Genetically-modified adoptive T cell therapy (ACT) involves the manufacture ex vivo of allogeneic or autologous cells genetically engineered to express either a modified T cell receptor (TCR) or a chimeric antigen receptor (CAR). Stunning responses in chemotherapy-refractory haematological malignancies with cluster of differentiation (CD) 19-targeted CARs have brought ACT into the mainstream of haemato-oncology.1–5 In 2017, a landmark approval was granted by the US Food and Drug Administration for tisagenlecleucel in acute lymphoblastic leukaemia, followed closely by axicabtagene ciloleucel in relapsed or refractory B cell lymphoma. This chapter introduces the history and current clinical development of ACT, focusing on the challenges unique to solid tumours.
The native TCR is a heterodimer (αβ- or γδ-TCRs). αβ-TCRs recognize antigenic peptides bound to human leucocyte antigens (HLAs). These αβ chains associate with a ‘CD3 complex’ responsible for transducing the intracellular signal (Figure 10.1). Successful activation of a naive T cell requires further activation through co-stimulatory receptors to avoid anergy.6
Schematic diagram of the structure of the TCR complex. The four monomers and two dimers form an eight-chain complex that incorporates antigen recognition through the α and β chains with transduction of signal 1 to the T cell through the γ, δ, ε and ζ chains.
The development of tumour-infiltrating lymphocyte (TIL) therapy in melanoma has established the feasibility of ACT in the clinic.7 The observation that the majority of TILs, across donors, were targeting the same antigens, melanoma antigen recognized by T cells 1 (MART-1) and gp100, led to the hypothesis that ‘universal’ TCR clones could be used to treat different patients so long as they expressed the specific HLA haplotype.8 Cloning the α and β chains from tumour-reactive TILs into a viral vector for introduction into T cells obviates the need for obtaining TILs from every patient individually and allows modification of the TCR (e.g. to increase affinity).8
An alternative strategy, avoiding the need for HLA restriction, is to transduce T cells with CARs. CARs are synthetic receptors composed of an extracellular antigen-binding domain, a transmembrane domain and an intracellular signalling domain, designed to deliver T cell activation on antigen engagement (Figure 10.2). The antigen-binding domain most commonly takes the form of a single-chain variable fragment (scFv) derived from an antibody specific to the tumour-associated antigen of choice, but may include other moieties such as natural or chimeric ligands.9–11
Diagram of CAR design incorporating an extracellular antigen-binding domain in series with intracellular signalling components. Evolution from first to third generation has involved the incorporation of co-stimulatory signalling domains to potentiate CAR signalling and T cell activation on antigen engagement.
CAR/TCR ACT has numerous attractive ...