Immunosuppression in Patients with High-Grade Gliomas Treated with Radiation and Temozolomide

Abstract

Purpose Patients with high grade gliomas (HGG) routinely receive radiation, temozolomide, and glucocorticoids. As each of these is immunosuppressive, we conducted a prospective, multicenter study to follow CD4 counts over time and determine if low CD4 counts were associated with adverse outcomes. Experimental design Patients with newly diagnosed HGG had CD4 counts drawn before initiating standard therapy and monthly thereafter for one year. Information on hospitalizations, infections, glucocorticoid use, survival, and cause of death were also collected. Results Ninety-six evaluable patients were accrued (85% glioblastoma, median age of 57, median KPS 90). The median CD4 count before radiation and temozolomide was 664 cells/mm3. The CD4 count nadir occurred 2 months after initiating therapy when 73% of patients had CD4 counts <300 cells/mm3 and 40% had <200 cells/mm3. CD4 counts remained low throughout the year of follow-up. Patients with CD4 counts <200 cells/mm3 at 2 months had shorter survival than those with higher counts (median 13.1 versus 19.7 months, p=0.002). Median survival was related to CD4 toxicity grades (I=23.8 months, II=19.7 months, III–IV=13.1 months, p=0.009). The adjusted hazard ratio for death attributable to 2-month CD4 count below 200 was 1.66 (p=0.03). Eighty-eight percent of deaths resulted from disease progression while only 2.5% were due to infection. Conclusions Severe reductions in CD4 counts in patients with newly diagnosed HGG treated with radiation and temozolomide are common, treatment-related, long-lasting, and associated with early death from tumor progression.

A comparison of DNA methylation specific droplet digital PCR (ddPCR) and real time qPCR with flow cytometry in characterizing human T cells in peripheral blood

“…These patients continued to have low T cell counts for the full year of follow-up and exhibited early mortality from tumor progression. 15 Other studies also have reported that low T cell counts were associated with poorer glioma survival times. 16,17 More generally, T cell lymphopenia has been shown to be a grave prognostic indicator in multiple types of cancers.…”

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

“…18,19 Gliomas have been shown to employ a variety of mechanisms to suppress the immune system, such as downregulation of MHC class I molecules, production of transforming growth factor-b (TGF-b), vascular endothelial growth factor (VEGF), prostaglandin E2, and IL-10, expression of ligands of checkpoint receptors, such as PD-1, and accumulation of immunosuppressive cells, such as myeloidderived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs). [23][24][25][26][27][28][29][30] It has been previously shown in human samples and experimental GBM models that MDSCs are powerful inhibitors of anti-tumor immune responses. 30,31 Through a variety of mechanisms that inhibit T cell activation and expansion, including the production of arginase and inducible nitric oxide synthase (iNOS), reactive oxygen species and/or reactive nitrogen species (ROS and/or RNS), release of IL-10, expansion of regulatory T cells (Tregs), and inhibition of T cell migration, MDSCs have been shown to promote immunosuppression and tumor progression.…”

The Burden of Oncology Promises not Kept in Glioblastoma

“…Rindopepimut failed to improve OS, which was the primary end point of the study, when compared with control arm (20.1 vs 20.0 months) [12]. Although the ACT IV is formally a negative study, rindopepimut may need further evaluation given the better-than-expected performance of the control group and the possibility that standard-dose temozolomide may have induced lymphocytopenia and immunosuppression in experimental arm [13]. The target population that is more likely to benefit from rindopepimut therapy may need to be better defined, possibly by optimization of selection criteria for residual disease after surgery or technique and cutoff used for definition of EGFRvIII expression versus nonexpression.…”