Immunotherapy has successfully been implemented as the standard of care in a number of oncologic indications. A hallmark of cancer immunotherapy is the successful activation of T cells against cancer cells, leading to unparalleled efficacy for some tumour entities. However, current approved approaches are not specific, limiting both their activity and their safety. A more tailored way of using the therapeutic potential of T cells is adoptive T cell therapy, which encompasses ex vivo T cell manipulation and reinfusion to patients suffering from cancer. In haematologic malignancies such as acute lymphatic leukaemia of the B cell lineage, T cells modified with a chimeric antigen receptor against the B cell lineage antigen CD19 induce remissions in a high proportion of patients. In contrast, patients suffering from advanced solid tumours have shown little benefit from cell-based approaches. This is partly due to limited access of T cells to the tumour tissue, consequently restricting T cell activity. In this review, we focus on the limitations of T cell trafficking towards solid tumours. We summarise the existing knowledge on lymphocyte migration to understand how this pathway may be used to open therapeutic approaches for a broader range of indications. We also review new strategies targeting the tumour site that aid naturally occurring or gene-engineered T cells to migrate to solid tumours. Finally, we discuss how guiding T cells towards the tumour might contribute in harnessing their full cytolytic potential.
Adoptive T cell therapy, homing, immune supression, antigen recognition, CAR T cells, TCR T cells, TILs, chemokine receptors
Bruno Cadilha, Klara Dorman, Felicitas Rataj, Stefan Endres and Sebastian Kobold have nothing to declare in relation to this article. No funding was received in the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
This study was supported by grants from the Wilhelm Sander Stiftung (grant number 2014.018.1 to SE and SK), the international doctoral program ‘i-Target: Immunotargeting of cancer’ funded by the Elite Network of Bavaria (to SK and SE), the Melanoma Research Alliance (grant number N269626 to SE and 409510 to SK), the Marie-Sklodowska-Curie ‘Training Network for the Immunotherapy of Cancer (IMMUTRAIN)’ funded by the H2020 program of the European Union (to SE and SK), the Else Kröner-Fresenius-Stiftung (to SK), the German Cancer Aid (to SK), the Ernst-Jung-Stiftung (to SK), by LMU Munich‘s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative (to SE and SK).
AuthorshipAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
February 24, 2017 Accepted
May 02, 2017
Sebastian Kobold, Division of Clinical Pharmacology, Klinikum der Universität München, Lindwurmstrasse 2a, 80337 Munich, Germany. E: email@example.com
Cancer immunotherapy has come of age and has successfully been implemented as the standard of care in a number of oncologic indications.1 Antibodies targeting cancer-associated antigens on the tumour cell, such as CD20, constituted the first wave of immunotherapies leading to the first approval of an antibody for cancer therapy. In 1997, rituximab, an anti-CD20 antibody was approved for the treatment of high-grade B cell lymphomas.2 Twenty-one compounds with similar tumour-targeted concepts have been approved for cancer treatment in Europe in the meantime. Despite being thought that the mode of action of such antibodies mainly relied on a direct antitumoural attack, emerging evidence suggests a contribution of the innate and adaptive immune system.3–6 Tumour-targeted monoclonal antibodies are now mainly considered as a passive immunotherapy.7–10
More recently, a paradigm change has occurred, moving the focus of therapeutic endeavours away from the cancer cell to effector components of the immune system, mainly T cells.11 Preclinical and clinical evidence have now demonstrated that allowing T cell activation results in antitumoural activity without bona fide tumour-targeting. Antibodies targeting checkpoint inhibitors on T cells such as, programmed death receptor 1 (PD-1) or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), reverse T cell anergy and lead to T cell-mediated remissions. Such antibodies can induce unparalleled activity in patients with advanced stage disease or having failed multiple lines of therapy, even in entities classically deemed nonsuitable for immunotherapies. As a consequence, approvals for cancer immunotherapies now span a broad scope of indications including acute lymphatic leukaemia (ALL), melanoma, nonsmall cell lung cancer, kidney cancer, Hodgkin lymphoma and head and neck cancer.12–17 A major limitation of the approach is its unspecific nature of T cell targeting, resulting in severe side effects.18–20 Strategies allowing for a more directed and specific therapeutic use of T cells may have advantages in terms of specificity and efficacy.
Adoptive T cell therapy (ACT) is a strategy that directly employs T cells with therapeutic intention against cancer.21 T cells can be isolated from a patient’s blood or tumour samples. Those derived from the tumour are also known as tumour-infiltrating lymphocytes (TILs).21,22 Isolation is followed by in vitro expansion and manipulation, and then reinfusion into the patient.21 ACT protocols that employ TILs are generally accompanied by preconditioning of the patients prior to treatment. In most cases, however, TILs cannot be isolated due to the lack of accessible tumour tissue or lack of tumour-specific T cells.23 Through genetic engineering, T cells can be rendered specific for a given target. This process encompasses the transduction or transient transfection with defined natural or synthetic genes. Two major strategies to engineer tumourspecific T cells have emerged: T cell receptors (TCRs)24–26 specific for a peptide presented in a major histocompatibility complex-dependent manner, and chimeric antigen receptors (CARs)27–30 which are synthetic T cell activating receptors targeting cell surface antigens. TCRs correspond to the natural molecule found in any T cell with modifications to enhance their biochemical and functional properties, while CARs are constituted of the variable fragment of an antibody fused to T cell activating CD3 zeta chain and co-stimulatory domains (overview in Figure 1). TILs, TCR and CAR T cells are currently being tested in various tumour indications in clinical trials (Figure 2).
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Adoptive T cell therapy, homing, immune supression, antigen recognition, CAR T cells, TCR T cells, TILs, chemokine receptors