P08.12.B NAVIG-1: A PHASE I/IIA STUDY EVALUATING AN ANTI-TELOMERASE IMMUNOTHERAPY IN GLIOBLASTOMA

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Abstract BACKGROUND Glioblastoma remains the most lethal brain tumor despite standard therapies, which include surgery, radiotherapy and chemotherapy. Immunotherapies, such as peptide vaccines, offer a promising strategy; however commonly used formulations have not yet demonstrated significant clinical efficacy. In preclinical studies, we have shown that a novel vaccine platform based on synthetic melanin nanoaggregates and a TLR9 agonist triggers strong immune responses and significantly inhibit tumor growth in several murine models. MATERIAL AND METHODS We developed a new melanin-based vaccine targeting the glioma-associated antigens telomerase and PTPRZ1. The efficacy of this vaccine in inducing an immune response and inhibiting tumor growth was first evaluated in a syngeneic glioma model (CT-2A) in C57BL/6 mice. The vaccine’s effectiveness was further validated in a sarcoma model using SureL1 humanized transgenic mice expressing human HLA-A2/DR1 (SARC-A2). The specific responses induced by the vaccine were assessed by IFN-γ ELISPOT 7 days after the last immunization. Anti-tumor efficacy was evaluated by comparing subcutaneous tumor growth in vaccinated mice with that in control groups. Building on these promising results, this vaccine is currently being evaluating in a multicenter Phase I/IIa clinical trial: NAVIG-1 (New Adjuvant Vaccine in Glioblastoma) (NCT06622434). The vaccine is administered to newly-diagnosed glioblastoma adult patients after completing concomitant radio-chemotherapy, in combination with adjuvant temozolomide. Phase I of the study will follow a modified Fibonacci dose escalation with three dose levels, with the primary objective of determining the maximum tolerated dose. The main objective of phase II is to evaluate the induction of specific immunity. In total, the NAVIG-1 trial will involve six centers and 35 treated patients. RESULTS In preclinical models, the NAVIG vaccine induced significantly higher anti-telomerase responses compared to commonly used vaccine formulations (peptide + CpG-ODN, peptide + CpG-ODN + IFA) in C57BL/6 and both higher anti-telomerase and anti-PTPRZ1 responses in humanized transgenic HLA-A2/DR1 mice (p<0.05). Additionally, the vaccine significantly inhibited tumor growth in both models compared to controls (p<0.05). Patient enrollment in NAVIG-1 Phase I study started in October 2024 and is ongoing. CONCLUSION The findings from NAVIG-1 trial will demonstrate the safety and efficacy of this new vaccine technology. Furthermore, since TERT overexpression is observed in more than 85% of all cancers, this vaccine formulation could potentially be adapted for other types of cancer.

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