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; Toni K Choueiri

doi:10.1038/s41586-024-08507-5

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 GreensladeKeerthi 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, Toni K Choueiri^*

^*Corresponding author af dette arbejde

Afdeling for Genomisk Medicin DIA

87 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature
Vol/bind	639
Udgave nummer	8054
Sider (fra-til)	474-482
Antal sider	9
ISSN	0028-0836
DOI	https://doi.org/10.1038/s41586-024-08507-5
Status	Udgivet - mar. 2025

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10.1038/s41586-024-08507-5Licens: CC BY-NC-ND

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Braun, D. A., Moranzoni, G., Chea, V., McGregor, B. A., Blass, E., Tu, C. R., Vanasse, A. P., Forman, C., Forman, J., Afeyan, A. B., Schindler, N. R., Liu, Y., Li, S., Southard, J., Chang, S. L., Hirsch, M. S., LeBoeuf, N. R., Olive, O., Mehndiratta, A., ... Choueiri, T. K. (2025). A neoantigen vaccine generates antitumour immunity in renal cell carcinoma. Nature, 639(8054), 474-482. https://doi.org/10.1038/s41586-024-08507-5

Braun, DA, Moranzoni, G, Chea, V, McGregor, BA, Blass, E, Tu, CR, Vanasse, AP, Forman, C, Forman, J, Afeyan, AB, Schindler, NR, Liu, Y, Li, S, Southard, J, Chang, SL, Hirsch, MS, LeBoeuf, NR, Olive, O, Mehndiratta, A, Greenslade, H, Shetty, K, Klaeger, S, Sarkizova, S, Pedersen, CB, Mossanen, M, Carulli, I, Tarren, A, Duke-Cohan, J, Howard, AA, Iorgulescu, JB, Shim, B, Simon, JM, Signoretti, S, Aster, JC, Elagina, L, Carr, SA, Leshchiner, I, Getz, G, Gabriel, S, Hacohen, N, Olsen, LR, Oliveira, G, Neuberg, DS, Livak, KJ, Shukla, SA, Fritsch, EF, Wu, CJ, Keskin, DB, Ott, PA & Choueiri, TK 2025, 'A neoantigen vaccine generates antitumour immunity in renal cell carcinoma', Nature, bind 639, nr. 8054, s. 474-482. https://doi.org/10.1038/s41586-024-08507-5

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title = "A neoantigen vaccine generates antitumour immunity in renal cell carcinoma",

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.",

keywords = "Adult, Aged, Antigens, Neoplasm/immunology, Cancer Vaccines/immunology, Carcinoma, Renal Cell/immunology, Class I Phosphatidylinositol 3-Kinases/genetics, DNA-Binding Proteins, Female, Humans, Ipilimumab/therapeutic use, Kidney Neoplasms/immunology, Male, Middle Aged, Mutation, Precision Medicine, T-Lymphocytes/immunology, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin Thiolesterase/genetics, Von Hippel-Lindau Tumor Suppressor Protein",

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

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doi = "10.1038/s41586-024-08507-5",

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T1 - A neoantigen vaccine generates antitumour immunity in renal cell carcinoma

AU - Braun, David A

AU - Moranzoni, Giorgia

AU - Chea, Vipheaviny

AU - McGregor, Bradley A

AU - Blass, Eryn

AU - Tu, Chloe R

AU - Vanasse, Allison P

AU - Forman, Cleo

AU - Forman, Juliet

AU - Afeyan, Alexander B

AU - Schindler, Nicholas R

AU - Liu, Yiwen

AU - Li, Shuqiang

AU - Southard, Jackson

AU - Chang, Steven L

AU - Hirsch, Michelle S

AU - LeBoeuf, Nicole R

AU - Olive, Oriol

AU - Mehndiratta, Ambica

AU - Greenslade, Haley

AU - Shetty, Keerthi

AU - Klaeger, Susan

AU - Sarkizova, Siranush

AU - Pedersen, Christina B

AU - Mossanen, Matthew

AU - Carulli, Isabel

AU - Tarren, Anna

AU - Duke-Cohan, Joseph

AU - Howard, Alexis A

AU - Iorgulescu, J Bryan

AU - Shim, Bohoon

AU - Simon, Jeremy M

AU - Signoretti, Sabina

AU - Aster, Jon C

AU - Elagina, Liudmila

AU - Carr, Steven A

AU - Leshchiner, Ignaty

AU - Getz, Gad

AU - Gabriel, Stacey

AU - Hacohen, Nir

AU - Olsen, Lars R

AU - Oliveira, Giacomo

AU - Neuberg, Donna S

AU - Livak, Kenneth J

AU - Shukla, Sachet A

AU - Fritsch, Edward F

AU - Wu, Catherine J

AU - Keskin, Derin B

AU - Ott, Patrick A

AU - Choueiri, Toni K

PY - 2025/3

Y1 - 2025/3

N2 - 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.

AB - 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.

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KW - Aged

KW - Antigens, Neoplasm/immunology

KW - Cancer Vaccines/immunology

KW - Carcinoma, Renal Cell/immunology

KW - Class I Phosphatidylinositol 3-Kinases/genetics

KW - DNA-Binding Proteins

KW - Female

KW - Humans

KW - Ipilimumab/therapeutic use

KW - Kidney Neoplasms/immunology

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KW - Middle Aged

KW - Mutation

KW - Precision Medicine

KW - T-Lymphocytes/immunology

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KW - Ubiquitin Thiolesterase/genetics

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DO - 10.1038/s41586-024-08507-5

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A neoantigen vaccine generates antitumour immunity in renal cell carcinoma

Abstract

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