Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer

Nofar Gumpert; Shira Sagie; Claudia Arnedo-Pac; Tomer Babu; Chen Weller; Abel Gonzalez-Perez; Yuan Wang; Lucas Michel Todó; Ronen Levy; Xi Chen; Polina Greenberg; Maria Dayan-Rubinov; Elizabeta Yakubovich; Talya Wasserman-Bartov; Mirie Zerbib; Jianhui Gong; Ryan J. Rebernick; Anna Oliveira Tercero; Laura Agundez Muriel; Gil Benedek; Merav Kedmi; Roni Oren; Shifra Ben-Dor; Yishai Levin; Olga G. Troyanskaya; Aslı D. Munzur; Alexander W. Wyatt; Marcin P. Cieslik; David A. Quigley; Eliezer M. Van Allen; Niroshana Anandasabapathy; Joaquin Mateo; Xinbo Yang; Francisco Martínez-Jiménez; Nuria Lopez-Bigas; Yardena Samuels

doi:10.1158/2159-8290.cd-24-1213

Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer

Nofar Gumpert
, Shira Sagie
, Claudia Arnedo-Pac
, Tomer Babu
, Chen Weller
, Abel Gonzalez-Perez
, Yuan Wang
, Lucas Michel Todó
, Ronen Levy
, Xi Chen
, Polina Greenberg
, Maria Dayan-Rubinov
, Elizabeta Yakubovich
, Talya Wasserman-Bartov
, Mirie Zerbib
, Jianhui Gong
, Ryan J. Rebernick
, Anna Oliveira Tercero
, Laura Agundez Muriel
, Gil Benedek

Merav Kedmi, Roni Oren, Shifra Ben-Dor, Yishai Levin, Olga G. Troyanskaya, Aslı D. Munzur, Alexander W. Wyatt, Marcin P. Cieslik, David A. Quigley, Eliezer M. Van Allen, Niroshana Anandasabapathy, Joaquin Mateo, Xinbo Yang, Francisco Martínez-Jiménez, Nuria Lopez-Bigas, Yardena Samuels^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

New approaches that generate long-lasting therapeutic responses in patients with therapy-resistant metastatic cancer are urgently needed. To address this challenge, we developed Spot Neoantigens in Metastases (SpotNeoMet), a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven therapy resistance mutations predicted to produce neopeptides presented by common HLAs. Using HLA immunopeptidomics, we discovered three novel neopeptides derived from androgen receptor (AR) H875Y, a common metastatic castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic and then isolated and characterized cognate T-cell receptors (TCR) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y-specific TCRs are highly specific and kill prostate cancer cells presenting AR neopeptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for patients with mCRPC. Moreover, SpotNeoMet offers a systematic route to identify "HLA-peptide" pairs and their cognate TCRs across treatment-resistant cancers.Significance: As the emergence of resistance to targeted treatments in patients with metastatic cancer, there is an urgent need for innovative therapeutic approaches for this population. Our study provides a new analytic framework to identify neoantigens from treatment-resistant mutations and a proof-of-concept T cell-based immunotherapy treatment for mCRPC.

Original language	English
Pages (from-to)	OF1-OF20
Number of pages	20
Journal	Cancer Discovery
Volume	16
Issue number	2
Early online date	10 Dec 2025
DOIs	https://doi.org/10.1158/2159-8290.cd-24-1213
Publication status	Published - 6 Feb 2026

Funding

Y. Samuels is supported by the Israel Science Foundation grant no. 2133/23, the European Research Council under the European Union’s Horizon 2020 research and innovation program (European Research Council, grant agreement no. 101094980), Israel Cancer Research Fund (award number: 20–802-ICG ), Melanoma Research Alliance (917324), Weizmann–Garvan Collaborative Program (149249), Alisa and Peter Savitz Foundation, Les and Cyndy Lederer, Brenda Gruss and Daniel Hirsch, The Moross Integrated Cancer Center, Donald Gordon Foundation, Sigmund and Sofie Englander Foundation, Dwek Institute for Cancer Therapy Research, Estate of Gerald Alexander, Estate of Jackson Toby, Estate of Gertrude Buchler, and Laboratory in the name of the M.E.H Fund established by Margot and Ernst Hamburger. Y. Samuels is the incumbent of the Knell Family Professorial Chair and is the head of the Moross Integrated Cancer Center. S. Sagie was supported by the Sheba Talpiot Medical Leadership Program, Israel and also by The Israel Science Foundation within the Postdoctoral Grants for Physician-Scientists Track of the MAVRI program (grant no. 2569/24). We gratefully acknowledge Prof. Michael Elkin for generously providing LNCaP cells used in this study. We acknowledge the use of data from The Cancer Genome Atlas and the Hartwig Medical Foundation in this study. The results published here are in part based on data generated by the TCGA Research Network: https://www.cancer.gov/tcga. We thank the TCGA program and its contributors for making this valuable resource publicly available. We also thank the Hartwig Medical Foundation for providing access to the genomic and clinical data, which significantly contributed to our research.

All Science Journal Classification (ASJC) codes

Oncology

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10.1158/2159-8290.cd-24-1213Licence: CC BY-NC-ND

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Gumpert, N., Sagie, S., Arnedo-Pac, C., Babu, T., Weller, C., Gonzalez-Perez, A., Wang, Y., Todó, L. M., Levy, R., Chen, X., Greenberg, P., Dayan-Rubinov, M., Yakubovich, E., Wasserman-Bartov, T., Zerbib, M., Gong, J., Rebernick, R. J., Tercero, A. O., Muriel, L. A., ... Samuels, Y. (2026). Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer. Cancer Discovery, 16(2), OF1-OF20. https://doi.org/10.1158/2159-8290.cd-24-1213

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title = "Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer",

abstract = "New approaches that generate long-lasting therapeutic responses in patients with therapy-resistant metastatic cancer are urgently needed. To address this challenge, we developed Spot Neoantigens in Metastases (SpotNeoMet), a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven therapy resistance mutations predicted to produce neopeptides presented by common HLAs. Using HLA immunopeptidomics, we discovered three novel neopeptides derived from androgen receptor (AR) H875Y, a common metastatic castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic and then isolated and characterized cognate T-cell receptors (TCR) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y-specific TCRs are highly specific and kill prostate cancer cells presenting AR neopeptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for patients with mCRPC. Moreover, SpotNeoMet offers a systematic route to identify {"}HLA-peptide{"} pairs and their cognate TCRs across treatment-resistant cancers.Significance: As the emergence of resistance to targeted treatments in patients with metastatic cancer, there is an urgent need for innovative therapeutic approaches for this population. Our study provides a new analytic framework to identify neoantigens from treatment-resistant mutations and a proof-of-concept T cell-based immunotherapy treatment for mCRPC.",

author = "Nofar Gumpert and Shira Sagie and Claudia Arnedo-Pac and Tomer Babu and Chen Weller and Abel Gonzalez-Perez and Yuan Wang and Tod{\'o}, \{Lucas Michel\} and Ronen Levy and Xi Chen and Polina Greenberg and Maria Dayan-Rubinov and Elizabeta Yakubovich and Talya Wasserman-Bartov and Mirie Zerbib and Jianhui Gong and Rebernick, \{Ryan J.\} and Tercero, \{Anna Oliveira\} and Muriel, \{Laura Agundez\} and Gil Benedek and Merav Kedmi and Roni Oren and Shifra Ben-Dor and Yishai Levin and Troyanskaya, \{Olga G.\} and Munzur, \{Aslı D.\} and Wyatt, \{Alexander W.\} and Cieslik, \{Marcin P.\} and Quigley, \{David A.\} and \{Van Allen\}, \{Eliezer M.\} and Niroshana Anandasabapathy and Joaquin Mateo and Xinbo Yang and Francisco Mart{\'i}nez-Jim{\'e}nez and Nuria Lopez-Bigas and Yardena Samuels",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors.",

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doi = "10.1158/2159-8290.cd-24-1213",

language = "English",

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Gumpert, N , Sagie, S, Arnedo-Pac, C, Babu, T, Weller, C, Gonzalez-Perez, A, Wang, Y, Todó, LM, Levy, R, Chen, X, Greenberg, P, Dayan-Rubinov, M, Yakubovich, E, Wasserman-Bartov, T, Zerbib, M, Gong, J, Rebernick, RJ, Tercero, AO, Muriel, LA, Benedek, G, Kedmi, M, Oren, R , Ben-Dor, S , Levin, Y, Troyanskaya, OG, Munzur, AD, Wyatt, AW, Cieslik, MP, Quigley, DA, Van Allen, EM, Anandasabapathy, N, Mateo, J, Yang, X, Martínez-Jiménez, F, Lopez-Bigas, N & Samuels, Y 2026, 'Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer', Cancer Discovery, vol. 16, no. 2, pp. OF1-OF20. https://doi.org/10.1158/2159-8290.cd-24-1213

TY - JOUR

T1 - Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer

AU - Gumpert, Nofar

AU - Sagie, Shira

AU - Arnedo-Pac, Claudia

AU - Babu, Tomer

AU - Weller, Chen

AU - Gonzalez-Perez, Abel

AU - Wang, Yuan

AU - Todó, Lucas Michel

AU - Levy, Ronen

AU - Chen, Xi

AU - Greenberg, Polina

AU - Dayan-Rubinov, Maria

AU - Yakubovich, Elizabeta

AU - Wasserman-Bartov, Talya

AU - Zerbib, Mirie

AU - Gong, Jianhui

AU - Rebernick, Ryan J.

AU - Tercero, Anna Oliveira

AU - Muriel, Laura Agundez

AU - Benedek, Gil

AU - Kedmi, Merav

AU - Oren, Roni

AU - Ben-Dor, Shifra

AU - Levin, Yishai

AU - Troyanskaya, Olga G.

AU - Munzur, Aslı D.

AU - Wyatt, Alexander W.

AU - Cieslik, Marcin P.

AU - Quigley, David A.

AU - Van Allen, Eliezer M.

AU - Anandasabapathy, Niroshana

AU - Mateo, Joaquin

AU - Yang, Xinbo

AU - Martínez-Jiménez, Francisco

AU - Lopez-Bigas, Nuria

AU - Samuels, Yardena

PY - 2026/2/6

Y1 - 2026/2/6

N2 - New approaches that generate long-lasting therapeutic responses in patients with therapy-resistant metastatic cancer are urgently needed. To address this challenge, we developed Spot Neoantigens in Metastases (SpotNeoMet), a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven therapy resistance mutations predicted to produce neopeptides presented by common HLAs. Using HLA immunopeptidomics, we discovered three novel neopeptides derived from androgen receptor (AR) H875Y, a common metastatic castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic and then isolated and characterized cognate T-cell receptors (TCR) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y-specific TCRs are highly specific and kill prostate cancer cells presenting AR neopeptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for patients with mCRPC. Moreover, SpotNeoMet offers a systematic route to identify "HLA-peptide" pairs and their cognate TCRs across treatment-resistant cancers.Significance: As the emergence of resistance to targeted treatments in patients with metastatic cancer, there is an urgent need for innovative therapeutic approaches for this population. Our study provides a new analytic framework to identify neoantigens from treatment-resistant mutations and a proof-of-concept T cell-based immunotherapy treatment for mCRPC.

AB - New approaches that generate long-lasting therapeutic responses in patients with therapy-resistant metastatic cancer are urgently needed. To address this challenge, we developed Spot Neoantigens in Metastases (SpotNeoMet), a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven therapy resistance mutations predicted to produce neopeptides presented by common HLAs. Using HLA immunopeptidomics, we discovered three novel neopeptides derived from androgen receptor (AR) H875Y, a common metastatic castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic and then isolated and characterized cognate T-cell receptors (TCR) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y-specific TCRs are highly specific and kill prostate cancer cells presenting AR neopeptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for patients with mCRPC. Moreover, SpotNeoMet offers a systematic route to identify "HLA-peptide" pairs and their cognate TCRs across treatment-resistant cancers.Significance: As the emergence of resistance to targeted treatments in patients with metastatic cancer, there is an urgent need for innovative therapeutic approaches for this population. Our study provides a new analytic framework to identify neoantigens from treatment-resistant mutations and a proof-of-concept T cell-based immunotherapy treatment for mCRPC.

UR - https://www.scopus.com/pages/publications/105029624061

U2 - 10.1158/2159-8290.cd-24-1213

DO - 10.1158/2159-8290.cd-24-1213

M3 - Article

C2 - 41056506

SN - 2159-8274

VL - 16

SP - OF1-OF20

JO - Cancer Discovery

JF - Cancer Discovery

IS - 2

ER -

Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer

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