Implications of GITR expression profile for precision immunotherapeutics.

Abstract

e14561 Background: Glucocorticoid-induced TNFR-related protein (GITR) is a type I transmembrane protein expressed mostly on CD25+CD4+ T-regs and upregulated on all T-cells upon activation. It serves as a T-cell co-stimulatory receptor and its role in cancer treatment is being explored. While pre-clinical data using combination therapies involving GITR agonism showed promise, early clinical trials have not shown improved outcomes to date. Methods: RNA expression levels of 397 genes in 514 patients with a variety of cancer types were assessed and analyzed at OmniSeq. Transcript levels were normalized to internal housekeeping gene profiles and ranked as percentiles using a reference population. High expression was defined as ≥ 75th percentile, and low-moderate as <75th percentile. Univariate p-values were calculated using Welch t-test or Fischer’s exact test. Multivariate p-values were calculated using logistical regression. Results: A total of 99 patients (19.3%) had GITR high expression. Cancers with the highest proportion of GITR high expression were lung (7/20, 35%) and breast (19/49, 39%), and both these cancers showed a statistically significant association with GITR high expression on multivariate analysis (lung: OR 3.5, p = 0.04, 95% confidence interval (CI) 1.06 – 10.06 CI and breast: OR 4.59, p <0.001, 95% CI: 2.11 – 9.85). 30% of lung and 30.6% of breast cancer patients had a GITR high with ligand low-moderate expression profile; these cancers had the highest proportion of patients with this profile. GITR high expression showed significant association with high RNA expression of multiple known immune checkpoint proteins (PD-1, PD-L1, CTLA4, LAG3, OX40, ICOS and CD137, but not TIM3) as well as PD-L1 IHC ≥1 on univariate analysis, but statistically significant association was only seen with PD-L1 IHC ≥1 (p = 0.007) and OX40 high expression (p = 0.001) on multivariate analysis. Conclusions: While clinical trials with GITR agonism are ongoing, our data suggests selection of certain types of malignancies depending on GITR status may be required. Moreover, there is a correlation between high GITR and high OX40 RNA expression, which could imply increased efficacy using this targeted combination. Further clinical development based on this immune-profiling is warranted. [Table: see text]