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.
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Acknowledgements
This study was supported, in part, by National Institutes of Health (NIH) grants R37 CA259177 (C.A.K.), R01 CA269733 (C.A.K.), R01 CA286507 (C.A.K.), R35 GM118166 (B.M.B.), R35 CA197633 (A.R.), P01 CA168585 (A.R.), P30 CA008748 (C.A.K.), and the NIH SPORE in Soft Tissue Sarcoma P50 CA217694 (C.A.K.); the Parker Institute for Cancer Immunotherapy (C.A.K. and A.R.); the Cancer Research Institute CRI3176 (C.A.K.); The Sarcoma Center at Memorial Sloan Kettering Cancer Center (MSKCC) (C.A.K.); the Mr. William H. Goodwin and Mrs Alice Goodwin and the Commonwealth Foundation for Cancer Research (C.A.K and S.S.C.); and The Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center (C.A.K and S.S.C.). S.A.Q. is funded by a CRUK Senior Cancer Research Fellowship (C36463/A22246) and a CRUK Biotherapeutic Programme Grant (C36463/A20764).
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C.A.K. wrote an initial draft of the manuscript. All authors edited and revised the final manuscript.
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Competing interests
C.A.K. and S.S.C. are inventors on patents related to T cell receptor (TCR) discovery and public neoantigen-specific TCRs and are recipients of licensing revenue from Intima Bioscience shared according to Memorial Sloan Kettering Cancer Center (MSKCC) institutional policies. C.A.K. has consulted for or is on the scientific advisory boards for Achilles Therapeutics, Affini-T Therapeutics, Aleta BioTherapeutics, Bellicum Pharmaceuticals, Bristol Myers Squibb, Catamaran Bio, Cell Design Labs, Decheng Capital, G1 Therapeutics, Klus Pharma, Obsidian Therapeutics, PACT Pharma, Roche/Genentech and T-knife, and is a scientific co-founder and equity holder in Affini-T Therapeutics. S.S.C. is a scientific advisor and equity holder in Affini-T Therapeutics. B.M.B. is an inventor on patents related to TCR engineering and neoantigen discovery, has consulted for Eureka Therapeutics and EnaraBio, and is on the scientific advisory board of T-cure Bioscience. S.A.Q is an inventor in patents related to the use of T cell therapies targeting tumour clonal neoantigens in cancer, and is also a founder, CSO and equity holder of Achilles Therapeutics. A.R. reports personal fees from Amgen, Chugai, Genentech, Merck, Novartis, Roche, Sanofi, Vedanta, 4C Biomed, Appia, Apricity, Arcus, Highlight, Compugen, ImaginAb, Kalthera/ImmPACT Bio, MapKure, Merus, Rgenix, Lutris, Nextech, PACT Pharma, Synthekine, Tango, Advaxis, CytomX, Five Prime, RAPT, Isoplexis and Kite/Gilead, and has received grants from Agilent and Bristol Myers Squibb outside the submitted work.
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Glossary
- γδ T cells
-
Approximately 1–5% of circulating T cells express a somatically recombined γδ T cell receptor (TCR) that associates with the CD3 subunits and mediates antigen-specific cellular immunity. γδ T cells recognize a limited number of ligands presented in the context of non-polymorphic antigen presentation molecules.
- Catch bond
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A property of many low-affinity cell surface adhesion systems, including selectins, integrins, adhesins and T cell receptors, in which a bond’s likelihood of separating is reduced as tensile force is applied. This property contrasts with the more common slip bond in which a bond disassociates rapidly following application of sheer force.
- Cellular indexing of transcriptomes and epitopes by sequencing
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(CITE-seq). A sequencing-based method that enables the simultaneous detection and quantification of cell surface proteins, immune receptor binding specificity and transcriptomic data at single-cell resolution.
- Common γ-chain cytokine
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A member of a family of six cytokines that share the common γ-chain (γc; CD132) as part of a receptor complex. Members of this cytokine family include IL-2, IL-7, IL-9, IL-15 and IL-21.
- DNA-barcoded p/HLA multimers
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A synthetic peptide/human leukocyte antigen molecule conjugated to a unique oligonucleotide sequence that is detected and quantified using next-generation sequencing methods. This reagent enables the parallel detection of >1,000 T cell specificities in a single sample.
- DNA mismatch repair proficiency
-
The vast majority (~95%) of colorectal cancers and other gastrointestinal malignancies are proficient in DNA mismatch repair enzymatic function. These cancers are associated with a modest tumour mutational burden and are largely unresponsive to immune checkpoint inhibitors (ICIs).
- HLA-restricted tumour antigens
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Cancer-specific and cancer-associated polypeptides resulting from proteasomal, endosomal or lysosomal protein degradation. These polypeptides are bound non-covalently within the binding groove of a human leukocyte antigen (HLA) class I or class II molecule and facilitate the activation of antigen-specific T cells.
- Human leukocyte antigen
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(HLA). A family of highly polymorphic, germline-encoded transmembrane proteins that bind proteolytically degraded polypeptides. In vertebrate species, related proteins are referred to as the major histocompatibility complex (MHC).
- Immune receptor tyrosine-based activation motif
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(ITAM). A conserved four amino acid sequence (YxxL/I) contained in the cytoplasmic tails of non-catalytic tyrosine-phosphorylated receptors found in immune cells.
- Investigational new drug application
-
Request from a clinical study sponsor to obtain authorization from the US Food and Drug Administration to administer an investigational drug or biological product to humans. An investigational new drug application comprises preclinical data establishing whether the product is reasonably safe and can be manufactured consistently alongside a protocol for the study’s conduct that ensures patients are not exposed to unnecessary risks.
- Leukapheresis
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An outpatient procedure to obtain large numbers of circulating T cells, B cells, NK cells and monocytes for downstream clinical applications, including genetic engineering and in vitro stimulation. In this procedure, mononuclear cells are separated from red blood cells, platelets and plasma through differential centrifugation.
- Melanoma antigen recognized by T cells 1
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(MART-1; also known as Melan-A). A transmembrane protein associated with normal melanocytes and expressed by the majority of melanomas.
- Paramagnetic artificial APC
-
An iron-dextran nanoparticle conjugated to a synthetic peptide/human leukocyte antigen complex and an anti-CD28 co-stimulatory antibody. In the presence of a magnetic column, this reagent simultaneously enriches for rare antigen-specific T cells and induces T cell proliferation.
- Sleeping Beauty transposon/transposase system
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A gene therapy method that uses co-transfer of two DNA plasmids to achieve stable transgene genomic integration and expression. One plasmid transiently expresses a transposase enzyme that digests the second plasmid, the Sleeping Beauty transposon, at inverted/direct repeats and ligates the transposon cassette containing a gene of interest into TA dinucleotide repeats within the genome.
- Somatic recombination
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The genes for the variable (V), diversity (D), junctional (J) and constant (C) segments of the T cell receptor-α (TCRα) and TCRβ hemichains do not encode functional proteins in their germline configuration. Rather, each segment undergoes site-specific recombination with the aid of recombination activation genes to assemble a single functional frame.
- Strep-tag II sequence
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A short polypeptide that binds with intermediate affinity to the biotin binding site of a mutated form of streptavidin. In the presence of excess d-biotin, Strep-tag II multimers dissociate into monomers. When peptide/human leukocyte antigen molecules are conjugated to Strep-tag II, this reagent facilitates the capture, enrichment and release of antigen-specific T cells.
- Tumour organoids
-
Multicellular in vitro structures that preserve the genetic diversity, phenotype and structural features of a tumour in vivo. In vitro responses of tumour organoids to different treatments, including immunotherapies, often correlate with patient responses.
- Uveal melanoma
-
A rare malignancy that arises from melanocytes within the uveal tract of the eye, which includes the iris, ciliary body and choroid. Unlike cutaneous melanoma, uveal melanomas are modestly mutated and generally respond poorly to immune checkpoint blockade.
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Cite this article
Klebanoff, C.A., Chandran, S.S., Baker, B.M. et al. T cell receptor therapeutics: immunological targeting of the intracellular cancer proteome. Nat Rev Drug Discov 22, 996–1017 (2023). https://doi.org/10.1038/s41573-023-00809-z
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DOI: https://doi.org/10.1038/s41573-023-00809-z
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