UCPVax

Glioblastomas (GBM) are the most frequent brain tumors and one of the most lethal adult cancers despite maximal multimodal therapy. Despite maximal safe resection followed by radiotherapy and temozolomide (TMZ) ± tumor-treating fields, median overall survival for newly diagnosed GBM remains around 18 months and long-term survival is rare, and recurrence is nearly universal. So, the development of new therapeutic strategies is a critical unmet need in GBM. Despite the limited success of anti-PD(L)-1 therapy, immunotherapy remains a promising option in GBM. Current challenge supports to develop combinatorial therapy approaches considering the particular immune tumor microenvironment in GBM. Anticancer vaccines have shown promising signs of efficacy in GBM but critical factors challenge their efficacy. CD4 T help is of major interest for cancer vaccine effectiveness and for immune checkpoint inhibitors success. We previously designed UCPVax a CD4 T helper-targeted cancer vaccine derived from telomerase (TERT), a very attractive GBM-associated antigen (Adotévi O, J Clin Oncol 2023 ; Laheurte C, Cell Report Med 2025). The induction of robust tumor reactive CD4 T cell response with UCPVax together with TMZ-mediated immune effects will promote recruitment of effectors immune cells into tumor bed creating a more suitable microenvironment for anti-PD-1 action. This is a proof-of-concept phase II trial to evaluate the efficacy of maintenance therapy evaluating UCPVax +/- pembrolizumab combined to standard treatment in newly diagnosed unmethylated MGMT glioblastoma. A translational research network will be implemented to better understand the therapeutic efficacy of this combination.

Primary outcome: Assessment of the Overall Survival (OS) at 18 months since randomization of patients with GBM treated in the experimental arm with UCPVax +/- pembrolizumab combined with standard treatment (Temozolomide +/- Novo-TTF-200A)

The TERTIO trial will propose to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer anti-telomerase vaccine (UCPVax) with anti-PD-L1 therapy (atezolizumab) and bevacizumab in unresectable HCC by evaluation of the objective response rate at 6 months (randomized phase II, 10 centers, 105 patients)

Primary outcome: objective response rate (ORR)

Lung cancer is the most commonly diagnosed malignancy and the leading cause of cancer-related mortality both in men and women worldwide. The past few years have demonstrated great progress in the field of tumor immunotherapy through agents that address mechanisms of immune escape notably, so called immune checkpoint inhibitors (ICB). Indeed, ICB have emerged as a fatal weapon in the anticancer treatment arsenal. Anti-PD-1 and anti-PD-L1 antibodies have shown promising results in several cancers including Non-small Cell Lung Cancer (NSCLC) patients. Although such ICB extend patient's survival compared with conventional systemic therapies, they fail to control cancer progression in a significant proportion of patients which can reach up to 50-60% in NSCLC. Recent literature highlights a range of factors involved in the heterogeneous responses and failures to ICB therapies. The challenge is how can ICB treatment efficacy be extended to majority patients? To respond to this question, to increase the success of immunotherapy, immuno-oncology community develops combinations approaches. The aim of these project is to evaluate the efficacy of Nivolumab plus a novel CD4Th1 inducer anti-cancer vaccine in NSCLC patients. Nivolumab (NIVO), which is an anti-PD-1 antibody, has shown promising results in 2nd line treatment for advanced NSCLC. UCPVax is a therapeutic anti-cancer vaccine based on the telomerase-derived helper peptides designed to induce strong TH1 CD4 T cell responses in cancer patients (NCT02818426).

Primary outcome: 6 months Progression-Free Survival (PFS) rate

Glioblastoma (GBM) is the most frequent primary brain tumor and the brain tumor with the poorest prognosis. The current treatment relies on surgical resection of gross tumor followed by radiochemotherapy and adjuvant therapy with temozolomide. After such therapy, most patients experiment recurrence and few therapeutic option are available. Despite such therapies, median survival only reaches around fifteen months. There is a strong rational to develop telomerase vaccine in GBM. Telomerase (TERT) is a major oncogene, particularly in primary brain tumors 24. Alterations in TERT are very frequent in central nervous system tumors, seen most commonly in gliomas25. Mutations in the TERT promoter are found in approximately 80% of primary glioblastoma (GBM). These findings strongly support the rational to develop vaccine targeting telomerase in GBM. The aim of this project is to evaluate UCPVax treatment in glioblastoma. UCPVax is a therapeutic anti-cancer vaccine based on the telomerase-derived helper peptides designed to induce strong TH1 CD4 T cell responses in cancer patients (NCT02818426).

Primary outcome: Immunogenicity

70% all cases of cervical cancer, 95% of anal cancers and about 70% of oropharyngeal cancers are linked to Human Papillomavirus (HPV) infection. HPV oncogenic proteins are trans-activators of telomerase. Indeed, E6 oncoprotein transactivates the human telomerase (hTert). Our group has conducted a clinical trial (NCT02402842) in advanced squamous cell anal cancer (SCCA) and investigators have shown a correlation between the presence of anti-HPV immunity and anti-telomerase T helpher 1 (TH1) CD4 T cell responses, establishing telomerase as an appropriate antigen in HPV-related cancers. Tumor-reactive CD4+ T cells have been found to ensure efficient effector Cytotoxic T Lymphocytes (CTL) recruitment at the tumor site. Promoting tumor specific TH1 CD4 activation might be an attractive therapeutic option to enhance anti-PD-1/PD-L1 (Programmed cell Death-1/Programmed cell Death-Ligand1) efficacy. However, no option is currently available to expand tumor specific TH1 lymphocytes in most patients. Then, investigators have identified four novel MHC (Major Histocompatibility Complex) class II-restricted peptides derived from human telomerase reverse transcriptase (TERT) referred as "Universal Cancer Peptides" (UCP). UCPVax is a therapeutic cancer vaccine developed by our team and composed of two separate peptides called UCP2 and UCP4 derived from telomerase. This UCPVax vaccine is currently evaluated in a multicenter phase I/II study in Non Small Lung Cancer (NSCLC) (NCT2818426) and seems to show to be safe and immunogenic. PD-1/PD-L1 immune checkpoint is a relevant candidate target for immunotherapy in HPV+ cancers, based on the prominent role of PD-1 and its ligand PD-L1 in HPV-driven immune-evasion. There is a strong rational of using PD-1 therapy in HPV+ cancers, however anti-PD-1/PD-L1 treatment induces a limited number of long term responses in HPV disease. Combining anti-PD-1/PD-L1 therapy with an antitumor vaccine gains serious consideration in HPV+ cancers. Indeed, anti-cancer vaccines can induce tumor-specific T cells expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. So investigators propose to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer vaccine (UCPVax) with atezolizumab in patients with HPV+ cancers by evaluation of the objective response rate at 4 months according to iRecist criteria.

Primary outcome: Objective response rate at 4 months

UCPVAx is a therapeutic vaccine based on the telomerase-derived UCP designed to induce strong TH1 CD4 T cell responses in cancer patients. Three doses of UCPVax (0,25 mg, 0,5 mg and 1 mg) will be tested in this phase I/II study by using Continuous Reassessment Method (CRML) dose escalation design model. The phase I is a dose escalation study designed to evaluate safety of use of UCPVax and to estimate its Maximum Tolerated Dose (MTD). The phase II is a dose deescalation designed to evaluate the immunogenicity of UCPVax according to the dose level.

Primary outcome: Dose Limiting Toxicity (DLT) of UCPVax (phase I)