KS04.6.A A PHASE II STUDY OF AN ANTI-TERT VACCINE (UCPVAX) WITH OR WITHOUT TEMOZOLOMIDE IN NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND UCPVax is a therapeutic vaccine designed to elicit CD4⁺ helper T-cell responses targeting telomerase (TERT), a tumor-associated antigen in glioblastoma (GBM). Temozolomide (TMZ) is known to induce CD4⁺ T-cell lymphopenia, potentially compromising vaccine-induced immune responses. We conducted a multicenter, two-cohort, phase IIa study to assess the immunogenicity and clinical efficacy of UCPVax, administered with or without TMZ, as adjuvant therapy in patients with newly diagnosed GBM following completion of chemoradiation. MATERIAL AND METHODS Patients with IDH1 wild-type glioblastoma (GBM) were enrolled one month after completing standard concurrent radiotherapy and temozolomide (TMZ). In Cohort A, patients received UCPVax alone, while Cohort B received UCPVax in combination with six monthly cycles of adjuvant TMZ. The primary endpoint was the induction of TERT-specific CD4⁺ T-cell responses, measured ex vivo using an IFN-γ ELISpot assay. Secondary endpoints included evaluation of epitope spreading, clinical efficacy, and safety. RESULTS Cohort A consisted of 31 glioblastoma (GBM) patients with unmethylated MGMT promoter status, while cohort B included 30 patients, half of whom had unmethylated MGMT. The vaccine demonstrated a favorable safety profile, with no serious adverse events attributed to it. TERT-specific CD4+ T cells expanded by the vaccine were detected ex vivo in 83% (25/30) of patients in cohort A (who did not receive additional temozolomide) and in 69% (18/26) of those in cohort B (who received additional TMZ). Evidence of epitope spreading was observed in 29 of the 55 patients assessed (52.7%). Patients exhibiting epitope spreading had a significantly longer median overall survival (19.3 months) compared to those without such a response (12.8 months; P = 0.03). Among the 44 patients with measurable disease at baseline, the radiological response rate—including minor responses—was 36%. Notably, response rates were higher in patients who developed epitope spreading (50%) versus those who did not (18.7%; P = 0.05). Additionally, TERT-specific tumor-infiltrating lymphocytes were identified in three vaccinated patients who underwent reoperation at recurrence. CONCLUSION UCPVax induced strong CD4⁺ T-cell responses, even when co-administered with TMZ. Epitope spreading was associated with improved overall survival, supporting further clinical evaluation of this TERT-targeted vaccine strategy in GBM.