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Background: Several cancer immunotherapies that target the PD-L1/PD-1 pathway show promising clinical activity in patients with hepatocellular carcinoma (HCC). However, the standard of care in first-line treatment with atezolizumab (anti-PD-L1 therapy) in combination with bevacizumab is associated with a limited objective response rate. Telomerase reverse transcriptase (TERT) activation meets the criteria of oncogenic addiction in HCC and could be actionable therapeutic target and a relevant tumor antigen. Therefore we hypothesized that combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine might be an attractive therapy in HCC. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (human TERT). UCPVax has been evaluated in a multicenter phase I/II study in non-small cell lung cancers and has demonstrated to be safe and immunogenic, and is under evaluation in combination with atezolizumab in a phase II clinical trial in tumors where telomerase reactivation contributes to an oncogene addiction (HPV +  cancers). The aim of the TERTIO study is to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer anti-telomerase vaccine (UCPVax) with atezolizumab and bevacizumab in unresectable HCC in a multicenter randomized phase II study., Methods: Patients with locally advanced, metastatic or unresectable HCC who have not previously received systemic anti-cancer treatment are eligible. The primary end point is the objective response rate at 6 months. Patients will be allocated to a treatment arm with a randomization 2:1. In both arms, patients will receive atezolizumab at fixed dose of 1200 mg IV infusion and bevacizumab at fixed dose of 15 mg/kg IV infusion, every 3 weeks, according to the standard of care. In the experimental arm, these treatments will be combined with the UCPVax vaccine at 0.5 mg subcutaneously., Discussion: Combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine gains serious consideration in HCC, in order to extend the clinical efficacy of anti-PD-1/PD-L1. Indeed, anti-cancer vaccines can induce tumor-specific T cell expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. Thus, there is a strong rational to combine immune checkpoint blockade therapy and anticancer vaccine (UCPVax) in order to activate antitumor T cell immunity and bypass the immunosuppression in the tumor microenvironment in HCC. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a CD4 Th1-inducer cancer vaccine derived from telomerase (UCPVax) and atezolizumab plus bevacizumab in unresectable HCC, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials., Trial Registration: NCT05528952., (© 2023. The Author(s).)

Background: Chemoradiotherapy alone is the standard treatment for locally advanced squamous cell anal carcinoma (SCAC). However, up to 50% of patients will experience recurrence; thus, there is a need for new treatments to improve outcomes. Modified docetaxel, cisplatin and 5-fluorouracil (mDCF) is a treatment option for first-line metastatic SCAC, having shown efficacy in the Epitopes-HPV01 and -02 trials (NCT01845779 and NCT02402842). mDCF treatment also plays a role in the modulation of anti-tumor immunity, suggesting it may be a good combination partner for immunotherapy in patients with SCAC. Anti-programmed death protein-1 (PD-1) immunotherapy has been shown to be effective in metastatic SCAC. We therefore designed the INTERACT-ION study to assess the combination of mDCF with ezabenlimab (BI 754091), an anti-PD-1 antibody, followed by chemoradiotherapy, in patients with Stage III SCAC., Methods: INTERACT-ION is a pivotal, open-label, single-arm phase II study in patients with treatment-naïve Stage III SCAC. Patients will receive induction treatment with mDCF (docetaxel 40 mg/m 2 and cisplatin 40 mg/m 2 on Day 1, 5-fluorouracil 1200 mg/m 2 /day for 2 days) every 2 weeks for 4 cycles and ezabenlimab (240 mg given intravenously) every 3 weeks for 3 cycles. In the absence of disease progression at 2 months, two additional cycles of mDCF and one additional cycle of ezabenlimab will be administered. Patients with radiological objective response, pathological complete/near-complete response and biological complete response will then receive an involved-node radiotherapy with intensity-modulated radiation therapy and concurrent chemotherapy, followed by ezabenlimab alone for seven cycles. All other patients will receive standard chemoradiotherapy. The primary endpoint is the clinical complete response rate 10 months after the first cycle of mDCF plus ezabenlimab. Major secondary endpoints are major pathological response and biological complete response after induction treatment. An extensive ancillary biomarker study in tumor tissue and peripheral blood will also be conducted., Discussion: The addition of immunotherapy to chemotherapy is an area of active interest in metastatic anal cancer. This pivotal study will evaluate this combination in the locally advanced setting. Ancillary biomarker studies will contribute to the understanding of predictors of response or resistance to treatment., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04719988, identifier NCT04719988., Competing Interests: SK reports a consulting or advisory role for Ipsen, Incyte, Boehringer Ingelheim, Sanofi and BeiGene and has received research funding from Pfizer, Roche, Novartis, Bristol-Myers Squibb, Boehringer Ingelheim and Sanofi. LE reports honoraria from Servier, Merck, Pierre Fabre and Amgen and travel and accommodation expenses from Merck and Servier. EF reports a consulting or advisory role for Pierre Fabre; has received travel and accommodation expenses from Pierre Fabre and honoraria from Amgen, Novartis, Pierre Fabre, and Merck Sharp & Dohme. LQ reports research funding from AstraZeneca, and travel and accommodation expenses from Astellas and Ipsen. CF reports a consulting or advisory role for Amgen, Bristol-Myers Squibb, Eisai, Pierre Fabre Oncologie, Roche, Servier and Ipsen; and travel and accommodation expenses from Eisai and Amgen. LD reports honoraria from Amgen, Bristol-Myers Squibb, Servier, Oseus and Mylan. OB reports honoraria from Roche, Amgen, Merck Serono, Servier, Pierre Fabre, Bayer, Sanofi and Grünenthal. BC reports a consulting or advisory role for BeiGene, Roche, Sanofi and Servier; travel and accommodation expenses from Sanofi, Merck, Merck Sharp & Dohme and Roche; and honoraria from Pfizer, Roche, Sanofi, Servier and Bayer. AF and CM are employees of Boehringer Ingelheim. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Boehringer Ingelheim., (Copyright © 2022 Kim, Boustani, Vernerey, Vendrely, Evesque, Francois, Quero, Ghiringhelli, de la Fouchardière, Dahan, Bouché, Chibaudel, Hajbi, Vernet, Rebucci-Peixoto, Feuersinger, Maritaz and Borg.)

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 H 1 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 H 1 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., Competing Interests: CB: Research grant from Bayer and Roche, advisory board for Bayer, Sanofi, MSD. FB: Novartis, Seagen, Daiichi Sankyo, Pierre Fabre, Astra-Zeneca, Clovis. SK: reports a consulting or advisory role for Ipsen, Incyte, Boehringer Ingelheim, Sanofi and BeiGene and has received research funding from Pfizer, Roche, Novartis, Bristol-Myers Squibb, Boehringer Ingelheim and Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rebucci-Peixoto, Vienot, Adotevi, Jacquin, Ghiringhelli, de la Fouchardière, You, Maurina, Kalbacher, Bazan, Meynard, Clairet, Fagnoni-Legat, Spehner, Bouard, Vernerey, Meurisse, Kim, Borg and Mansi.)

Background: Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients., Methods: Patients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS) < 2 will be eligible. The primary endpoint is a 12-month PFS rate. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 80%, the upper critical value for the 12-month PFS rate is 47% to reject H0. Assuming 5% lost to follow-up, 99 patients will be randomized on a 2:1 basis, 66 to the experimental arm (arm A, mDCF plus atezolizumab) and 33 to the standard arm (arm B, mDCF). In both arms, 8 cycles of mDCF will be administered. In arm A, patients receive mDCF with a fixed dose of atezolizumab (800 mg every 2 weeks) and are followed up to 1 year. Secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and an extensive biomarker programme and its correlation with the treatment efficacy., Discussion: Although the Epitopes-HPV02 trial has changed long-lasting prognosis of patients with SCCA in advanced stage disease, more than 50% of patients will progress at 12 months. The purpose of the SCARCE trial to establish the addition of atezolizumab to mDCF as a new standard in this rare disease. Associated biomarker studies and the control arm could contribute to better understanding of the potential synergic and tumour resistance mechanisms in SCCA., Trial Registration: NCT03519295.