A phase II study of an anti-telomerase CD4+ T-helper vaccine (UCPVax) with or without temozolomide in newly diagnosed glioblastoma.

2006 Background: UCPVax is a therapeutic vaccine designed to stimulate CD4+ helper T cell responses against telomerase (TERT), a protein highly expressed in glioblastoma (GBM). Temozolomide (TMZ), a standard chemotherapeutic agent in the treatment of GBM, has been shown to induce CD4+ T-cell lymphopenia, which could potentially impair the immune response to the vaccine. We conducted a multicenter, 2-cohort, phase IIa study to evaluate the immunogenicity and efficacy of UCPVax, with or without TMZ, as adjuvant therapy in patients with newly diagnosed GBM following chemoradiation. Methods: Patients with non-mutated IDH1 glioblastoma (GBM) were enrolled one month after completing concurrent radiotherapy and temozolomide (TMZ). Cohort A received the vaccine alone, without additional TMZ, while Cohort B was treated with both the vaccine and six monthly cycles of TMZ. The primary endpoint was the induction of TERT-specific CD4+ T cell responses, assessed ex vivo using the INF-γ ELISpot assay. Secondary endpoints included epitope spreading, clinical outcomes, and safety. Results: Thirty-one GBM patients with unmethylated MGMT status were included in cohort A, and 30 patients (50% with unmethylated MGMT status) were included in cohort B. The vaccine was well tolerated, with no vaccine-related serious adverse events. Vaccine-expanded TERT-specific CD4+ T cells were detectable ex vivo in 25/30 (83%) of patients in cohort A (no additional TMZ) and in 18/26 69% of patients in cohort B (treated with additional TMZ). Epitope spreading was induced in 29 out of 55 evaluable patients (52.7%), corresponding to 15/26 (57.7%) in cohort A and 14/29 (48%) in cohort B. Median overall survival (OS) was significantly improved in patients who developed an epitope spread response compared to those who did not (19.3 vs. 12.8 months, P = 0.03). In the 44 patients with measurable disease at the time of inclusion, the radiological response rate (RR) was 34%, including minor responses. In patients who developed epitope spreading after vaccination (n = 22), the RR was 50%, compared to 18.7% in patients without epitope spreading (P = 0.05). Furthermore, tumor-infiltrating lymphocytes against TERT were detected in 3 vaccinated patients who underwent surgery at recurrence. Conclusions: UCPVax demonstrated robust immunogenicity, even when co-administered with TMZ, and was associated with improved overall survival (OS) in GBM patients who developed an epitope spreading response. These findings support further clinical investigation of TERT-derived CD4+ helper vaccine in GBM patients. Clinical trial information: NCT04280848 .