PMID- 34172517
OWN - NLM
STAT- MEDLINE
DCOM- 20220111
LR  - 20220111
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 9
IP  - 6
DP  - 2021 Jun
TI  - Identification and validation of expressed HLA-binding breast cancer neoepitopes 
      for potential use in individualized cancer therapy.
LID - 10.1136/jitc-2021-002605 [doi]
LID - e002605
AB  - BACKGROUND: Therapeutic regimens designed to augment the immunological response 
      of a patient with breast cancer (BC) to tumor tissue are critically informed by 
      tumor mutational burden and the antigenicity of expressed neoepitopes. Herein we 
      describe a neoepitope and cognate neoepitope-reactive T-cell identification and 
      validation program that supports the development of next-generation 
      immunotherapies. METHODS: Using GPS Cancer, NantOmics research, and The Cancer 
      Genome Atlas databases, we developed a novel bioinformatic-based approach which 
      assesses mutational load, neoepitope expression, human leukocyte antigen 
      (HLA)-binding prediction, and in vitro confirmation of T-cell recognition to 
      preferentially identify targetable neoepitopes. This program was validated by 
      application to a BC cell line and confirmed using tumor biopsies from two 
      patients with BC enrolled in the Tumor-Infiltrating Lymphocytes and Genomics 
      (TILGen) study. RESULTS: The antigenicity and HLA-A2 restriction of the BC cell 
      line predicted neoepitopes were determined by reactivity of T cells from 
      HLA-A2-expressing healthy donors. For the TILGen subjects, tumor-infiltrating 
      lymphocytes (TILs) recognized the predicted neoepitopes both as peptides and on 
      retroviral expression in HLA-matched Epstein-Barr virus-lymphoblastoid cell line 
      and BC cell line MCF-7 cells; PCR clonotyping revealed the presence of T cells in 
      the periphery with T-cell receptors for the predicted neoepitopes. These 
      high-avidity immune responses were polyclonal, mutation-specific and restricted 
      to either HLA class I or II. Interestingly, we observed the persistence and 
      expansion of polyclonal T-cell responses following neoadjuvant chemotherapy. 
      CONCLUSIONS: We demonstrate our neoepitope prediction program allows for the 
      successful identification of neoepitopes targeted by TILs in patients with BC, 
      providing a means to identify tumor-specific immunogenic targets for 
      individualized treatment, including vaccines or adoptively transferred cellular 
      therapies.
CI  - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Reimann, Hannah
AU  - Reimann H
AD  - Department of Internal Medicine 5, Hematology/Oncology, Friedrich-Alexander 
      University Erlangen-Nuremberg, Erlangen, Germany.
FAU - Nguyen, Andrew
AU  - Nguyen A
AD  - NantHealth, Inc, Santa Cruz, California, USA.
FAU - Sanborn, J Zachary
AU  - Sanborn JZ
AD  - NantHealth, Inc, Santa Cruz, California, USA.
FAU - Vaske, Charles J
AU  - Vaske CJ
AD  - ImmunityBio, Inc, Culver City, California, USA.
FAU - Benz, Stephen C
AU  - Benz SC
AD  - NantHealth, Inc, Santa Cruz, California, USA.
FAU - Niazi, Kayvan
AU  - Niazi K
AD  - ImmunityBio, Inc, Culver City, California, USA.
FAU - Rabizadeh, Shahrooz
AU  - Rabizadeh S
AD  - ImmunityBio, Inc, Culver City, California, USA.
FAU - Spilman, Patricia
AU  - Spilman P
AUID- ORCID: 0000-0003-2626-6475
AD  - ImmunityBio, Inc, Culver City, California, USA patricia.spilman@immunitybio.com.
FAU - Mackensen, Andreas
AU  - Mackensen A
AD  - Department of Internal Medicine 5, Hematology/Oncology, Friedrich-Alexander 
      University Erlangen-Nuremberg, Erlangen, Germany.
FAU - Ruebner, Matthias
AU  - Ruebner M
AD  - Department of Gynecology and Obstetrics, Friedrich Alexander University 
      Erlangen-Nuremberg, Erlangen, Germany.
FAU - Hein, Alexander
AU  - Hein A
AD  - Department of Gynecology and Obstetrics, Friedrich Alexander University 
      Erlangen-Nuremberg, Erlangen, Germany.
FAU - Beckmann, Matthias W
AU  - Beckmann MW
AD  - Department of Gynecology and Obstetrics, Friedrich Alexander University 
      Erlangen-Nuremberg, Erlangen, Germany.
FAU - van der Meijden, Edith D
AU  - van der Meijden ED
AD  - Department of Internal Medicine 5, Hematology/Oncology, Friedrich-Alexander 
      University Erlangen-Nuremberg, Erlangen, Germany.
FAU - Bausenwein, Judith
AU  - Bausenwein J
AD  - Department of Internal Medicine 5, Hematology/Oncology, Friedrich-Alexander 
      University Erlangen-Nuremberg, Erlangen, Germany.
FAU - Kretschmann, Sascha
AU  - Kretschmann S
AD  - Department of Internal Medicine 5, Hematology/Oncology, Friedrich-Alexander 
      University Erlangen-Nuremberg, Erlangen, Germany.
FAU - Griffioen, Marieke
AU  - Griffioen M
AD  - Department of Hematology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Schlom, Jeffrey
AU  - Schlom J
AD  - Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National 
      Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
FAU - Gulley, James L
AU  - Gulley JL
AUID- ORCID: 0000-0002-6569-2912
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, Maryland, USA.
FAU - Lee, Karin L
AU  - Lee KL
AD  - Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National 
      Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
FAU - Hamilton, Duane H
AU  - Hamilton DH
AD  - Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National 
      Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
FAU - Soon-Shiong, Patrick
AU  - Soon-Shiong P
AD  - ImmunityBio, Inc, Culver City, California, USA.
FAU - Fasching, Peter A
AU  - Fasching PA
AD  - Department of Gynecology and Obstetrics, Friedrich Alexander University 
      Erlangen-Nuremberg, Erlangen, Germany.
FAU - Kremer, Anita N
AU  - Kremer AN
AD  - Department of Internal Medicine 5, Hematology/Oncology, Friedrich-Alexander 
      University Erlangen-Nuremberg, Erlangen, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Histocompatibility Antigens Class I)
SB  - IM
MH  - Antigens, Neoplasm/*genetics
MH  - Breast Neoplasms/*genetics
MH  - Female
MH  - Histocompatibility Antigens Class I/*immunology
MH  - Humans
MH  - Immunotherapy/*methods
PMC - PMC8237736
OTO - NOTNLM
OT  - antigens
OT  - breast neoplasms
OT  - neoplasm
COIS- Competing interests: None declared.
EDAT- 2021/06/27 06:00
MHDA- 2022/01/12 06:00
PMCR- 2021/06/25
CRDT- 2021/06/26 05:41
PHST- 2021/05/10 00:00 [accepted]
PHST- 2021/06/26 05:41 [entrez]
PHST- 2021/06/27 06:00 [pubmed]
PHST- 2022/01/12 06:00 [medline]
PHST- 2021/06/25 00:00 [pmc-release]
AID - jitc-2021-002605 [pii]
AID - 10.1136/jitc-2021-002605 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2021 Jun;9(6):e002605. doi: 10.1136/jitc-2021-002605.