T cell receptor therapeutics: Immunological targeting of the intracellular cancer proteome Review
| Authors: | Klebanoff, C. A.; Chandran, S. S.; Baker, B. M.; Quezada, S. A.; Ribas, A. |
| Review Title: | T cell receptor therapeutics: Immunological targeting of the intracellular cancer proteome |
| Abstract: | The T cell receptor (TCR) complex is a naturally occurring antigen sensor that detects, amplifies and coordinates cellular immune responses to epitopes derived from cell surface and intracellular proteins. Thus, TCRs enable the targeting of proteins selectively expressed by cancer cells, including neoantigens, cancer germline antigens and viral oncoproteins. As such, TCRs have provided the basis for an emerging class of oncology therapeutics. Herein, we review the current cancer treatment landscape using TCRs and TCR-like molecules. This includes adoptive cell transfer of T cells expressing endogenous or engineered TCRs, TCR bispecific engagers and antibodies specific for human leukocyte antigen (HLA)-bound peptides (TCR mimics). We discuss the unique complexities associated with the clinical development of these therapeutics, such as HLA restriction, TCR retrieval, potency assessment and the potential for cross-reactivity. In addition, we highlight emerging clinical data that establish the antitumour potential of TCR-based therapies, including tumour-infiltrating lymphocytes, for the treatment of diverse human malignancies. Finally, we explore the future of TCR therapeutics, including emerging genome editing methods to safely enhance potency and strategies to streamline patient identification. © 2023, Springer Nature Limited. |
| Keywords: | signal transduction; protein expression; unclassified drug; review; drug safety; drug targeting; neoplasm; neoplasms; cd8+ t lymphocyte; cd8-positive t-lymphocytes; proteome; metabolism; cancer immunotherapy; antineoplastic activity; drug potency; tumor antigen; patient identification; t lymphocyte receptor; antigens, neoplasm; receptors, antigen, t-cell; zinc finger nuclease; immunomodulating agent; protein structure; cross reaction; mutagenesis; adoptive immunotherapy; lymphocyte antigen receptor; protein modification; t lymphocyte antigen; hla antibody; transcription activator like effector nuclease; protein engineering; humans; human; immunoreceptor tyrosine based activation motif; gene editing; crispr-cas9 system; sleeping beauty transposon; t cell antigen coupler; t cell receptor fusion construct; cancer t cell immunotherapy; til therapy |
| Journal Title: | Nature Reviews Drug Discovery |
| Volume: | 22 |
| Issue: | 12 |
| ISSN: | 1474-1776 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-12-01 |
| Start Page: | 996 |
| End Page: | 1017 |
| Language: | English |
| DOI: | 10.1038/s41573-023-00809-z |
| PUBMED: | 37891435 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Christopher A. Klebanoff -- Source: Scopus |
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