Intratumoural administration and tumour tissue targeting of cancer immunotherapies

Abstract

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. 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. 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.