Trends in Molecular Medicine
ReviewCAR–T cells and solid tumors: tuning T cells to challenge an inveterate foe
Section snippets
A short history of the therapeutic success of CAR–T cells
The concept of the chimeric antigen receptor (CAR) originated in response to the growing understanding of the barriers to the effective immune therapy of cancer. T cells armed with CARs (CAR–T cells) recognize cell surface antigens directly and are not compromised by tumor variants that possess lowered surface expression of major histocompatibility complex (MHC) antigens – a commonly observed mechanism of tumor immune escape 1, 2.
Recent clinical studies have underscored the potential of this
Chimeric antigen receptors: how many building blocks do we need?
CARs are fusion proteins consisting of extracellular antibody-type recognition domains fused to intracellular T cell signaling proteins [10]. Surface expression of a CAR endows the T cell with redirected functional activity [11], whereby CAR–T cells recognize target cells through the antigen-specific binding of antibody-defined targets on the cell surface. The modular design of these receptors has been exploited to utilize different target binding domains fused to various transmembrane and
Early trials targeting solid tumor antigens teach important lessons
Two trials using CAR–T cells specific for either carbonic anhydrase IX (CAIX) or the α folate receptor, antigens overexpressed in renal cell or ovarian carcinoma, respectively, failed to achieve effective antitumor responses or CAR–T cell persistence in the peripheral blood of the treated patients 24, 25. In the CAIX CAR–T cell trial, patients were treated with low T cell doses (starting with 2×108 T cells) and these patients demonstrated reversible yet discrete cholangitis and damage to bile
Success of current trials: choice of tumor antigen versus improved CAR–T cell therapy
The most recent clinical studies of CAR–T cell therapy employed second generation CAR–T cells to target the CD19 antigen on B cell leukemia or lymphomas. The complete clinical response of three patients with CLL, who had high tumor burden and were refractory to standard treatments, has strongly stimulated the CAR–T cell field [5]. This particular study employed a CD19-specific CAR:CD137-ζ, whereas further studies in other centers targeting CLL are reporting encouraging clinical responses using
CAR–T cells and solid tumors: a challenge that can be met
The majority of solid tumors are not ideal targets. Although the choice of tumor antigen is critical, achieving long-term persistence of CAR–T cells is required as well as efficient trafficking of sufficient numbers of CAR–T cells from the peripheral blood to the tumor tissue. Once arrived, these CAR–T cells must functionally respond against tumor cells resident within a strongly immunosuppressive environment (Box 2). Whether the above-mentioned second generation CAR together with more recent
The three T's of T cell manipulation
- (a)
T cell subset
CAR–T cell populations produced using current methods, although effective in terms of T cell expansion, tend to generate T cells of late effector status; recent experimental studies strongly suggest that naïve (TN) or central memory (TCM) T cells engraft and persist to a greater extent in vivo than more differentiated T cells 31, 32, 33. One approach being considered is to enrich for TN and/or TCM cells before genetic modification, T cell stimulation, and transduction using cell
Future directions for CAR–T cells
Several clinical trials using CAR–T cells have been completed, and a significant number of other trials are ongoing or at the advanced planning stage (see Box 2 for a current overview of clinical trials reported, ongoing, or planned with CAR–T cells). At this infant stage of clinical development, CAR–T cells offer much promise (Figure 2). However, the diversity of current trials employing varying CARs, target clinical populations, and preconditioning regimes means it will be highly problematic
Acknowledgments
D.E.G., R.D., R.E.H., and H.A. have all been supported by the European Union FP6 project ‘ATTACK’ and FP7 training network ‘ATTRACT’. M.P. has been supported by the European Union FP6 project ‘CHILDHOPE’. D.E.G. and R.E.H. have also been supported by Cancer Research UK and the Kay Kendall Leukaemia Fund. H.A. has been supported by Deutsche Forschungsgemeinschaft (DFG), Deutsche Krebshilfe and Wilhelm Sander-Stiftung.
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