Additionally, we have demonstrated that the COX-2 pathway and prostaglandin-E2 (PGE2) are critical for the immunosuppressive function of myeloid-derived suppressor cells in glioma ( 13). Accordingly, we recently found that the presence of tumor-infiltrating bone marrow–derived myeloid cells is associated with decreased overall survival in patients with low-grade glioma (LGG) ( 12).
Type 1–polarized T cells expressing IFN can migrate to and mediate effective antiglioma immunity ( 10, 11) however, tumor-associated myeloid cells can produce immunosuppressive cytokines, altering these T cells to an ineffective type 2–polarized state. Multiple factors likely contribute to this, including antigen loss ( 6), low MHC expression on tumor cells ( 7), inhibitory checkpoint pathways ( 8), and the accumulation of immunosuppressive T regulatory and myeloid cells ( 9). Despite frequently eliciting biologic responses, tumor shrinkage is often not observed. Numerous studies evaluating peptide-based vaccine approaches for adult and pediatric brain tumors have demonstrated the feasibility and safety associated with this approach ( 1– 6). Future clinical trials, including our ongoing phase II LGG vaccine immunotherapy, should monitor these response patterns. Overall, our data support the presence of unique peripheral immune patterns in LGG patients associated with different radiographic responses to our peptide vaccine immunotherapy.
Finally, low IDO1 and PD-L1 expression before treatment and early elevated levels of T cell activation markers were associated with prolonged progression-free survival. Interestingly, HLA-V expression, before or during therapy, and an early monocytic hematopoietic response were strongly associated with SD. Patients with PR demonstrated a unique, late monocyte response signature. At week 34, patients with CR demonstrated both IFN signaling and Poly-IC:LC adjuvant response patterns. Patients who showed CR demonstrated elevated levels of T cell activation markers, accompanied by a cytotoxic T cell response shortly after treatment initiation. To identify biomarkers of clinical response in peripheral blood, we performed RNA sequencing on PBMC samples collected at multiple time points. Additionally, we observed radiologic responses of stable disease (SD), partial response (PR), and near-complete/complete response (CR) following therapy.
CLC GENOMICS WORKBENCH TRIAL TRIAL
We recently reported an early phase clinical trial of a peptide-based vaccine, which elicited consistent antigen-specific T cell responses in pediatric LGG patients. Low-grade gliomas (LGGs) are the most common brain tumor affecting children.
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