Emmers Mitchell, Welters Marij J P, Dietz Michelle V, Santegoets Saskia J, Boekesteijn Sanne, Stolk Anouk, Loof Nikki M, Dumoulin Daphne W, Geel Annemarie L, Steinbusch Lauri C, Valentijn A Rob P M, Cohen Danielle, de Miranda Noel F C C, Smit Egbert F, Gelderblom Hans, van Hall Thorbald, Aerts Joachim G, van der Burg Sjoerd H
Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.
Nat Commun. 2025 May 28;16(1):4958. doi: 10.1038/s41467-025-60281-8.
Functional loss of the intracellular peptide Transporter associated with Antigen Processing (TAP) fosters resistance to T-cell based immunotherapy. We discovered the presentation of an alternative set of shared tumor antigens on such escaped cancers and developed a LRPAP1 synthetic long peptide vaccine (TEIPP24) to stimulate T-cell immunity. In this first-in-human multicenter dose-escalation study with extension cohort, HLA-A*0201-positive patients with non-small cell lung cancer progressive after checkpoint blockade were treated with TEIPP24 (NCT05898763). Dose escalation followed an adapted 3 + 3 scheme where in each cohort six patients received the TEIPP24 peptide emulsified in Montanide ISA-51 at either 20, 40, 100 µg of peptide, subcutaneously injected three times every three weeks in alternating limbs. The extension cohort of six patients received the highest safe dose of TEIPP24 combined with the PD-1 checkpoint blocker pembrolizumab. The primary objectives of the study were safety, tolerability and immunogenicity of the TEIPP24 vaccine. Secondary objectives included the evaluation of specificity and immune modulatory effects of the vaccine, antigen and immune status of the patients, progression free (PFS) and overall survival (OS) and radiological tumor response rate and duration. A total of 26 patients were enrolled across 2 institutions. Treatment was well tolerated, and vaccine-induced LRPAP1-specific CD8 T cells were detected in 20 of 24 evaluable patients (83%). In 13 of 21 tested cases (62%) vaccine-specific CD4 T cells were also detected. The increase in activated polyfunctional CD8 effector T cells was influenced by vaccine dose, number of vaccines administered, induction of a CD4 T-cell response, and the pre-existing frequency of monocytic cells. Co-administration of pembrolizumab resulted in the ex-vivo detection of activated (HLA-DR , PD-1 , ICOS ) LRPAP1-specific CD8 T cells. The observation of one PR, 8 stable diseases and 2 mixed responses in 24 evaluable patients after vaccination, correlated with a stronger vaccine-induced CD8 T-cell response to this single epitope from this new class of cancer antigens.
与抗原加工相关的细胞内肽转运体（TAP）的功能丧失促进了对基于T细胞的免疫疗法的抗性。我们发现了此类逃逸癌症上一组替代性共享肿瘤抗原的呈递，并开发了一种LRPAP1合成长肽疫苗（TEIPP24）来刺激T细胞免疫。在这项针对扩展队列的首例人体多中心剂量递增研究中，对经检查点阻断治疗后病情进展的HLA-A*0201阳性非小细胞肺癌患者使用TEIPP24进行治疗（NCT05898763）。剂量递增遵循改良的3+3方案，即每个队列中的6名患者接受在Montanide ISA-51中乳化的TEIPP24肽，肽剂量分别为20、40、100μg，每三周在交替的肢体皮下注射三次。6名患者的扩展队列接受了最高安全剂量的TEIPP24联合PD-1检查点阻断剂帕博利珠单抗。该研究的主要目标是TEIPP24疫苗的安全性、耐受性和免疫原性。次要目标包括评估疫苗的特异性和免疫调节作用、患者的抗原和免疫状态、无进展生存期（PFS）和总生存期（OS）以及放射学肿瘤反应率和持续时间。共有26名患者在2个机构入组。治疗耐受性良好，在24名可评估患者中的20名（83%）检测到疫苗诱导的LRPAP1特异性CD8 T细胞。在21例检测病例中的13例（62%）也检测到了疫苗特异性CD4 T细胞。活化的多功能CD8效应T细胞的增加受疫苗剂量、接种疫苗的次数、CD4 T细胞反应的诱导以及单核细胞的预先存在频率的影响。帕博利珠单抗的联合给药导致在体外检测到活化的（HLA-DR 、PD-1 、ICOS ）LRPAP1特异性CD8 T细胞。在接种疫苗后的24名可评估患者中观察到1例部分缓解、8例病情稳定和2例混合反应，这与疫苗诱导的针对这类新的癌症抗原中这个单一表位的更强CD8 T细胞反应相关。
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