Author(s): Hinrich Abken aff1 aff2
adoptive cell therapy; cancer; CAR; chimeric antigen receptor; gene transfer; T cell
Concept of CAR & T cells directed for universal cytokine-mediated killing modified T cells
The concept of adoptive cell therapy with chimeric antigen receptor (CAR, immunoreceptor) modified cells is based on patient's T cells that are redirected with predefined specificity toward autologous cancer cells to execute their immune response. T cells are ex vivo modified with a recombinant receptor molecule which by the extracellular part recognizes a pre-defined target by an antibody derived binding domain and by the intracellular T-cell receptor (TCR) derived signaling part initiates T-cell activation upon target engagement (Figure 1) [1 ]. Such CAR T cells (also nick-named 'T-bodies') recognize their target independently of presentation through the major histocompatibility complex (MHC) and are thus not compromised by alterations in the antigen processing and presentation machinery as often observed during tumor progression [2,3 ]. CAR T cells can furthermore be modified to act as a 'factory' to produce a transgenic protein upon CAR engagement of target. Such T cell redirected for universal cytokine-mediated killing (TRUCKs) deliver in a coordinated and locally restricted fashion a 'payload' which may be a cytokine like IL-12 which in turn activates an innate immune response toward tumors [4,5 ]. For further details we refer to recent reviews [5-7 ].
Compared with physiological TCR recognition, the CAR mediated T-cell activation provides several advantages in the context of adoptive cell therapy. First, CARs can redirect T cells toward a broad variety of targets as long as a binding domain with suitable specificity is available. Potential CAR targets in addition to classical MHC bound peptides also include nonclassical TCR targets such as carbohydrates, lipids and conformational epitopes. While most CARs use an antibody derived scFv for targeting, some CARs were reported, which consist of receptor ligands as binding domain fused to the transmembrane and intracellular signaling moiety. Examples are heregulin and IL-13 mutein to target Her3/4 receptor and IL-13 receptor-[alpha], respectively [8,9 ]. To be recognized by CAR T cells, the antigen needs to be present on the cell surface of the targeted cell; however, TCR-like CARs were reported, which recognize intracellular antigens presented by the MHC [10,11 ]. In contrast to cell-bound antigen, soluble antigen, which frequently accumulates in the serum of cancer patients, does not sufficiently activate CAR T cells [12 ].
CAR redirected T-cell activation initiates a plethora of T-cell effector functions including cytokine release, lytic degranulation, T-cell amplification, maturation and migration. Clinical efficacy requires lasting persistence of CAR T cells which need to be protected from activation induced cell death through appropriate costimulation, for example, CD28 or 4-1BB. This is underscored by the clinical observation that patients with achieved lasting remission showed long-term CAR T-cell persistence [13 ]. CAR T cells can moreover provide target-specific memory which may help to prevent tumor relapse [14 ].
CAR signaling blocks: combined primary & costimulatory signals are superior
The intracellular signaling moiety is commonly derived from the CD3ζ chain; other...