Rebucci-Peixoto Magali, Vienot Angélique, Adotevi Olivier, Jacquin Marion, Ghiringhelli Francois, de la Fouchardière Christelle, You Benoit, Maurina Tristan, Kalbacher Elsa, Bazan Fernando, Meynard Guillaume, Clairet Anne-Laure, Fagnoni-Legat Christine, Spehner Laurie, Bouard Adeline, Vernerey Dewi, Meurisse Aurélia, Kim Stefano, Borg Christophe, Mansi Laura
Department of Oncology, Centre Hospitalier Universitaire, Besançon, France.
Clinical Investigational Center, CIC-1431, Centre Hospitalier Universitaire, Besançon, France.
Front Oncol. 2022 Jul 19;12:957580. doi: 10.3389/fonc.2022.957580. eCollection 2022.
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.
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.
Anti-cancer vaccines can restore cancer-immunity the expansion and activation of tumor-specific T cells in patients lacking pre-existing anti-tumor responses. Moreover, preclinical data showed that specific T1 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 T1 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.
https://www.clinicaltrials.gov/, identifier NCT03946358.
在人乳头瘤病毒（HPV）引发的癌症中，使用抗程序性细胞死亡蛋白1及其配体（抗PD-1/L1）抗体具有充分的合理性。然而，抗PD-1/L1作为单一疗法诱导的客观缓解数量有限。因此，开发新的联合疗法以提高抗PD-1/L1的临床疗效备受关注。在HPV阳性（+）癌症中，将抗PD-1/L1疗法与抗肿瘤疫苗联合使用似乎很有前景。UCPVax是一种治疗性癌症疫苗，由源自端粒酶（hTERT，人端粒酶逆转录酶）的两种不同肽组成。UCPVax正在一项针对非小细胞肺癌（NSCLC）的多中心I/II期研究中进行评估，已证明其具有安全性和免疫原性。VolATIL研究的目的是在一项针对HPV相关癌症患者的多中心II期研究中评估阿替利珠单抗（一种抗PD-L1）与UCPVax疫苗的联合应用。
患有HPV相关癌症（肛管、头颈部、宫颈或外阴）、处于局部晚期或转移阶段且对至少一线全身化疗耐药的患者符合条件。主要终点是4个月时的客观缓解率（ORR）。患者将每3周接受一次固定剂量1200mg的阿替利珠单抗，同时皮下注射1mg的UCPVax疫苗。
抗癌疫苗可以恢复癌症免疫——在缺乏预先存在的抗肿瘤反应的患者中，促进肿瘤特异性T细胞的扩增和激活。此外，临床前数据表明，特定的T1 CD4 T细胞维持抗原特异性CD8 T细胞免疫的质量和归巢。在先前的临床研究中，抗hTERT免疫的诱导与晚期鳞状肛管癌患者的生存显著相关。因此，将抗癌hTERT疫苗与免疫检查点抑制剂联合使用以激活和促进抗肿瘤T细胞免疫具有充分的合理性。这项关键的概念验证研究将评估基于端粒酶的T1诱导疫苗（UCPVax）与抗PD-L1（阿替利珠单抗）免疫疗法联合应用于HPV相关癌症的疗效和安全性，以及确认它们的协同机制，并为未来临床试验的新联合疗法奠定基础。
