Optimizing T-cell receptor gene therapy for hematologic malignancies

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 nonmalignant cells may contribute to the efficacy of T-cell therapy by maintaining effector function and promoting memory. Although CAR recognition is limited to cell surface structures, T-cell receptors (TCRs) can recognize intracellular proteins. This not only expands the range of tumor-associated self-antigens that are amenable for T-cell therapy, but 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 TCRs 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. Recent gene-editing tools, such as transcription activator–like effector nucleases and clustered regularly interspaced short palindromic repeats, provide a platform to delete endogenous TCR and HLA genes, which removes alloreactivity and decreases immunogenicity of third-party T cells. This represents an important step toward generic off-the-shelf T-cell products that may be used in the future for the treatment of large numbers of patients.

Recent advances in T‐cell immunotherapy for haematological malignancies

“…Despite these drawbacks, numerous studies have explored the potential of engineered TCRs both at the bench and in the clinic. (Morris and Stauss 2016)…”

Cytotoxic T cells and Cancer Therapy

“…Some prominent genetically modified anti-cancer T cells are those with chimeric antigen receptors (CARs) or neoantigen-specific T-cell receptors that are extensively used in adoptive immunotherapy as promising candidates in combating tumorcell immune evasion (Morris & Stauss, 2016;Ye et al, 2017). Development of various investigative avenues for the expansion and increase in the specificity of adoptively transferred T cells is still under process.…”

Immunotherapy for opportunistic infections: Current status and future perspectives

“…We are able to prepare for variety of TCRs with high avidity against respective HLA molecules with virus-derived peptide. 61 Techniques to isolate each peptide-specific T cells might be useful to facilitate the identification and isolation of antigen-specific T cells. 62 T cells with genetically engineered TCR would contribute to break a major obstacle in a patient or donor with low frequency of specific T cells.…”