Outcomes and immune response after peptide vaccination targeting human cytomegalovirus antigen pp65 in children and young adults with recurrent high-grade glioma and medulloblastoma

Background: The human cytomegalovirus (CMV) antigen pp65 is ubiquitously expressed in high-grade glioma (HGG) and medulloblastoma but not in adjacent brain. The primary objective of this first-in-human phase I trial (NCT03299309) was to assess the safety and feasibility of a novel peptide vaccine targeting pp65 (PEP-CMV) in children/young adults with recurrent medulloblastoma and HGG. Methods: The vaccine is comprised of a synthetic long peptide of 26 amino acids and is administered as an emulsion in Montanide ISA 51. Patients receive a single 5-day course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning to promote dendritic cell migration, then PEP-CMV administered intradermally in the groin every two weeks for 3 doses, then monthly. Results: Forty-two patients were enrolled. Diagnoses include medulloblastoma (n=2), glioblastoma (n=21), anaplastic oligodendroglioma (n=3), anaplastic astrocytoma (n=11), and malignant glioma NOS (n=5). The median time from initial diagnosis to treatment was 24 months (range 4–35) and the median number of prior chemotherapy regimens was 4 (range 0–15). The mean age was 23.2 6 9.3 years. 55% of patients were male. The median KPS was 80. Of the 38 patients who received PEP-CMV, the maximum grade adverse event (AE) possibly, probably, or definitely related to PEP-CMV was as follows: 17 (45%) had Grade 1 adverse events (AE), 16 (42%) had Grade 2 AEs, 2 (5%) had Grade 3 AEs (encephalopathy and pyramidal tract syndrome), and one (3%) had a Grade 4 AE (cerebral edema). One patient developed symptoms and had elevated inflammatory cytokines consistent with cytokine release syndrome (Grade 2). The median progression-free survival was 2.5 months (95% CI:2.2,3.2) and median overall survival was 6.4 months (95% CI: 3.4,7.9). The 12-month OS was 26.6% (95% CI:14,41.1%). Of the 22 patients with evaluable immune monitoring data, T cell reactivity on IFNg pp65 ELISpot was increased after PEP-CMV delivery (median spot pretreatment vs. prior to vaccine #4: 1 vs 30, P=0.004, Table). Lower percentage of pretreatment regulatory T cells and higher percentage of terminally differentiated effector T cells at vaccine #4 were associated with longer subsequent survival. Conclusions: PEP-CMV is well-tolerated and elicits an antigen-specific immune response in heavily pretreated, multiply recurrent patients with a 12-month OS of 26.6%. A multiinstitutional Phase II trial (NCT05096481) of PEP-CMV is opening imminently. Clinical trial information: NCT03299309. Research Sponsor: Pediatric Brain Tumor Foundation.