Abstract
Altered cellular growth and suppression of anti-tumor immune response collectively drive progression and therapeutic resistance of high-grade gliomas (HGGs), suggesting that successful treatments will likely target these key mechanisms. Janus-associated kinase (JAK)-STAT pathway comprises one such therapeutic node, as STAT3 signaling is upregulated in proliferating glioma cells and immunosuppressive cell types. We performed retrospective analysis on 13 HGG patients treated with the JAK1/2 inhibitor ruxolinitib in combination with radiation or radiation plus temozolomide in a Phase I setting (NCT03514069). Disease progression and treatment response was determined based on the Response Assessment in Neuro-Oncology (RANO) criteria. Peripheral blood mononuclear cells (PBMCs) cells were collected from patients prior to treatment, and 2- 4- and 6-week time points to characterize early immunological changes that are indicative of treatment response with flow cytometry. 6 patients responded favorably, define as progression-free survival >6 months. Investigation of myeloid and lymphoid cell populations revealed no differences in dendritic cell, myeloid-derived suppressor cell and CD8+ T cell subset frequencies in blood. Similarly, expression of checkpoint inhibitors PD-1, TIGIT, CTLA-4 and TIM3 were not altered with ruxolinitib treatment. However, there was a ~2-fold reduction in the frequency of peripheral B cells in favorable responders at 4-week time point, whereas the levels remained stable in non-responders (p<0.05). In addition, while 5 out of 7 non-responders had increased CD4+ T cells by 4-weeks, 5 out of 6 responders had stable or reduced CD4+ T cells. This effect was driven by reduction in immunosuppressive regulatory T cells (Tregs) as the relative ratio of immunostimulatory T helper 1 (Th1)-to-Treg ratio was 3-fold higher in responders compared to non-responders. These results support evaluation of B and CD4+ T cells in the peripheral blood as biomarkers to identify HGG patients likely to benefit from such approach.