Current opinion in immunology
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Curr. Opin. Immunol. · Apr 2009
ReviewAdoptive transfer of virus-specific and tumor-specific T cell immunity.
The adoptive transfer of T cells isolated or engineered to have specificity for diseased cells represents an ideal approach for the targeted therapy of human viral and malignant diseases. The therapeutic potential of adoptive T cell therapy for infections and cancer was demonstrated in rodent models long ago, but the task of translating this approach into an effective clinical therapy has not been easy. Carefully designed clinical trials have evaluated the transfer of antigen-specific T cells in humans, and provided insight into the barriers to efficacy and strategies to improve T cell therapy. The importance of altering the host environment to facilitate persistence and function of transferred T cells and intrinsic properties of T cells that are selected or engineered for therapy in determining their fate in vivo are key issues that have recently emerged and are informing the design of the next generation of clinical trials.
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Curr. Opin. Immunol. · Apr 2009
ReviewThe promise and potential pitfalls of chimeric antigen receptors.
One important purpose of T cell engineering is to generate tumor-targeted T cells through the genetic transfer of antigen-specific receptors, which consist of either physiological, MHC-restricted T cell receptors (TCRs) or non MHC-restricted chimeric antigen receptors (CARs). CARs combine antigen-specificity and T cell activating properties in a single fusion molecule. First generation CARs, which included as their signaling domain the cytoplasmic region of the CD3zeta or Fc receptor gamma chain, effectively redirected T cell cytotoxicity but failed to enable T cell proliferation and survival upon repeated antigen exposure. ⋯ First generation CARs have been tested in phase I clinical studies in patients with ovarian cancer, renal cancer, lymphoma, and neuroblastoma, where they have induced modest responses. Second generation CARs, which are just now entering the clinical arena in the B cell malignancies and other cancers, will provide a more significant test for this approach. If the immunogenicity of CARs can be averted, the versatility of their design and HLA-independent antigen recognition will make CARs tools of choice for T cell engineering for the development of targeted cancer immunotherapies.