A neoantigen vaccine generates antitumour immunity in renal cell carcinoma

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Yale University; Yale University; Yale New Haven Hospital; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Technical University of Denmark; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Copenhagen; Copenhagen University Hospital; Rigshospitalet; Harvard University; Harvard T.H. Chan School of Public Health; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Boston University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Boston University; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3439
• DOI: 10.1038/s41586-024-08507-5
• 发表日期: 2025-03-13
• 关键词: dendritic cells; adjuvant pembrolizumab; phase-iii; cancer; nephrectomy; RISK; multicenter; sunitinib; therapy; TRIAL

摘要

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 phase I trial (ClinicalTrials.gov identifier NCT02950766) to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV) with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 months 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 T cell 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 T cell clones. Moreover, T cell 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.