近日，美国丹娜-法伯癌症研究所Toni K. Choueiri等研究人员合作发现，一种新抗原疫苗在肾细胞癌中产生抗肿瘤免疫。相关论文于2025年2月5日在线发表于国际学术期刊《自然》。

研究人员开展了一项I期临床试验（ClinicalTrials.gov标识符NCT02950766），测试一种针对新抗原的个性化癌症疫苗（PCV）在高风险、完全切除的透明细胞肾细胞癌（RCC；III或IV期）患者中的效果，部分患者在疫苗接种后接受了ipilimumab治疗。

经过手术后的中位随访40.2个月，9名参与者中没有人发生RCC复发。未观察到剂量限制性毒性。所有患者均对PCV抗原产生了T细胞免疫反应，包括对RCC驱动突变（VHL、PBRM1、BAP1、KDM5C和PIK3CA）的反应。接种疫苗后，外周T细胞克隆出现持久扩展。

此外，在9名患者中有7名检测到了针对自体肿瘤的T细胞反应。这些结果表明，针对新抗原的PCV在高风险RCC患者中具有高度免疫原性，能够靶向关键的驱动突变，并能诱导抗肿瘤免疫。这些观察结果，再加上所有9名接种疫苗的患者未出现复发，突显了PCV作为RCC有效辅助治疗的前景。

据悉，PCV可以产生针对预测新抗原的循环免疫反应。然而，这些反应是否能够靶向癌症驱动突变，导致免疫系统识别患者的肿瘤并产生临床效果，目前尚不清楚。对于那些突变负担较低的肿瘤患者，这些问题尤为重要。

附：英文原文

Title: A neoantigen vaccine generates antitumour immunity in renal cell carcinoma

Author: Braun, David A., Moranzoni, Giorgia, Chea, Vipheaviny, McGregor, Bradley A., Blass, Eryn, Tu, Chloe R., Vanasse, Allison P., Forman, Cleo, Forman, Juliet, Afeyan, Alexander B., Schindler, Nicholas R., Liu, Yiwen, Li, Shuqiang, Southard, Jackson, Chang, Steven L., Hirsch, Michelle S., LeBoeuf, Nicole R., Olive, Oriol, Mehndiratta, Ambica, Greenslade, Haley, Shetty, Keerthi, Klaeger, Susan, Sarkizova, Siranush, Pedersen, Christina B., Mossanen, Matthew, Carulli, Isabel, Tarren, Anna, Duke-Cohan, Joseph, Howard, Alexis A., Iorgulescu, J. Bryan, Shim, Bohoon, Simon, Jeremy M., Signoretti, Sabina, Aster, Jon C., Elagina, Liudmila, Carr, Steven A., Leshchiner, Ignaty, Getz, Gad, Gabriel, Stacey, Hacohen, Nir, Olsen, Lars R., Oliveira, Giacomo, Neuberg, Donna S., Livak, Kenneth J., Shukla, Sachet A., Fritsch, Edward F., Wu, Catherine J., Keskin, Derin B., Ott, Patrick A., Choueiri, Toni K.

Issue&Volume: 2025-02-05

Abstract: Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens1,2,3,4,5,6. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient’s tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden. Here we conducted a phaseI trial (ClinicalTrials.gov identifier NCT02950766) to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stageIII or IV) with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2months after surgery, none of the 9 participants enrolled in the study had a recurrence of RCC. No dose-limiting toxicities were observed. All patients generated Tcell immune responses against the PCV antigens, including to RCC driver mutations in VHL, PBRM1, BAP1, KDM5C and PIK3CA. Following vaccination, there was a durable expansion of peripheral Tcell clones. Moreover, Tcell reactivity against autologous tumours was detected in seven out of nine patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations and can induce antitumour immunity. These observations, in conjunction with the absence of recurrence in all nine vaccinated patients, highlights the promise of PCVs as effective adjuvant therapy in RCC.

DOI: 10.1038/s41586-024-08507-5

Source: https://www.nature.com/articles/s41586-024-08507-5