Identification of α‐fetoprotein‐specific T‐cell receptors for hepatocellular carcinoma immunotherapy

Zhu, Wei; Peng, Yibing; Wang, Lan; Yuan, Hong; Jiang, Xiaotao; Li, Qi; Li, Heping; Huang, Lei; Wu, Juan; Celis, Esteban; Merchen, Todd; Kruse, Edward; He, Yukai

doi:10.1002/hep.29844

Cited by 89 publications

(104 citation statements)

References 53 publications

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“…Protection of mice against subcutaneous xenografts of tumor cell lines has been used to assess the potency of TCRs in vivo ; however, these models involve immune‐compromised hosts. Syngeneic grafts in wt animals tend to elicit stronger responses than naturally evolved tumors .…”

Section: Discussionmentioning

confidence: 99%

“…Several studies were able to find a “therapeutic window” of TCR affinity within which efficient tumor killing occurred with no or manageable damage to healthy tissue . New TCRs recognizing AFP 158‐166 /HLA‐A*02:01 have been described recently . T cells transduced with these TCRs protected mice against subcutaneous tumor xenografts and displayed cytotoxicity against a limited number of AFP + , but not AFP – , cell lines.…”

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confidence: 99%

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Tuning T‐Cell Receptor Affinity to Optimize Clinical Risk‐Benefit When Targeting Alpha‐Fetoprotein–Positive Liver Cancer

et al. 2019

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Patients with hepatocellular carcinoma (HCC) have a poor prognosis and limited therapeutic options. Alpha‐fetoprotein (AFP) is often expressed at high levels in HCC and is an established clinical biomarker of the disease. Expression of AFP in nonmalignant liver can occur, particularly in a subset of progenitor cells and during chronic inflammation, at levels typically lower than in HCC. This cancer‐specific overexpression indicates that AFP may be a promising target for immunotherapy. We verified expression of AFP in normal and diseased tissue and generated an affinity‐optimized T‐cell receptor (TCR) with specificity to AFP/HLA‐A*02+ tumors. Expression of AFP was investigated using database searches, by qPCR, and by immunohistochemistry (IHC) analysis of a panel of human tissue samples, including normal, diseased, and malignant liver. Using in vitro mutagenesis and screening, we generated a TCR that recognizes the HLA‐A*02‐restricted AFP158‐166 peptide, FMNKFIYEI, with an optimum balance of potency and specificity. These properties were confirmed by an extension of the alanine scan (X‐scan) and testing TCR‐transduced T cells against normal and tumor cells covering a variety of tissues, cell types, and human leukocyte antigen (HLA) alleles. Conclusion: We have used a combination of physicochemical, in silico, and cell biology methods for optimizing a TCR for improved affinity and function, with properties that are expected to allow TCR‐transduced T cells to differentiate between antigen levels on nonmalignant and cancer cells. T cells transduced with this TCR constitute the basis for a trial of HCC adoptive T‐cell immunotherapy.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Tuning T‐Cell Receptor Affinity to Optimize Clinical Risk‐Benefit When Targeting Alpha‐Fetoprotein–Positive Liver Cancer

et al. 2019

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“…TCR-Ts targeting a number of tumor antigens are currently under clinical trials including MAGE-A3, MAGE-A4, GD2, mesothelin, gp100, MART1, CD19, AFP, CEA, NY-ESO-1, HER2, HPV, EBV, etc. NY-ESO-1 is the most promising target for many cancer immunotherapy [12][13][14] ( Table 1).…”

Section: Tcr Engineered T Cells (Tcr-t)mentioning

confidence: 99%

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

Jiang

Liu

et al. 2019

Cancer Letters

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“…The gene expression of special proteins may be typical marker under physiological and pathological conditions. In the field of clinical medicine, biomarkers such as calcitonin for medullary thyroid carcinoma, alpha fetoprotein for hepatocellular carcinoma, glial fibrillary acidic protein for glioma, carcinoma antigen 15‐3 for breast cancer, and so on, are often utilized for diagnosis and prognostic evaluation of relevant tumors . In addition, F13A1 gene is for screening abnormal bleeding risk .…”

Section: Introductionmentioning

confidence: 99%

A brief procedure for big data analysis of gene expression

Wang¹,

Li²

2018

Anim Models and Exp Med

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There are a lot of biological and experimental data from genomics, proteomics, drug screening, medicinal chemistry, etc. A large amount of data must be analyzed by special methods of statistics, bioinformatics, and computer science. Big data analysis is an effective way to build scientific hypothesis and explore internal mechanism. Here, gene expression is taken as an example to illustrate the basic procedure of the big data analysis.

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Identification of α‐fetoprotein‐specific T‐cell receptors for hepatocellular carcinoma immunotherapy

Abstract: We have identified AFP-specific murine TCR genes that can redirect human T cells to specifically recognize and kill HCC tumor cells, and those AFP -specific TCRs have a great potential to engineer a patient's autologous T cells to treat HCC tumors. (Hepatology 2018).

Cited by 89 publications

References 53 publications

Tuning T‐Cell Receptor Affinity to Optimize Clinical Risk‐Benefit When Targeting Alpha‐Fetoprotein–Positive Liver Cancer

Tuning T‐Cell Receptor Affinity to Optimize Clinical Risk‐Benefit When Targeting Alpha‐Fetoprotein–Positive Liver Cancer

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

A brief procedure for big data analysis of gene expression

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