Orthotopic T-Cell Receptor Replacement—An “Enabler” for TCR-Based Therapies

Abstract

Natural adaptive immunity co-evolved with pathogens over millions of years, and adoptive transfer of non-engineered T cells to fight infections or cancer so far exhibits an exceptionally safe and functional therapeutic profile in clinical trials. However, the personalized nature of therapies using virus-specific T cells, donor lymphocyte infusion, or tumor-infiltrating lymphocytes makes implementation in routine clinical care difficult. In principle, genetic engineering can be used to make T-cell therapies more broadly applicable, but so far it significantly alters the physiology of cells. We recently demonstrated that orthotopic T-cell receptor (TCR) replacement (OTR) by clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein 9 (Cas9) can be used to generate engineered T cells with preservation of near-physiological function. In this review, we present the current status of OTR technology development and discuss its potential for TCR-based therapies. By providing the means to combine the therapeutic efficacy and safety profile of physiological T cells with the versatility of cell engineering, OTR can serve as an “enabler” for TCR-based therapies.

T Cell Repertoire During Ontogeny and Characteristics in Inflammatory Disorders in Adults and Childhood

“…It could be demonstrated that investigations in the TCR repertoire can help to develop new biomarkers. Furthermore, new therapeutic options were established in cancer therapy using engineered T cell subsets ( 78 , 79 ). Whether these advantages are suitable for clinical application and could be transferred to chronic infections and autoinflammatory diseases is still a topic of research ( 80 ).…”

Advances in identification and selection of personalized neoantigen/T-cell pairs for autologous adoptive T cell therapies

“… 99 Especially, T cells with orthotropic T-cell receptor replacement, which preserve near-physiological function, seem like a promising way forward. 100 Worth mentioning, a recent study revealed a dynamic dysfunctional immune macroenvironment, the immune system beyond the tumor microenvironment, due to the cancer burden. 101 Hence, it is possible that even freshly sourced T cells from the blood of some cancer patients may be dysfunctional.…”

Breaking Bottlenecks for the TCR Therapy of Cancer

“…Therefore, measures to prevent TCR mispairing, like murinization of constant TCR chains [ 162 ], codon optimization, cysteineization [ 163 ], or disruption of the endogenous TCR genes is imperative. In the past, the latter has necessitated additional manipulation with e.g., ZFNs, TALENs [ 83 , 84 ], or RNA interference (RNAi) [ 161 , 164 , 165 ], but can now be accomplished concomitantly with the TCR transfer, using newer, TCR locus-specific CRISPR-based gene editing methods [ 79 , 166 , 167 ]. The resulting T cells show physiological regulation and higher expression levels of the introduced TCRs [ 161 , 167 , 168 ], superior antitumor activity in vivo, and reduced GvHD mortality [ 83 , 161 , 164 , 166 ].…”