Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec 31;20(1):2414542.
doi: 10.1080/21645515.2024.2414542. Epub 2024 Nov 13.

Establishment of potent TCR-T cells specific for cisplatin-resistance related tumor-associated antigen, CLSPN using codon-optimization

Kanta Hori  1   2 , Shuhei Yamada  1   2 , Kenji Murata  1 , Haruka Miyata  2 , Yuka Mizue  1 , Aiko Murai  1 , Tomoyuki Minowa  1   3 , Kenta Sasaki  1 , Naoki Shijubou  1 , Terufumi Kubo  1 , Rena Morita  1 , Serina Tokita  1 , Takayuki Kanaseki  1 , Tomohide Tsukahara  1 , Takashige Abe  2 , Nobuo Shinohara  2 , Yoshihiko Hirohashi  1 , Toshihiko Torigoe  1
Affiliations

Establishment of potent TCR-T cells specific for cisplatin-resistance related tumor-associated antigen, CLSPN using codon-optimization

Kanta Hori et al. Hum Vaccin Immunother. .

Abstract

Adoptive T cell therapy, using T cell receptor-engineered T (TCR-T) cells and chimeric antigen receptor T (CAR-T) cells, is a potent immunotherapy option. Bladder cancer is a prevalent urological malignancy, particularly in cases of muscle invasion and metastasis, for which systemic therapy is crucial. Immunotherapy utilizing immune checkpoint blockade has been approved for bladder cancer treatment. The antitumor effect of an immune checkpoint blockade based on cytotoxic T cells (CTLs) and the patient's immune status is essential. The chemotherapeutic drug cisplatin (CDDP) is a key drug in bladder cancer treatment. However, it has been shown to suppress T cells, making combination therapy with CDDP and immunotherapy difficult. To address this, we developed TCR-T cells specific for bladder cancer cells. In previous studies, we found that the tumor-associated antigen CLSPN is overexpressed in CDDP-resistant bladder cancer cells and that the antigenic peptide HLA-A*02:01/CLSPN1254-1262, encoded by CLSPN, could be targeted by a CTL clone. The TCR was cloned from the HLA-A*02:01/CLSPN1254-1262 specific CTL clone yc3. We also designed a codon-optimized TCR sequence using GeneArt® GeneOptimizer® (Opt TCR) and compared the TCR-T cells using the original TCR sequence (Ori TCR-T cells) and the codon-optimized TCR sequence (Opt TCR-T cells). Opt TCR-T cells exhibited higher TCR transduction efficiency, higher TCR expression levels, higher avidity, and greater cytotoxicity than did Ori TCR-T cells. These results suggest that HLA-A*02:01/CLSPN1254-1262 specific Opt TCR-T cells are promising candidates for CDDP combination therapy.

Keywords: CLSPN; TCR-T; Urothelial carcinoma; cisplatin resistance; immunotherapy.

PubMed Disclaimer

Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Schematic diagram of establishment of T cell receptor-engineered T (TCR-T) cells from CLSPN specific CTL (yc3).
Figure 2.
Figure 2.
The transduction efficacy and expression levels of TCRs.
Figure 3.
Figure 3.
IFN-γ ELISpot assay of the TCR-T cells.
Figure 4.
Figure 4.
CLSPN peptide titration assay.
Figure 5.
Figure 5.
Cytotoxic activity of the TCR-T cells.
Figure 6.
Figure 6.
Schematic summary of potential clinical translation of codon-optimized TCR-T cells.
See this image and copyright information in PMC

References

    1. van Hoogstraten LMC, Vrieling A, van der Heijden AG, Kogevinas M, Richters A, Kiemeney LA.. Global trends in the epidemiology of bladder cancer: challenges for public health and clinical practice. Nat Rev Clin Oncol. 2023;20(5):287–7. doi:10.1038/s41571-023-00744-3. - DOI - PubMed
    1. Sternberg CN, Yagoda A, Scher HI, Watson RC, Herr HW, Morse MJ, Sogani PC, Vaughan ED, Bander N, Weiselberg LR. M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol. 1988;139(3):461–469. doi:10.1016/S0022-5347(17)42494-3. - DOI - PubMed
    1. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068–3677. doi:10.1200/JCO.2000.18.17.3068. - DOI - PubMed
    1. von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602–4608. doi:10.1200/JCO.2005.07.757. - DOI - PubMed
    1. Powles T, Bellmunt J, Comperat E, De Santis M, Huddart R, Loriot Y, Necchi A, Valderrama BP, Ravaud A, Shariat SF, et al. Bladder cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(3):244–258. doi:10.1016/j.annonc.2021.11.012. - DOI - PubMed

Publication types

MeSH terms