A neoantigen vaccine generates antitumour immunity in renal cell carcinoma

Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens<sup>1-6</sup>. 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.

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Publication Details

Journal
Nature
Published
2025-02-05
DOI
https://doi.org/10.1038/s41586-024-08507-5
Citations
129
Primary Topic
Cancer Genomics and Diagnostics
Type
article
Field-Weighted Citation Impact
119.84
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article

A neoantigen vaccine generates antitumour immunity in renal cell carcinoma

Shuqiang Li, Derin B. Keskin, Gad A. Getz, Jeremy M. Simon et al.
129 citations
Nature
Cancer Genomics and Diagnostics
119.84
article

A neoantigen vaccine generates antitumour immunity in renal cell carcinoma

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

Abstract

Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens<sup>1-6</sup>. 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.

NatureVol. 639(8054)
Broad Institute (US), Boston University (US), Brigham and Women's Hospital (US), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), Copenhagen University Hospital (DK), Yale Cancer Center (US), Yale University (US), Massachusetts General Hospital (US), Dana-Farber Cancer Institute (US), Dana-Farber Brigham Cancer Center (US), Technical University of Denmark (DK)
Good health and well-being
Openalex Percentile: Top 0%
Cancer Genomics and Diagnostics
119.84
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