RT Journal Article
SR Electronic
T1 Identification and validation of expressed HLA-binding breast cancer neoepitopes for potential use in individualized cancer therapy
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e002605
DO 10.1136/jitc-2021-002605
VO 9
IS 6
A1 Hannah Reimann
A1 Andrew Nguyen
A1 J Zachary Sanborn
A1 Charles J Vaske
A1 Stephen C Benz
A1 Kayvan Niazi
A1 Shahrooz Rabizadeh
A1 Patricia Spilman
A1 Andreas Mackensen
A1 Matthias Ruebner
A1 Alexander Hein
A1 Matthias W Beckmann
A1 Edith D van der Meijden
A1 Judith Bausenwein
A1 Sascha Kretschmann
A1 Marieke Griffioen
A1 Jeffrey Schlom
A1 James L Gulley
A1 Karin L Lee
A1 Duane H Hamilton
A1 Patrick Soon-Shiong
A1 Peter A Fasching
A1 Anita N. Kremer
YR 2021
UL http://jitc.bmj.com/content/9/6/e002605.abstract
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.Data are available upon reasonable request. Data have largely been presented in the text; other data are available upon request.