Identification and validation of expressed HLA-binding breast cancer neoepitopes for potential use in individualized cancer therapy

Reimann H, Nguyen A, Sanborn JZ, Vaske CJ, Benz SC, Niazi K, Rabizadeh S, Spilman P, Mackensen A, Rübner M, Hein A, Beckmann M, van der Meijden E, Bausenwein J, Kretschmann S, Griffioen M, Schlom J, Gulley JL, Lee KL, Hamilton DH, Soon-Shiong P, Fasching P, Kremer A (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 9

Article Number: e002605

Journal Issue: 6

DOI: 10.1136/jitc-2021-002605

Abstract

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.

Authors with CRIS profile

Involved external institutions

NantHealth, Inc. United States (USA) (US) ImmunityBio Inc United States (USA) (US) National Cancer Institute (NCI) United States (USA) (US) Leiden University Medical Center Netherlands (NL)

How to cite

APA:

Reimann, H., Nguyen, A., Sanborn, J.Z., Vaske, C.J., Benz, S.C., Niazi, K.,... Kremer, A. (2021). Identification and validation of expressed HLA-binding breast cancer neoepitopes for potential use in individualized cancer therapy. Journal for ImmunoTherapy of Cancer, 9(6). https://doi.org/10.1136/jitc-2021-002605

MLA:

Reimann, Hannah, et al. "Identification and validation of expressed HLA-binding breast cancer neoepitopes for potential use in individualized cancer therapy." Journal for ImmunoTherapy of Cancer 9.6 (2021).

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