Abstract 1694: Systemic granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment increases T cell receptor diversity in localized and metastatic prostate cancer patients

Abstract

Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) is frequently utilized as an adjuvant in cancer immunotherapies, and has known effects as a growth factor. However the extent to which GM-CSF modulates the adaptive immune response, including possible effects on the antigenic repertoire, remains unclear. We used next-generation sequencing of T cell receptor (TCR) beta chain sequences amplified from total RNA from peripheral blood mononuclear cells using consensus primers to assess changes in the circulating antigenic repertoire of prostate cancer patients treated with GM-CSF in multiple clinical trials. Administration of systemic GM-CSF monotherapy to patients with localized prostate cancer prior to planned radical prostatectomy (NCT00305669) results in a significant decline in clonality from the pre-treatment timepoint to the 2-week timepoint on treatment, indicative of increased early repertoire diversity (p=0.039 by Wilcoxon signed rank test). In a separate clinical trial (NCT00064129), the combination of systemic GM-CSF (250 μg/m2/day on days 1-14 of each cycle) with ipilimumab in metastatic castrate-resistant prostate cancer (mCRPC) patients also resulted in a significant decline in clonality from pre-treatment samples to the 2-week timepoint on treatment (p=0.002). In contrast, mCRPC patients who received ipilimumab alone in a separate study (NCT00323882) did not experience a similar decline in clonality after 3 weeks on treatment (p=0.625). In addition, comparison of the dynamics of specific clonotypes between the paired timepoints in the two mCRPC studies demonstrates that while there is no significant difference in the ratios of post-treatment to pre-treatment clonality between studies, patients treated with the combination of iplilimumab and GM-CSF show more repertoire change, with lower Morisita’s distance for all clones found at either timepoint (p=0.023), smaller intraclass correlation coefficient (p=0.028), and a smaller proportion of clonotypes that remain unchanged (defined by +/- 2-fold change for clones found at both timepoints) (p=0.002). These results indicate increased repertoire turnover when GM-CSF is combined with checkpoint inhibition. Hence data from both localized and metastatic prostate cancer, and from monotherapy and combination therapy regimens, supports a role for GM-CSF in inducing early diversification of the TCR repertoire. Citation Format: David Y. Oh, Li Zhang, Jason Cham, Alan Paciorek, Mark Klinger, Malek Faham, Susan F. Slovin, Lawrence Fong. Systemic granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment increases T cell receptor diversity in localized and metastatic prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1694. doi:10.1158/1538-7445.AM2017-1694