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Review Immunology Enabling T Cell Recruitment to Tumours as a Strategy for Improving Adoptive T Cell Therapy Bruno Cadilha, Klara Dorman, Felicitas Rataj, Stefan Endres and Sebastian Kobold Center for Integrated Protein Science Munich (CIPSM) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany, Member of the German Center for Lung Research I mmunotherapy 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. Keywords Adoptive T cell therapy, homing, immune supression, antigen recognition, CAR T cells, TCR T cells, TILs, chemokine receptors Disclosure: 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. Acknowledgements: 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). Authorship: All 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. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non- commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 24 February 2017 Accepted: 2 May 2017 Citation: European Oncology & Haematology, 2017;13(1):66–73 Corresponding Author: Sebastian Kobold, Division of Clinical Pharmacology, Klinikum der Universität München, Lindwurmstrasse 2a, 80337 Munich, Germany. E: sebastian.kobold@med.uni-muenchen.de 66 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, non- small 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. TOU C H ME D ICA L ME D IA