Augmenting engineered T-cell strategies in solid cancers through epigenetic priming
- PDF / 1,356,235 Bytes
- 10 Pages / 595.276 x 790.866 pts Page_size
- 58 Downloads / 133 Views
REVIEW
Augmenting engineered T‑cell strategies in solid cancers through epigenetic priming Aaraby Y. Nielsen1 · Maria Ormhøj2 · Sofie Traynor1 · Morten F. Gjerstorff1,3,4 Received: 7 April 2020 / Accepted: 3 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract T-cell receptor (TCR)- and chimeric antigen receptor (CAR)-based adoptive cell transfer (ACT) has shown promising results in hematological malignancies, but remains immature in solid cancers. The challenges associated with identification of tumor-specific targets, the heterogenic antigen expression, limited T-cell trafficking to tumor sites and the hostile tumor microenvironment (TME), are all factors contributing to the limited efficacy of ACT therapies against solid tumors. Epigenetic priming of tumor cells and the microenvironment may be a way of overcoming these obstacles and improving the clinical efficacy of adoptive T-cell therapies in the future. Here, we review the current literature and suggest combining epigenetic modulators and ACT strategies as a way of augmenting the efficacy of TCR- and CAR-engineered T cells against solid tumors. Keyword Cancer immunotherapy · Genetically modified T cells · Solid tumors · Epigenetic drugs · Cancer/testis antigens · Combination therapy
Background Discovering the ability of the immune system to recognize and eradicate tumor cells has, in recent years, revolutionized the treatment of patients with incurable cancers [1]. These findings are now being leveraged to produce highly potent “living drugs” in the form of T-cell-based ACT products produced by expanding T cells from a patients’ blood or tumor ex vivo and reinfusing them into the patient, where they have the potential to eliminate tumor cells. Tumorinfiltrating T cells (TILs) are expected to be largely tumor antigen-specific, and T-cell products derived from tumors Aaraby Y. Nielsen and Maria Ormhøj authors contributed equally. * Morten F. Gjerstorff [email protected] 1
Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
2
Department of Health Technology, Technical University of Denmark, Lyngby, Denmark
3
Department of Oncology, Odense University Hospital, Odense, Denmark
4
Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, Odense, Denmark
depend on the repertoire of native TCRs for tumor cell recognition. Alternatively, T cells can be genetically modified during ex vivo culturing to express the αβ chains of a TCR or a CAR [2, 3]. In this way, T cells from patients can be redirected against a specific target antigen expressed on the tumor cells of the patient. CARs are fusion proteins composed of an extracellular targeting moiety, often derived from a monoclonal antibody, coupled to intracellular T-cell signaling domains [3]. In the context of TCR-engineered T cells, the transgene consists of a synthetic αβ TCR heterodimer. While CAR T cells recognize antigens expressed on the surface of tumor cells in
Data Loading...
