A Phase II Study Evaluating the Interest to Combine UCPVax, a Telomerase CD4 TH1-Inducer Cancer Vaccine, and Atezolizumab for the Treatment of HPV Positive Cancers: VolATIL Study

Abstract

Background: There is a strong rational of using anti-programmed cell death protein-1 and its ligand (anti-PD-1/L1) antibodies in human papillomavirus (HPV)-induced cancers. However, anti-PD-1/L1 as monotherapy induces a limited number of objective responses. The development of novel combinations in order to improve the clinical efficacy of an anti-PD-1/L1 is therefore of interest. Combining anti-PD-1/L1 therapy with an antitumor vaccine seems promising in HPV-positive (+) cancers. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (hTERT, human telomerase reverse transcriptase). UCPVax is being evaluated in a multicenter phase I/II study in NSCLC (non-small cell lung cancer) and has demonstrated to be safe and immunogenic. The aim of the VolATIL study is to evaluate the combination of atezolizumab (an anti-PD-L1) and UCPVax vaccine in a multicenter phase II study in patients with HPV⁺ cancers.

Methods: Patients with HPV⁺ cancer (anal canal, head and neck, and cervical or vulvar), at locally advanced or metastatic stage, and refractory to at least one line of systemic chemotherapy are eligible. The primary end point is the objective response rate (ORR) at 4 months. Patients will receive atezolizumab every 3 weeks at a fixed dose of 1,200 mg in combination with the UCPVax vaccine at 1 mg subcutaneously.

Discussion: Anti-cancer vaccines can restore cancer-immunity via the expansion and activation of tumor-specific T cells in patients lacking pre-existing anti-tumor responses. Moreover, preclinical data showed that specific T_H1 CD4 T cells sustain the quality and homing of an antigen-specific CD8⁺ T-cell immunity. In previous clinical studies, the induction of anti-hTERT immunity was significantly correlated to survival in patients with advanced squamous anal cell carcinoma. Thus, there is a strong rational to combine an anti-cancer hTERT vaccine and an immune checkpoint inhibitor to activate and promote antitumor T-cell immunity. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a telomerase-based T_H1 inducing vaccine (UCPVax) and an anti-PD-L1 (atezolizumab) immunotherapy in HPV⁺ cancers, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials.

Clinical trial registration: https://www.clinicaltrials.gov/, identifier NCT03946358.

Keywords: HPV-related cancer; anal carcinoma; atezolizumab; cervix; head and neck; immunotherapy; vaccine.

Figure 1

Injection sites of each peptide. The two UCPVax peptides, UCP2 and UCP4 at 1 mg/ml (combined with Montanide ISA51 as adjuvant), will be injected subcutaneously in two separate sites (one site per peptide) at days 1, 8, 15, 29, 36, and 43 (priming phase) following by boost vaccinations: every 6 weeks for the two first boosts (W13 and W19) and every 9 weeks afterward (W28, W37, and W46).

Figure 2

Therapeutic sequences. Part 1 Induction phase: Atezolizumab (1,200 mg IV) will be administrated every 3 weeks starting at day 1. UCPVax will be injected subcutaneously at weeks 1, 2, 3, 5, 6, and 7. The two peptides included (UCP2 and UCP4) in UCPVax will be injected subcutaneously in separate sites (one site per peptide) after emulsion in the adjuvant (Montanide ISA-51 VG). Part 2: Boost phase of UCPVax+. Atezolizumab: Atezolizumab will be administered at the standard dose of 1,200 mg IV every 3 weeks. UCPVax boosts vaccine will be performed every 6 weeks for the two first boosts (W13 and W19) and then every 9 weeks thereafter (W28, W37, and W46). Part 3: Atezolizumab in monotherapy will be administrated every 3 weeks until disease progression or unacceptable toxicities for a maximum of 1 year since the last vaccine.