A neoantigen vaccine generates antitumour immunity in renal cell carcinoma

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

Nature, 2025, vol. 639, issue 8054, 474-482

Abstract: Abstract Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens1–6. 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.

Date: 2025
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DOI: 10.1038/s41586-024-08507-5

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