Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphoma.

Abstract

GSK-3β is a serine/threonine kinase implicated in tumorigenesis and chemotherapy resistance. GSK-3β blockade downregulates the NF-κB 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-3β 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 3rd 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-γ, granzyme B, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, treatment of a patient with refractory ATLL with the GSK-3β 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.

• Authors: Andrew Hsu, Kelsey E Huntington, Andre De Souza, Lanlan Zhou, Adam J Olszewski, Nirav P Makwana, Diana O Treaba, Ludimila Cavalcante, Francis J Giles, Howard Safran, Wafik S El-Deiry, Benedito A Carneiro
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 23 Issue 1 Pg. 417-423 (12 31 2022) ISSN: 1555-8576 [Electronic] United States
• PMID: 35815408 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Protein Kinase Inhibitors
• Glycogen Synthase Kinase 3 beta

Topics

• Adult
• Apoptosis
• Glycogen Synthase Kinase 3 beta
• Humans
• Leukemia-Lymphoma, Adult T-Cell (drug therapy)
• Lymphoma
• Male
• NF-kappa B (metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)