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 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-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.

Elraglusib (9-ING-41), a selective small-molecule inhibitor of glycogen synthase kinase-3 beta, reduces expression of immune checkpoint molecules PD-1, TIGIT and LAG-3 and enhances CD8+ T cell cytolytic killing of melanoma cells

“…The case study reported here is from a patient in an ongoing clinical trial and provided rationale for this work, which indicates elraglusib’s potential utility in combination strategies with checkpoint blockade immunotherapy. In patients on this ongoing study, durable clinical responses to single-agent elraglusib have been observed, including in patients with refractory acute T cell leukaemia/lymphoma and malignant gliomas, with a favourable adverse event profile [ 28 , 29 ].…”

“…These studies have utilized elraglusib as both a single agent as well as in combination with standard cytotoxic agents [ 23 , 25 ] or BCL-2 and CDK-9 antagonists [ 27 ]. Elraglusib’s clinical activity has also been reported in patients with advanced refractory cancers [ 28 , 29 ]. In the present study, we evaluate elraglusib in vitro and in a B16 melanoma mouse model and compare its efficacy with anti-PD-1 mAb therapy as both a single agent and when combined with PD-1 mAb therapy.…”

Challenges Coexist with Opportunities: Spatial Heterogeneity Expression of PD‐L1 in Cancer Therapy

“…[ 118 ] 9‐ING‐41 selectively inhibits GSK‐3β, thus suppressing cPD‐L1 expression and subsequently exerting excellent in vivo antitumor activity against refractory adult T‐cell leukemia/lymphoma. [ 119 ] Calcium channel blockers, including amlodipine, lercanidipine, and compound F4, can decrease cPD‐L1 expression by reducing the level of cytosolic calcium ion and cleavage of Becklin1 by Calpain, which can improve the efficacy of anti‐PD‐L1 antibodies. [ 106,120 ] Lercanidipine also increases the phosphorylation of STAT1 at Tyr701 and Ser727, inducing the degradation of cPD‐L1.…”

Histological Characteristics of Experimental Wounds of Soft Tissues of the Femur of Rats and the Role of IFN-γ in the Dynamics of their Healing

“…Очевидно, це пов'язано також із здатністю цього цитокіну опосередковано, через дію на клітини впливати на ремоделювання матриксу. Ряд досліджень вказують на здатність IFN-γ індукувати апоптоз [17,18,19], а також координувати не тільки імунну регуляцію, але й проліферацію клітин. [20].…”