Ks01.6.a ucpvax-glio: a phase ii trial evaluating the immunogenicity and efficacy of an anti-telomerase vaccine in patients with newly diagnosed gbm

Abstract BACKGROUND The Telomerase Reverse Transcriptase (TERT) is activated in 85%-90% of cancers, and glioblastomas (GBM) harbor the highest incidence of activating mutations within its promoter (over 85% of patients). This high expression of TERT in cancers and its role in oncogenesis make TERT a very promising tumor antigen for immunotherapy, especially in GBM. UCPvax is a therapeutic vaccine in which two CD4 helper peptides derived from TERT are mixed with the Montanide adjuvant. This phase IIa trial was designed to test the immunogenicity, safety and efficacy of UCPvax in patients with newly diagnosed GBM. PATIENTS AND METHODS In this first cohort of the UCPvax-glio trial (NCT04280848), patients with unmethylated MGMT non-mutated IDH1 GBM were included if they had a Karnofsky Performance status (KPS) ≥ 70%, a steroid treatment < 10mg/ day equivalent prednisone, and lymphocytes count ≥ 0.8 x 109/L. One month after completion of radiation/ temozolomide (TMZ), patients started UCPvax vaccinations on days 1, 8, 15, 29, 36 and 43, then every two months until tumor progression. Patients did not receive any additional cure of TMZ because of the unmethylated MGMT promoter status. Peripheral blood mononuclear cells were collected before treatment, at 1 and 2 months after treatment, and at each vaccination boost. The primary endpoint was the anti-TERT specific CD4 T-cell response at 2 months using IFN-gamma ELISPOT. Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). RESULTS All the 31 patients (median age 60-yr old, median KPS 90%) included in this study received at least one vaccination. Vaccinations were given for 4.5 months on average (min 2- max 14). At baseline, only one patient had a pre-existing anti-TERT CD4 T-cell response (3%). After immunizations, de novo induction and/or amplification of an anti-TERT response were found in 29/30 patients (97%). An epitope spread response against other tumor-associated antigens was detected in 12/25 patients (48%). All patients developed local skin reactions (≤ grade 2), 16 patients complained of transient asthenia (≤grade 2), and 13 patients experienced local pain (≤grade 2). No severe (grade 3-4) toxicity was attributable to the vaccination. In the intent-to-treat population (n = 31), the PFS was 8.9 months (95% CI: 7.6-10.6) and the median OS was 17.9 months (95% CI: 16-23). Two years after diagnosis, 26% of the patients were still alive. OS was significantly improved in the patients developing an epitope spread response vs the others (20.8 versus 14.1 months, respectively, p = 0.03). CONCLUSION s: In this population of unmethylated MGMT GBM patients, UCPVax is highly immunogenic and provides an interesting OS rate. These data strongly support the completion of the second ongoing cohort, assessing UCPvax in combination with TMZ for GBM patients with methylated MGMT promoter status.