Abstract
After the recent success and approvals of chimeric antigen receptor (CAR) T cells in haematological malignancies, its efficacy is currently evaluated in a broad spectrum of tumor entities including melanoma. However, severe and potentially life-threatening side effects like cytokine release syndrome, neurologic toxicities, and the competing risk of morbidity and mortality from the treatment itself are still a major limiting factor in the current CAR T-cell landscape. In addition, especially in solid tumors, the lack of ideal target antigens to avoid on-target/off-tumor toxicities also restricts its use. While various groups are working on strategies to boost CAR T-cell efficacy, mechanisms to increase engineered T-cell safety should not move out of focus. Thus, the aim of this article is to summarize and to discuss current and potential future strategies and mechanisms to increase CAR T-cell safety in order to enable the wide use of this promising approach in melanoma and other tumor entities.
Highlights
While the first engineered T cells in adoptive cell therapy (ACT) were used over a decade ago with a tumor antigen specific T-cell receptor (TCR) targeting a human leucocyte antigen (HLA)-A2restricted peptide from a melanocytic differentiation antigen in melanoma patients and showed great potential,[1,2,3] major breakthrough was reached with the introduction of a chimeric antigen receptor (CAR) into T cells.[4,5,6,7,8]
As the CAR construct comprises a single chain variable fragment derived from a monoclonal antibody, whole cell surface antigens on cancer cells are recognized independent of antigen processing and major histocompatibility complex (MHC) presentation, which represents an advantage over TCR T cells.[5,13,14]The intracellular structures of a CAR typically include the zeta subunit of the CD3 complex as a signalling domain derived from the TCR and one or more co-stimulatory motifs, for example CD28, 4-1BB or OX40.[5,14]
While it is essential and necessary to work on improving CAR T-cell efficacy to increase response rates, safety aspects should not move out of focus during these developments in order to fasten the seat belt of CAR T cells
Summary
While the first engineered T cells in adoptive cell therapy (ACT) were used over a decade ago with a tumor antigen specific T-cell receptor (TCR) targeting a human leucocyte antigen (HLA)-A2restricted peptide from a melanocytic differentiation antigen in melanoma patients and showed great potential,[1,2,3] major breakthrough was reached with the introduction of a chimeric antigen receptor (CAR) into T cells.[4,5,6,7,8] Especially for therapy-refractory B-cell acute lymphoblastic leukaemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL), CD19-directed CAR T-cell therapy revealed impressive response rates in clinical trials.[9,10,11,12]This has lead to the approval of two CD19 CAR T-cell constructs in the United States and other parts of the world including Europe.[5]. After the recent success and approvals of CAR T cells in haematological malignancies, its efficacy is currently evaluated in a broad spectrum of tumor entities.[15,16,17,18,19] Especially the application of CAR T cells in solid tumors including melanoma, still lacks a major breakthrough.[15,16,17,18,19] Reasons for a lower impact comprise hampered T-cell trafficking into cancer site,[19,20,21,22] as well as the immunosuppressive tumor microenvironment (TME) due to, eg immunosuppressive cytokines, regulatory T cells (Tregs) and upregulation of inhibitory receptors on T cells.[23,24,25,26] Other obstacles include tumor escape mechanisms like antigen downregulation or antigen loss which can be developed by. Severe side effects refractory to these therapies, are still frequently observed.[32] In this context, while focusing on mechanisms to increase CAR T-cell efficacy for its use in a broad spectrum of tumor entities, mechanisms to increase CAR T-cell safety should not move out of focus.
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