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Researchers at University of Tsukuba conducted a physician-initiated Phase II clinical trial of dasatinib in patients with relapsed or refractory T-follicular helper cell lymphoma (TFHL), an aggressive and difficult-to-treat blood cancer. The study identified genetic alterations and features of the immune microenvironment associated with treatment response. These findings may help identify patients who are more likely to benefit from dasatinib and inform the development of personalized treatment strategies and novel immunotherapeutic approaches.

Tsukuba, Japan—T-follicular helper cell lymphoma (TFHL) is a subtype of peripheral T-cell lymphoma associated with a poor prognosis and limited treatment options following relapse. TFHL is characterized by specific molecular abnormalities, including frequent activation of the T-cell receptor (TCR) signaling pathway. In previous Phase I studies, researchers demonstrated that dasatinib, a drug originally developed to treat leukemia, suppresses abnormal TCR signaling and has shown promising clinical activity in patients with TFHL.

In this study, researchers conducted a physician-initiated, multicenter Phase II clinical trial involving 13 institutions across Japan to evaluate the efficacy and safety of dasatinib and identify factors associated with treatment response. The research team performed comprehensive genetic analyses of tumor tissue and blood samples, as well as single-cell transcriptomic profiling in 17 patients.

Clinical responses were observed in patients with mutations related to TCR signaling. These patients also exhibited clonal expansion of CD8-positive effector T cells, which play a key role in tumor cell elimination, along with enhanced antitumor immune activity. In contrast, patients with a high burden of clonal hematopoiesis-associated mutations were less likely to benefit from treatment and showed impaired antitumor immune responses. Clonal hematopoiesis is an age-related phenomenon characterized by the acquisition of somatic mutations and subsequent clonal expansion of hematopoietic stem cells.

These findings suggest that both the genetic characteristics of tumors and the immune microenvironment influence the therapeutic efficacy of dasatinib. The identified biomarkers may help guide patient selection and inform treatment strategies in future studies and support the development of therapies targeting the tumor immune microenvironment. In addition, the results provide new insights into the potential role of clonal hematopoiesis in shaping antitumor immunity.

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This work was supported by Grants-in-Aid for Scientific Research (KAKENHI: JP23K15317 and JP25K19567 [S.S.], JP21K16262 and JP25K19550 [Y.S.], JP21K16239 and JP25K19551 [M.F.], JP23K15316 and JP25K10578 [K. Hattori], JP23K15293 [K. Makishima], JP21K16261 [T.S.], and JP21H02945, JP22K19451, and JP25H01055 [M.S.-Y.]) from the Ministry of Education, Culture, Sports, and Science of Japan; AMED (JP25ama221545 and JP26ama221545 [S.S.], JP22ck0106544, JP23ck0106797, JP22zf0127009 (the Moonshot Research and Development Program), JP25gm2010006 (CREST), and JP26ck0106087 [M.S.-Y.], JP18lm0203077 and JP21lm0203097 [S.C.]); the Kobayashi Foundation for Cancer Research, Takeda Science Foundation, Japan Leukemia Research Fund, The Uehara Memorial Foundation, and The NOVARTIS Foundation (Japan) for the Promotion of Science [S.S.]; and the Kobayashi Foundation for Cancer Research, the Kobayashi Foundation, and the Chemo-Sero Therapeutic Research Institute [M.S.-Y.].

Original Paper

Title of original paper:

A multi-center, single-arm, phase 2 trial of dasatinib in T follicular helper cell lymphomas

Journal:

Nature Communications

DOI:

10.1038/s41467-026-78100-z

Correspondence

Professor SAKATA-YANAGIMOTO Mamiko
Specially Appointed Assistant Professor SUMA Sakurako
Institute of Medicine, University of Tsukuba

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Institute of Medicine