Research Scientist Duke University School of Medicine Durham, North Carolina, United States
Disclosure(s):
Kelly Hotchkiss: No financial relationships to disclose
Introduction/Rationale: Immunotherapy has yet to show efficacy in glioblastoma (GBM). To enhance immune priming, the ETAPA phase 1 trial (NCT05283109) evaluated P30-EPS, a multicomponent peptide vaccine linking class I tumor-associated antigens (CMV pp65, Survivin, EphA2) to the universal class II tetanus toxoid epitope P30 (TVSFWLRVPKVSASHLE), designed to promote coordinated CD4⁺ and CD8⁺ activation.
Methods: Adults with newly diagnosed, MGMT-unmethylated GBM (n = 18) received 7 intramuscular vaccinations with the TLR3 agonist Hiltonol (20 µg/kg) at doses of 300 µg or 400 µg P30-EPS. Peripheral blood mononuclear cells were assessed longitudinally by IFN-γ ELISPOT, spectral flow cytometry, and TCR sequencing to evaluate cytokine secretion, T-cell phenotype, and repertoire diversity. In parallel, baseline and selected on-treatment tumor samples are being analyzed by Xenium spatial transcriptomics and CODEX multiplex proteomics to map local immune remodeling and spatial coordination of CD4⁺ and CD8⁺ responses.
Results: The vaccine was well tolerated (all adverse events ≤ grade 2). P30-EPS induced robust antigen-specific IFN-γ responses in 11 of 12 evaluable patients, with stronger recall responses at 400 µg. Patients with longer progression-free survival exhibited higher baseline frequencies of naïve CD4⁺ T cells and reduced terminally differentiated effector-memory (CD45RA⁺CCR7⁻) subsets, indicating a less exhausted, more adaptable helper T-cell pool conducive to effective priming. Single cell 5’ TCR sequencing revealed expansion of unique clonotypes following booster vaccination, consistent with durable memory formation.
Conclusion: ETAPA achieved its objectives and the universal CD4 epitope enhanced magnitude and quality of CD8⁺ cytotoxic and memory responses. Ongoing spatial profiling will define intratumoral correlates of systemic immune activation. These results are informing an epitope-linked and retroviral antigen–targeted vaccine that we are developing next to broaden anti-tumor immunity in CNS malignancies.
