Abstract 3614: T cell receptor-engineered T cell therapy using TCR gene derived from an HLA-A2 hepatoblastoma patient who was completely cured by administration of glypican-3 peptide vaccine
Authors: Tsuyoshi Terada, Kazunobu Ohnuki, Manami Shimomura, Toshihiro Suzuki, Yasunori Amaishi, Kaho Takeichi, Sachiko Okamoto, Norihiro Fujinami, Kazumasa Takenouchi, Nobuo Tsukamoto, Kayoko Shoda, Toshiaki Yoshikawa, Tetsuya Nakatsura
Journal: Cancer Research (2024)

Abstract Glypican-3 (GPC3) is highly expressed in many of hepatocellular carcinoma, hepatoblastoma, ovarian clear cell carcinoma, and squamous cell lung carcinoma, but not expressed in almost all normal tissues, making it an excellent target for cancer immunotherapy. We identified each HLA-A24 and -A2-restricted GPC3-derived peptide and had conducted various clinical trials administering these peptides. All five cases of refractory hepatoblastoma, who had repeated relapses and remissions, are surviving for more than 9 years without recurrence by the only administering these peptide vaccines. We established many kinds of peptide-specific CTL clones with high avidity from PBMC of one of the female HLA-A*02:01-positive refractory hepatoblastoma patient treated with GPC3-derived peptide. Through collaborating research with Takara Bio Inc., which has siTCR technology and extensive experience in developing TCR-T cell therapies including NY-ESO-1 TCR-T, we identified most effective two kinds of TCR by creating a viral vector, preparing TCR-expressing T cells, and evaluating them in various in vitro/in vivo experiments. These TCR-gene engineered T cell can kill cancer cells presenting glypican-3-derived peptides, so this TCR-T therapy has proven to be a promising treatment for patients with cancers that are HLA-A2 positive and express GPC3. The development of TCR-T has been overshadowed by the overwhelming increase in the number of CAR-Ts developed in recent years, but while CAR-Ts have struggled in solid cancers, there have been some reports of successful cases in TCR-Ts and remains a promising treatment. Although GPC3 is a membrane protein, it is not necessarily expressed on the cell membrane and is often expressed within the cell, so we believe that TCR-T is more effective than CAR-T, which targets GPC3. TCR-T cell therapy targeting GPC3 has not yet been implemented anywhere in the world, and we hope this TCR-T therapy as an effective treatment for hepatocellular carcinoma, an intractable cancer with a 10-year survival rate of only 15%, refractory childhood hepatoblastoma, ovarian clear cell carcinoma and lung squamous cell carcinoma that are difficult to respond to anticancer drugs. This development was based on an unmet medical need, and HLA-A2 is found not only in 40% of Japanese, but also in many Caucasians, making it versatile and possible for international expansion. Citation Format: Tsuyoshi Terada, Kazunobu Ohnuki, Manami Shimomura, Toshihiro Suzuki, Yasunori Amaishi, Kaho Takeichi, Sachiko Okamoto, Norihiro Fujinami, Kazumasa Takenouchi, Nobuo Tsukamoto, Kayoko Shoda, Toshiaki Yoshikawa, Tetsuya Nakatsura. T cell receptor-engineered T cell therapy using TCR gene derived from an HLA-A2 hepatoblastoma patient who was completely cured by administration of glypican-3 peptide vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3614.