell design: goals and strategies

The major goals of T cell engineering address tumour targeting, T cell potency (intrinsic, that is, functionality and persistence; extrinsic: action on the tumour microenvironment), safety and cell manufacturing. Research strategies are exemplified for each one of these goals.

Figure 4. Cell sources for T cell engineering

a, Post-thymic differentiation of memory and effector T cell subsets. T memory stem cells (T_SCM) and central memory T cells (T_CM) are derived following antigen activation of naive T cells (T_N), and reside in low frequency in blood and higher frequency in lymphoid organs. T_CM have been shown in clonogenic assays to be capable of both self-renewal and differentiation to more distal effector memory (T_EM) and effector (T_E) cells. T_EM and T_E are incapable of self-renewal, and T_E, which can be present at high frequency at the peak of an immune response, are short-lived. A resident memory (T_RM) subset resides in peripheral tissues but recirculates very poorly, if at all. Acquisition of effector functions increases as T cells progressively differentiate. The individual memory T cell subsets can be distinguished by the cell surface markers, which can be used for purification for genetic modification. b, Pluripotent stem-cell-derived T cells. Human T lymphocytes may be derived in culture from pluripotent stem cells. Several functionalities (cytotoxic, helper, regulatory) could be obtained in principle. αβ-like T cells normally proceed through a double-positive (CD4⁺CD8⁺) intermediate stage, which is not required for the genesis of γδ-like T cells. The stem cell platform is attractive for its ease of genetic engineering and function as a permanent T cell reservoir. T-iPS, T cell-derived induced pluripotent stem cell; eT-iPS, engineered T-iPS (here expressing a CAR).