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Optimizing T cell receptor gene therapy for hematologic malignancies

Emma C. Morris and Hans J. Stauss

Abstract

Recent advances in genetic engineering have enabled the delivery of clinical trials using patient T cells redirected to recognize tumor-associated antigens. The most dramatic results have been seen with T cells engineered to express a chimeric antigen receptor (CAR) specific for CD19, a differentiation antigen expressed in B cells and B lineage malignancies. We propose, that antigen expression in non-malignant cells may contribute to the efficacy of T cell therapy by maintaining effector function and promoting memory. While CAR recognition is limited to cell surface structures, T cell receptors (TCR) can recognize intracellular proteins. This not only expands the range of tumor-associated self-antigens that are amenable for T cell therapy, but it also allows TCR targeting of the cancer mutagenome. We will highlight biological bottlenecks that potentially limit mutation-specific T cell therapy and may require high avidity TCR that are capable of activating effector function when the concentrations of mutant peptides are low. Unexpectedly, modified TCRs with artificially high affinities function poorly in response to low concentration of cognate peptide, but pose an increased safety risk as they may respond optimally to cross-reactive peptides. The recent gene editing tools, such as TALEN and CRIPSR, provide a platform to delete endogenous TCR and HLA genes, which removes allo-reactivity and decreases immunogenicity of third party T cells. This represents an important step towards generic off-the-shelf T cell products that may be used in the future for the treatment of large numbers of patients.

  • Submitted November 30, 2015.
  • Accepted January 27, 2016.