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      Intratumoural administration and tumour tissue targeting of cancer immunotherapies


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          Immune-checkpoint inhibitors and chimeric antigen receptor (CAR) T cells are revolutionizing oncology and haematology practice. With these and other immunotherapies, however, systemic biodistribution raises safety issues, potentially requiring the use of suboptimal doses or even precluding their clinical development. Delivering or attracting immune cells or immunomodulatory factors directly to the tumour and/or draining lymph nodes might overcome these problems. Hence, intratumoural delivery and tumour tissue-targeted compounds are attractive options to increase the in situ bioavailability and, thus, the efficacy of immunotherapies. In mouse models, intratumoural administration of immunostimulatory monoclonal antibodies, pattern recognition receptor agonists, genetically engineered viruses, bacteria, cytokines or immune cells can exert powerful effects not only against the injected tumours but also often against uninjected lesions (abscopal or anenestic effects). Alternatively, or additionally, biotechnology strategies are being used to achieve higher functional concentrations of immune mediators in tumour tissues, either by targeting locally overexpressed moieties or engineering ‘unmaskable’ agents to be activated by elements enriched within tumour tissues. Clinical trials evaluating these strategies are ongoing, but their development faces issues relating to the administration methodology, pharmacokinetic parameters, pharmacodynamic end points, and immunobiological and clinical response assessments. Herein, we discuss these approaches in the context of their historical development and describe the current landscape of intratumoural or tumour tissue-targeted immunotherapies.


          Limited penetration into tumour tissue can restrict the activity of systemically delivered cancer immunotherapies, whereas exposure of various non-malignant tissues to high levels of such agents can lead to problematic toxicities. Intratumoural administration and/or biotechnology strategies for selective targeting of tumour tissues have the potential to circumvent these issues and thereby increase the therapeutic index. Herein, the authors review the historical origins and current landscape of intratumoural and tumour tissue-targeted immunotherapies.

          Key points

          • Repeated intratumoural injections with agents designed to enhance antitumour immune responses constitutes a feasible strategy to reduce the risk of systemic toxicities and achieve higher local bioactive drug concentrations.

          • Spearheaded by the oncolytic virus talimogene laheparepvec, the first intratumoural immunotherapy approved by the FDA and EMA, and supported by a strong preclinical rationale, many intratumoural immunotherapies are now being developed in clinical trials.

          • These immunotherapies include microorganisms (viruses or bacteria) and synthetic compounds mimicking infectious agents (such as pattern recognition receptor agonists), as well as immunomodulatory monoclonal antibodies, cytokines and chimeric proteins.

          • Higher locoregional concentrations of immunotherapy agents can also be achieved through molecular engineering, for example, to target them towards moieties that are enriched in the tumour microenvironment.

          • Increased specificity in tumour targeting can also be attained through the development of prodrug forms of immunotherapies that become functional only after entering tumour tissue (pro-immunodrugs).

          • Procedural, pharmaceutical, regulatory and analytical challenges require multidisciplinary expert consensus and systematic research to maximize the potential of these modes of administration.

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          Most cited references268

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          Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

          First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.
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            Cancer immunotherapy using checkpoint blockade

            The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte antigen-4 (CTLA-4) or the programmed death-1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the pre-existence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long lasting disease control, yet one third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon gamma signaling pathways. New generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.
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              Oncology meets immunology: the cancer-immunity cycle.

              The genetic and cellular alterations that define cancer provide the immune system with the means to generate T cell responses that recognize and eradicate cancer cells. However, elimination of cancer by T cells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell T cell inhibitory signals, including PD-L1, has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

                Author and article information

                Nat Rev Clin Oncol
                Nat Rev Clin Oncol
                Nature Reviews. Clinical Oncology
                Nature Publishing Group UK (London )
                18 May 2021
                : 1-19
                [1 ]GRID grid.411730.0, ISNI 0000 0001 2191 685X, Department of Immunology, , Clínica Universidad de Navarra, ; Pamplona, Spain
                [2 ]GRID grid.411730.0, ISNI 0000 0001 2191 685X, Department of Oncology, , Clínica Universidad de Navarra, ; Pamplona, Spain
                [3 ]GRID grid.5924.a, ISNI 0000000419370271, Program for Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), , Universidad de Navarra, ; Pamplona, Spain
                [4 ]Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
                [5 ]GRID grid.413448.e, ISNI 0000 0000 9314 1427, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), ; Madrid, Spain
                [6 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, Département d’Innovation Thérapeutique et d’Essais Précoces (DITEP), , Université Paris Saclay, Gustave Roussy, ; Villejuif, France
                [7 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, INSERM U1015, Gustave Roussy, ; Villejuif, France
                [8 ]GRID grid.7429.8, ISNI 0000000121866389, Biotherapies for In Situ Antitumor Immunization (BIOTHERIS), Centre d’Investigation Clinique INSERM CICBT1428, ; Villejuif, France
                © Springer Nature Limited 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                Review Article

                immunotherapy,cancer immunotherapy,drug development
                immunotherapy, cancer immunotherapy, drug development


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