Evolution of CD8 T Cell Receptor (TCR) Engineered Therapies for the Treatment of Cancer

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2021 Sep 28

PMID 34572028

Citations 21

Authors

Yimo Sun

Fenge Li

Heather Sonnemann

Kyle R Jackson

Amjad H Talukder

Arjun S Katailiha

Gregory Lizee

Affiliations

Soon will be listed here.

Abstract

Engineered T cell receptor T (TCR-T) cell therapy has facilitated the generation of increasingly reliable tumor antigen-specific adaptable cellular products for the treatment of human cancer. TCR-T cell therapies were initially focused on targeting shared tumor-associated peptide targets, including melanoma differentiation and cancer-testis antigens. With recent technological developments, it has become feasible to target neoantigens derived from tumor somatic mutations, which represents a highly personalized therapy, since most neoantigens are patient-specific and are rarely shared between patients. TCR-T therapies have been tested for clinical efficacy in treating solid tumors in many preclinical studies and clinical trials all over the world. However, the efficacy of TCR-T therapy for the treatment of solid tumors has been limited by a number of factors, including low TCR avidity, off-target toxicities, and target antigen loss leading to tumor escape. In this review, we discuss the process of deriving tumor antigen-specific TCRs, including the identification of appropriate tumor antigen targets, expansion of antigen-specific T cells, and TCR cloning and validation, including techniques and tools for TCR-T cell vector construction and expression. We highlight the achievements of recent clinical trials of engineered TCR-T cell therapies and discuss the current challenges and potential solutions for improving their safety and efficacy, insights that may help guide future TCR-T studies in cancer.

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References

Weigand L, Liang X, Schmied S, Mall S, Klar R, Stotzer O . Isolation of human MHC class II-restricted T cell receptors from the autologous T-cell repertoire with potent anti-leukaemic reactivity. Immunology. 2012; 137(3):226-38. PMC: 3482680. DOI: 10.1111/imm.12000. View

Nagarsheth N, Norberg S, Sinkoe A, Adhikary S, Meyer T, Lack J . TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat Med. 2021; 27(3):419-425. PMC: 9620481. DOI: 10.1038/s41591-020-01225-1. View

Ott P, Hu Z, Keskin D, Shukla S, Sun J, Bozym D . An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017; 547(7662):217-221. PMC: 5577644. DOI: 10.1038/nature22991. View

Bendle G, Linnemann C, Hooijkaas A, Bies L, de Witte M, Jorritsma A . Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy. Nat Med. 2010; 16(5):565-70, 1p following 570. DOI: 10.1038/nm.2128. View

Bonini C, Mondino A . Adoptive T-cell therapy for cancer: The era of engineered T cells. Eur J Immunol. 2015; 45(9):2457-69. DOI: 10.1002/eji.201545552. View

Dembic Z, Haas W, Weiss S, McCubrey J, Kiefer H, von Boehmer H . Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature. 1986; 320(6059):232-8. DOI: 10.1038/320232a0. View

Lawrence M, Stojanov P, Polak P, Kryukov G, Cibulskis K, Sivachenko A . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499(7457):214-218. PMC: 3919509. DOI: 10.1038/nature12213. View

van der Bruggen P, Zhang Y, Chaux P, Stroobant V, Panichelli C, Schultz E . Tumor-specific shared antigenic peptides recognized by human T cells. Immunol Rev. 2002; 188:51-64. DOI: 10.1034/j.1600-065x.2002.18806.x. View

Gubin M, Zhang X, Schuster H, Caron E, Ward J, Noguchi T . Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014; 515(7528):577-81. PMC: 4279952. DOI: 10.1038/nature13988. View

10.

Gros A, Parkhurst M, Tran E, Pasetto A, Robbins P, Ilyas S . Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med. 2016; 22(4):433-8. PMC: 7446107. DOI: 10.1038/nm.4051. View

11.

Linnemann C, Heemskerk B, Kvistborg P, Kluin R, Bolotin D, Chen X . High-throughput identification of antigen-specific TCRs by TCR gene capture. Nat Med. 2013; 19(11):1534-41. DOI: 10.1038/nm.3359. View

12.

Zhang X, Qi Y, Zhang Q, Liu W . Application of mass spectrometry-based MHC immunopeptidome profiling in neoantigen identification for tumor immunotherapy. Biomed Pharmacother. 2019; 120:109542. DOI: 10.1016/j.biopha.2019.109542. View

13.

Rossjohn J, Gras S, Miles J, Turner S, Godfrey D, McCluskey J . T cell antigen receptor recognition of antigen-presenting molecules. Annu Rev Immunol. 2014; 33:169-200. DOI: 10.1146/annurev-immunol-032414-112334. View

14.

Depil S, Duchateau P, Grupp S, Mufti G, Poirot L . 'Off-the-shelf' allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 2020; 19(3):185-199. DOI: 10.1038/s41573-019-0051-2. View

15.

Cai A, Keskin D, DeLuca D, Alonso A, Zhang W, Lan Zhang G . Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients. Clin Cancer Res. 2012; 18(20):5761-72. PMC: 3759991. DOI: 10.1158/1078-0432.CCR-12-1182. View

16.

Cameron B, Gerry A, Dukes J, Harper J, Kannan V, Bianchi F . Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med. 2013; 5(197):197ra103. PMC: 6002776. DOI: 10.1126/scitranslmed.3006034. View

17.

Albers J, Ammon T, Gosmann D, Audehm S, Thoene S, Winter C . Gene editing enables T-cell engineering to redirect antigen specificity for potent tumor rejection. Life Sci Alliance. 2019; 2(2). PMC: 6421629. DOI: 10.26508/lsa.201900367. View

18.

Matsushita H, Vesely M, Koboldt D, Rickert C, Uppaluri R, Magrini V . Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature. 2012; 482(7385):400-4. PMC: 3874809. DOI: 10.1038/nature10755. View

19.

Garber K . Driving T-cell immunotherapy to solid tumors. Nat Biotechnol. 2018; 36(3):215-219. DOI: 10.1038/nbt.4090. View

20.

Singh-Jasuja H, Emmerich N, Rammensee H . The Tübingen approach: identification, selection, and validation of tumor-associated HLA peptides for cancer therapy. Cancer Immunol Immunother. 2004; 53(3):187-95. PMC: 11032959. DOI: 10.1007/s00262-003-0480-x. View