Zareian Nahid, Eremin Oleg, Pandha Hardev, Baird Richard, Kwatra Vineet, Funingana Gabriel, Verma Chandan, Choy Desmond, Hargreaves Steven, Moghimi Pejvak, Shepherd Adrian, Lobo Dileep N, Eremin Jennifer, Farzaneh Farzin, Kordasti Shahram, Spicer James
School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre, Queen's Medical Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, United Kingdom.
Exp Biol Med (Maywood). 2024 Jan 31;249:10021. doi: 10.3389/ebm.2024.10021. eCollection 2024.
The presence of inhibitory immune cells and difficulty in generating activated effector T cells remain obstacles to development of effective cancer vaccines. We designed a vaccine regimen combining human telomerase reverse transcriptase (hTERT) peptides with concomitant therapies targeting regulatory T cells (Tregs) and cyclooxygenase-2 (COX2)-mediated immunosuppression. This Phase 1 trial combined an hTERT-derived 7-peptide library, selected to ensure presentation by both HLA class-I and class-II in 90% of patients, with oral low-dose cyclophosphamide (to modulate Tregs) and the COX2 inhibitor celecoxib. Adjuvants were Montanide and topical TLR-7 agonist, to optimise antigen presentation. The primary objective was determination of the safety and tolerability of this combination therapy, with anti-cancer activity, immune response and detection of antigen-specific T cells as additional endpoints. Twenty-nine patients with advanced solid tumours were treated. All were multiply-pretreated, and the majority had either colorectal or prostate cancer. The most common adverse events were injection-site reactions, fatigue and nausea. Median progression-free survival was 9 weeks, with no complete or partial responses, but 24% remained progression-free for ≥6 months. Immunophenotyping showed post-vaccination expansion of CD4 and CD8 T cells with effector phenotypes. The re-challenge of T cells with hTERT peptides, TCR sequencing, and TCR similarity index analysis demonstrated the expansion following vaccination of oligoclonal T cells with specificity for hTERT. However, a population of exhausted PD-1 cytotoxic T cells was also expanded in vaccinated patients. This vaccine combination regimen was safe and associated with antigen-specific immunological responses. Clinical activity could be improved in future by combination with anti-PD1 checkpoint inhibition to address the emergence of an exhausted T cell population.
抑制性免疫细胞的存在以及难以产生活化的效应T细胞仍然是有效癌症疫苗开发的障碍。我们设计了一种疫苗方案，将人端粒酶逆转录酶（hTERT）肽与针对调节性T细胞（Tregs）和环氧合酶-2（COX2）介导的免疫抑制的伴随疗法相结合。这项1期试验将一个hTERT衍生的7肽文库（选择该文库以确保在90%的患者中通过HLA I类和II类呈递）与口服低剂量环磷酰胺（用于调节Tregs）和COX2抑制剂塞来昔布相结合。佐剂为Montanide和局部TLR-7激动剂，以优化抗原呈递。主要目标是确定这种联合疗法的安全性和耐受性，将抗癌活性、免疫反应和抗原特异性T细胞的检测作为附加终点。29例晚期实体瘤患者接受了治疗。所有患者均经过多次预处理，大多数患有结直肠癌或前列腺癌。最常见的不良事件是注射部位反应、疲劳和恶心。无进展生存期的中位数为9周，没有完全或部分缓解，但24%的患者在≥6个月内无进展。免疫表型分析显示接种疫苗后具有效应表型的CD4和CD8 T细胞扩增。用hTERT肽对T细胞进行再刺激、TCR测序和TCR相似性指数分析表明，接种疫苗后对hTERT具有特异性的寡克隆T细胞扩增。然而，在接种疫苗的患者中，一群耗竭的PD-1细胞毒性T细胞也有所扩增。这种疫苗联合方案是安全的，并且与抗原特异性免疫反应相关。未来通过与抗PD1检查点抑制相结合以解决耗竭T细胞群体的出现，可能会改善临床活性。
