小分子选择性糖原合成酶激酶-3β（GSK-3β）抑制剂 9-ING-41 在难治性成人 T 细胞白血病/淋巴瘤中的临床活性

GSK-3 is a serine/threonine kinase implicated in tumorigenesis and chemotherapy resistance. GSK-3 blockade downregulates the NF- B pathway, modulates immune cell PD-1 and tumor cell PD-L1 expression, and increases CD8 + T cell and NK cell function.

We report a case of adult T-cell leukemia/lymphoma (ATLL) treated with 9-ING-41, a selective GSK-3 inhibitor in clinical development, who achieved a durable response. A 43-year-old male developed diffuse lymphadenopathy, and biopsy of axillary lymph node showed acute-type ATLL. Peripheral blood flow cytometry revealed a circulating clonal T cell population, and CSF was positive for ATLL involvement.

After disease progression on the 3 rd line of treatment, he started treatment with 9-ING-41 monotherapy in a clinical trial (NCT03678883). CT imaging after seven months showed a partial response. Sustained reduction of peripheral blood ATLL cells lasted 15 months. Treatment of patient-derived CD8 + T cells with 9-ING-41 increased the secretion of IFN- , granzyme B, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).

In conclusion, treatment of a patient with refractory ATLL with the GSK-3 inhibitor 9-ING-41 resulted in a prolonged response. Ongoing experiments are investigating the hypothesis that 9-ING-41-induced T cell activation and immunomodulation contributes to its clinical activity.

Further clinical investigation of 9-ING-41 for treatment of ATLL is warranted.