T-cell receptor-based therapy: an innovative therapeutic approach for solid tumors

AbstractT-cell receptor (TCR)-based adoptive therapy employs genetically modified lymphocytes that are directed against specific tumor markers. This therapeutic modality requires a structured and integrated process that involves patient screening (e.g., for HLA-A*02:01 and specific tumor targets), leukapheresis, generation of transduced TCR product, lymphodepletion, and infusion of the TCR-based adoptive therapy. In this review, we summarize the current technology and early clinical development of TCR-based therapy in patients with solid tumors. The challenges of TCR-based therapy include those associated with TCR product manufacturing, patient selection, and preparation with lymphodepletion. Overcoming these challenges, and those posed by the immunosuppressive microenvironment, as well as developing next-generation strategies is essential to improving the efficacy and safety of TCR-based therapies. Optimization of technology to generate TCR product, treatment administration, and patient monitoring for adverse events is needed. The implementation of novel TCR strategies will require expansion of the TCR approach to patients with HLA haplotypes beyond HLA-A*02:01 and the discovery of novel tumor markers that are expressed in more patients and tumor types. Ongoing clinical trials will determine the ultimate role of TCR-based therapy in patients with solid tumors.

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Faculty Opinions recommendation of Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726014870.793523076 ◽

2016 ◽

Author(s):

David Kranz

Keyword(s):

Gene Therapy ◽

T Cell ◽

Solid Tumors ◽

Point Mutation ◽

T Cell Receptor ◽

Cell Receptor ◽

Specific Point ◽

Receptor Targeting ◽

Single Cancer

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Cytotoxic T lymphocytes specific for self tumor immunoglobulin express T cell receptor delta chain.

Journal of Experimental Medicine ◽

10.1084/jem.169.5.1557 ◽

1989 ◽

Vol 169 (5) ◽

pp. 1557-1564 ◽

Cited By ~ 67

Author(s):

A Wright ◽

J E Lee ◽

M P Link ◽

S D Smith ◽

W Carroll ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

B Cell ◽

T Cell Receptor ◽

Cytotoxic T Lymphocytes ◽

Cell Receptor ◽

Transformed Cells ◽

Adoptive Therapy ◽

Specific Antigens

CTL are thought to play a role in the elimination of transformed cells in vivo. The effectiveness of such CTL is in part dependent on recognition of tumor specific antigens. Among the best characterized tumor-specific antigens are the unique or idiotypic determinants on the Ig of B cell lymphomas. Here we describe the generation and properties of human CTL specific for the idiotype on autologous B cell tumors. These cells are CD3+,CD4-,CD8- and express the delta chain of the TCR. Such cells may prove useful in tumor-specific adoptive therapy.

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Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy

Science Translational Medicine ◽

10.1126/scitranslmed.aaz6667 ◽

2020 ◽

Vol 12 (571) ◽

pp. eaaz6667

Author(s):

Meixi Hao ◽

Siyuan Hou ◽

Weishuo Li ◽

Kaiming Li ◽

Lingjing Xue ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Surface ◽

Cell Therapy ◽

Solid Tumors ◽

T Cell Receptor ◽

Chimeric Antigen Receptor ◽

Cell Receptor ◽

T Cell Therapy ◽

Engineered T Cells

Treatment of solid tumors with T cell therapy has yielded limited therapeutic benefits to date. Although T cell therapy in combination with proinflammatory cytokines or immune checkpoints inhibitors has demonstrated preclinical and clinical successes in a subset of solid tumors, unsatisfactory results and severe toxicities necessitate the development of effective and safe combinatorial strategies. Here, the liposomal avasimibe (a metabolism-modulating drug) was clicked onto the T cell surface by lipid insertion without disturbing the physiological functions of the T cell. Avasimibe could be restrained on the T cell surface during circulation and extravasation and locally released to increase the concentration of cholesterol in the T cell membrane, which induced rapid T cell receptor clustering and sustained T cell activation. Treatment with surface anchor-engineered T cells, including mouse T cell receptor transgenic CD8+ T cells or human chimeric antigen receptor T cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma. Glioblastoma was completely eradicated in three of the five mice receiving surface anchor-engineered chimeric antigen receptor T cells, whereas mice in other treatment groups survived no more than 64 days. Moreover, the administration of engineered T cells showed no obvious systemic side effects. These cell-surface anchor-engineered T cells hold translational potential because of their simple generation and their safety profile.

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The Emerging World of TCR-T Cell Trials Against Cancer: A Systematic Review

Technology in Cancer Research & Treatment ◽

10.1177/1533033819831068 ◽

2019 ◽

Vol 18 ◽

pp. 153303381983106 ◽

Cited By ~ 29

Author(s):

Jianxiang Zhang ◽

Lingyu Wang

Keyword(s):

Clinical Trials ◽

T Cell ◽

Cell Therapy ◽

Solid Tumors ◽

T Cell Receptor ◽

Chimeric Antigen Receptor ◽

Hematological Malignancies ◽

Antigen Receptor ◽

Cell Receptor ◽

T Cell Therapy

T-cell receptor–engineered T-cell therapy and chimeric antigen receptor T-cell therapy are 2 types of adoptive T-cell therapy that genetically modify natural T cells to treat cancers. Although chimeric antigen receptor T-cell therapy has yielded remarkable efficacy for hematological malignancies of the B-cell lineages, most solid tumors fail to respond significantly to chimeric antigen receptor T cells. T-cell receptor–engineered T-cell therapy, on the other hand, has shown unprecedented promise in treating solid tumors and has attracted growing interest. In order to create an unbiased, comprehensive, and scientific report for this fast-moving field, we carefully analyzed all 84 clinical trials using T-cell receptor–engineered T-cell therapy and downloaded from ClinicalTrials.gov updated by June 11, 2018. Informative features and trends were observed in these clinical trials. The number of trials initiated each year is increasing as expected, but an interesting pattern is observed. NY-ESO-1, as the most targeted antigen type, is the target of 31 clinical trials; melanoma is the most targeted cancer type and is the target of 33 clinical trials. Novel antigens and underrepresented cancers remain to be targeted in future studies and clinical trials. Unlike chimeric antigen receptor T-cell therapy, only about 16% of the 84 clinical trials target against hematological malignancies, consistent with T-cell receptor–engineered T-cell therapy’s high potential for solid tumors. Six pharma/biotech companies with novel T-cell receptor–engineered T-cell ideas and products were examined in this review. Multiple approaches have been utilized in these companies to increase the T-cell receptor’s affinity and efficiency and to minimize cross-reactivity. The major challenges in the development of the T-cell receptor–engineered T-cell therapy due to tumor microenvironment were also discussed here.

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Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-15-2361 ◽

2015 ◽

Vol 22 (11) ◽

pp. 2734-2743 ◽

Cited By ~ 43

Author(s):

Matthias Leisegang ◽

Boris Engels ◽

Karin Schreiber ◽

Poh Yin Yew ◽

Kazuma Kiyotani ◽

...

Keyword(s):

Gene Therapy ◽

T Cell ◽

Solid Tumors ◽

Point Mutation ◽

T Cell Receptor ◽

Cell Receptor ◽

Specific Point ◽

Receptor Targeting ◽

Single Cancer

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Multi-cistronic vector encoding optimized safety switch for adoptive therapy with T-cell receptor-modified T cells

Gene Therapy ◽

10.1038/gt.2013.4 ◽

2013 ◽

Vol 20 (8) ◽

pp. 861-867 ◽

Cited By ~ 6

Author(s):

M M van Loenen ◽

R de Boer ◽

R S Hagedoorn ◽

V Jankipersadsing ◽

A L Amir ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Adoptive Therapy

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OS12.4.A MHC class II-restricted transgenic T cell receptor therapy targeting mutant capicua transcriptional repressor in experimental gliomas

Neuro-Oncology ◽

10.1093/neuonc/noab180.048 ◽

2021 ◽

Vol 23 (Supplement_2) ◽

pp. ii15-ii15

Author(s):

M Kilian ◽

M Friedrich ◽

K Sanghvi ◽

E Green ◽

S Pusch ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Mhc Class Ii ◽

Transcriptional Repressor ◽

Cell Receptor ◽

Class Ii ◽

Therapeutic Interventions ◽

Humanized Mice ◽

Adoptive Therapy

Abstract BACKGROUND Glioma subtypes are classified according to their characteristic mutations and show a high degree of resistance to standard therapeutic interventions such as radiotherapy and alkylating chemotherapy. Some of these characteristic mutations have shown to generate immunogenic neoepitopes that can be targeted with immunotherapy. 70% of oligodendrogliomas carry capicua transcriptional repressor (CIC) inactivating mutations. RESULTS In a screen for potential immunogenic glioma neoepitopes we identified recurrent CIC hotspot mutations at position 215 (CICR215W/Q) expressed in a subset of oligodendrogliomas as an immunogenic major histocompatibility complex (MHC) class II-restricted neoepitopes. Peptide-based vaccination of MHC-humanized mice resulted in the generation of robust mutation-specific T cell responses against CICR215W/Q, restricted to MHC class II. Droplet-based single cell T cell receptor (TCR) sequencing from CICR215W-specific T cell lines enabled retrieval of MHC class II-restricted CICR215W-reactive TCRs. By retroviral transduction of T cells, we established a flow cytometry-based testing platform of retrieved TCRs and were able to show the top reactive TCR against CICR215W to be shared between individual mice. Using a newly developed glioma model in MHC-humanized mice induced by CRISPR-based delivery of tumor suppressor targeting guide RNAs, we show that adoptive intraventricular transfer of CICR215W-specific TCR-transgenic T cells exert anti-tumor responses against CICR215W-expressing syngeneic gliomas. CONCLUSION The integration of immunocompetent MHC-humanized orthotopic glioma models in the discovery of shared immunogenic glioma neoepitopes facilitates the identification and preclinical testing of HLA-restricted neoepitope-specific TCRs for locoregional TCR-transgenic T cell adoptive therapy.

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