Characterization of an immunogenic mutation in a patient with metastatic triple-negative breast cancer

Yasmine Assadipour, Nikolaos Zacharakis, Jessica S. Crystal, Todd D. Prickett, Jared J. Gartner, Robert P.T. Somerville, Hui Xu, Mary A. Black, Li Jia, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John R. Wunderlich, Zhili Zheng, Yong Chen Lu, Paul F. Robbins, Steven A. Rosenberg, Stephanie L. Goff, Steven A. Feldman

Research output: Contribution to journalArticle

Abstract

Purpose: The administration of autologous tumor-infiltrating lymphocytes (TILs) can mediate durable tumor regressions in patients with melanoma likely based on the recognition of immunogenic somatic mutations expressed by the cancer. There are limited data regarding the immunogenicity of mutations in breast cancer. We sought to identify immunogenic nonsynonymous mutations in a patient with triple-negative breast cancer (TNBC) to identify and isolate mutation-reactive TILs for possible use in adoptive cell transfer. Experimental Design: A TNBC metastasis was resected for TIL generation and whole-exome sequencing. Tandem minigenes or long 25-mer peptides encoding selected mutations were electroporated or pulsed onto autologous antigen-presenting cells, and reactivity of TIL was screened by upregulation of CD137 and IFNγ ELISPOT. The nature of the T-cell response against a unique nonsynonymous mutation was characterized. Results: We identified 72 nonsynonymous mutations from the tumor of a patient with TNBC. CD4+ and HLA-DRB1* 1501–restricted TILs isolated from this tumor recognized a single mutation in RBPJ (recombination signal binding protein for immunoglobulin kappa J region). Analysis of 16 metastatic sites revealed that the mutation was ubiquitously present in all samples. Conclusions: Breast cancers can express naturally processed and presented unique nonsynonymous mutations that are recognized by a patient's immune system. TILs recognizing these immunogenic mutations can be isolated from a patient's tumor, suggesting that adoptive cell transfer of mutation-reactive TILs could be a viable treatment option for patients with breast cancer.

Original languageEnglish (US)
Pages (from-to)4347-4353
Number of pages7
JournalClinical Cancer Research
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

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Triple Negative Breast Neoplasms
Tumor-Infiltrating Lymphocytes
Mutation
Adoptive Transfer
Neoplasms
Breast Neoplasms
Exome
Enzyme-Linked Immunospot Assay
HLA-DRB1 Chains
Autoantigens
Antigen-Presenting Cells
Genetic Recombination
Immunoglobulins
Immune System
Melanoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Assadipour, Y., Zacharakis, N., Crystal, J. S., Prickett, T. D., Gartner, J. J., Somerville, R. P. T., ... Feldman, S. A. (2017). Characterization of an immunogenic mutation in a patient with metastatic triple-negative breast cancer. Clinical Cancer Research, 23(15), 4347-4353. https://doi.org/10.1158/1078-0432.CCR-16-1423

Characterization of an immunogenic mutation in a patient with metastatic triple-negative breast cancer. / Assadipour, Yasmine; Zacharakis, Nikolaos; Crystal, Jessica S.; Prickett, Todd D.; Gartner, Jared J.; Somerville, Robert P.T.; Xu, Hui; Black, Mary A.; Jia, Li; Chinnasamy, Harshini; Kriley, Isaac; Lu, Lily; Wunderlich, John R.; Zheng, Zhili; Lu, Yong Chen; Robbins, Paul F.; Rosenberg, Steven A.; Goff, Stephanie L.; Feldman, Steven A.

In: Clinical Cancer Research, Vol. 23, No. 15, 01.08.2017, p. 4347-4353.

Research output: Contribution to journalArticle

Assadipour, Y, Zacharakis, N, Crystal, JS, Prickett, TD, Gartner, JJ, Somerville, RPT, Xu, H, Black, MA, Jia, L, Chinnasamy, H, Kriley, I, Lu, L, Wunderlich, JR, Zheng, Z, Lu, YC, Robbins, PF, Rosenberg, SA, Goff, SL & Feldman, SA 2017, 'Characterization of an immunogenic mutation in a patient with metastatic triple-negative breast cancer', Clinical Cancer Research, vol. 23, no. 15, pp. 4347-4353. https://doi.org/10.1158/1078-0432.CCR-16-1423
Assadipour Y, Zacharakis N, Crystal JS, Prickett TD, Gartner JJ, Somerville RPT et al. Characterization of an immunogenic mutation in a patient with metastatic triple-negative breast cancer. Clinical Cancer Research. 2017 Aug 1;23(15):4347-4353. https://doi.org/10.1158/1078-0432.CCR-16-1423
Assadipour, Yasmine ; Zacharakis, Nikolaos ; Crystal, Jessica S. ; Prickett, Todd D. ; Gartner, Jared J. ; Somerville, Robert P.T. ; Xu, Hui ; Black, Mary A. ; Jia, Li ; Chinnasamy, Harshini ; Kriley, Isaac ; Lu, Lily ; Wunderlich, John R. ; Zheng, Zhili ; Lu, Yong Chen ; Robbins, Paul F. ; Rosenberg, Steven A. ; Goff, Stephanie L. ; Feldman, Steven A. / Characterization of an immunogenic mutation in a patient with metastatic triple-negative breast cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 15. pp. 4347-4353.
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abstract = "Purpose: The administration of autologous tumor-infiltrating lymphocytes (TILs) can mediate durable tumor regressions in patients with melanoma likely based on the recognition of immunogenic somatic mutations expressed by the cancer. There are limited data regarding the immunogenicity of mutations in breast cancer. We sought to identify immunogenic nonsynonymous mutations in a patient with triple-negative breast cancer (TNBC) to identify and isolate mutation-reactive TILs for possible use in adoptive cell transfer. Experimental Design: A TNBC metastasis was resected for TIL generation and whole-exome sequencing. Tandem minigenes or long 25-mer peptides encoding selected mutations were electroporated or pulsed onto autologous antigen-presenting cells, and reactivity of TIL was screened by upregulation of CD137 and IFNγ ELISPOT. The nature of the T-cell response against a unique nonsynonymous mutation was characterized. Results: We identified 72 nonsynonymous mutations from the tumor of a patient with TNBC. CD4+ and HLA-DRB1* 1501–restricted TILs isolated from this tumor recognized a single mutation in RBPJ (recombination signal binding protein for immunoglobulin kappa J region). Analysis of 16 metastatic sites revealed that the mutation was ubiquitously present in all samples. Conclusions: Breast cancers can express naturally processed and presented unique nonsynonymous mutations that are recognized by a patient's immune system. TILs recognizing these immunogenic mutations can be isolated from a patient's tumor, suggesting that adoptive cell transfer of mutation-reactive TILs could be a viable treatment option for patients with breast cancer.",
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T1 - Characterization of an immunogenic mutation in a patient with metastatic triple-negative breast cancer

AU - Assadipour, Yasmine

AU - Zacharakis, Nikolaos

AU - Crystal, Jessica S.

AU - Prickett, Todd D.

AU - Gartner, Jared J.

AU - Somerville, Robert P.T.

AU - Xu, Hui

AU - Black, Mary A.

AU - Jia, Li

AU - Chinnasamy, Harshini

AU - Kriley, Isaac

AU - Lu, Lily

AU - Wunderlich, John R.

AU - Zheng, Zhili

AU - Lu, Yong Chen

AU - Robbins, Paul F.

AU - Rosenberg, Steven A.

AU - Goff, Stephanie L.

AU - Feldman, Steven A.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Purpose: The administration of autologous tumor-infiltrating lymphocytes (TILs) can mediate durable tumor regressions in patients with melanoma likely based on the recognition of immunogenic somatic mutations expressed by the cancer. There are limited data regarding the immunogenicity of mutations in breast cancer. We sought to identify immunogenic nonsynonymous mutations in a patient with triple-negative breast cancer (TNBC) to identify and isolate mutation-reactive TILs for possible use in adoptive cell transfer. Experimental Design: A TNBC metastasis was resected for TIL generation and whole-exome sequencing. Tandem minigenes or long 25-mer peptides encoding selected mutations were electroporated or pulsed onto autologous antigen-presenting cells, and reactivity of TIL was screened by upregulation of CD137 and IFNγ ELISPOT. The nature of the T-cell response against a unique nonsynonymous mutation was characterized. Results: We identified 72 nonsynonymous mutations from the tumor of a patient with TNBC. CD4+ and HLA-DRB1* 1501–restricted TILs isolated from this tumor recognized a single mutation in RBPJ (recombination signal binding protein for immunoglobulin kappa J region). Analysis of 16 metastatic sites revealed that the mutation was ubiquitously present in all samples. Conclusions: Breast cancers can express naturally processed and presented unique nonsynonymous mutations that are recognized by a patient's immune system. TILs recognizing these immunogenic mutations can be isolated from a patient's tumor, suggesting that adoptive cell transfer of mutation-reactive TILs could be a viable treatment option for patients with breast cancer.

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