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.

Fig. 1. Strengths, weaknesses, opportunities and threats of intratumoural delivery of immunotherapies.

a | Comparison of immunotherapy delivery strategies graphically depicting the typical biodistribution of intravenously administered systemic and tumour tissue-targeted immunotherapies and intratumourally administered immunotherapies. Intravenous delivery has certain practical advantages but also carries a higher risk of adverse events, particularly on-target, off-tumour toxicities related to systemic exposure to the active compound. On the contrary, intratumoural delivery presents technical and logistical challenges but can increase the therapeutic index of immunotherapies within the treated lesions, typically with a low risk of on-target, off-tumour toxicities. b | Summary of the internal strengths and weaknesses as well as external opportunities and threats (SWOT analysis) of intratumoural immunotherapy, all of which need to be balanced against the current clinical drug development landscape of cancer immunotherapy, which encompasses a multitude of novel agents. irAEs, immune-related adverse events; itRECIST, Response Criteria for Intratumoral Immunotherapy in Solid Tumors.

Fig. 2. Current landscape of active clinical trials of intratumoural immunotherapies.

a | Classification of the different types of immunotherapy agents that are currently being investigated in clinical trials involving intratumoural administration as of 1 December 2020 (data obtained from the ClinicalTrials.gov database using the search term “intratumoral OR intralesional AND cancer AND immunotherapy”). b | Visualization of the number of clinical trials for each type of agent outlined in the classification by circle packing, whereby the circle diameter indicates the relative proportion of ongoing or completed clinical trials identified. The trials included in this figure are listed in Supplementary Tables 1–7. CAR, chimeric antigen receptor; DCs, dendritic cells; ICD, immunogenic cell death; LL37, 37-residue cathelicidin antimicrobial peptide; mAb, monoclonal antibody; NK, natural killer; PRR, pattern recognition receptor; RLR, RIG-I-like receptor; STING, stimulator of interferon genes; TAA, tumour-associated antigen; TCR, T cell receptor; TILs, tumour-infiltrating lymphocytes; TLR, Toll-like receptor.

Fig. 3. Boosting the intratumoural cancer immunity cycle.

By selecting therapeutic agents based on their immunological properties, local immunotherapy — achieved either directly through intratumoural administration or indirectly through selective delivery to or activation in the tumour following systemic administration — can specifically enhance each step of the cancer immunity cycle described by Chen and Mellman. Examples of key cell types, processes and immunotherapy agents that are relevant to each step of this cycle are noted in the figure. Importantly, in accordance with steps 4 and 5 of the cycle, local immunotherapies need to result in redistribution of effector immune cells or antibodies via the circulation for abscopal or anenestic responses against distant untreated lesions and micrometastases. ADCs, antibody–drug conjugates; APCs, antigen-presenting cells; CAR, chimeric antigen receptor; CLEVER1, common lymphatic endothelial and vascular endothelial receptor 1 (also known as stabilin 1); PRR, pattern recognition receptor; Siglec-15, sialic acid-binding Ig-like lectin 15; SIRPα, signal-regulatory protein-α; TCR, T cell receptor, TILs, tumour-infiltrating lymphocytes; T_reg, regulatory T.

Fig. 4. Targeted approaches to immunotherapy against solid tumours.

Multiple strategies are currently being developed to promote the selective homing, accumulation and/or activation of immunotherapeutic agents inside tumours following systemic administration. These novel drugs, which include bispecific biologics, antibody Fab fragments, full antibodies, DARPins, immunocytokines and probodies, have diverse structures and target various factors present on tumour cells, in the tumour stroma and/or on immune cells to facilitate selective activation of immune responses in malignant tissues. Examples of targets for tumour cell valency or immune cell valency are listed in the figure. Such targeting strategies could also be of great interest for local immunotherapy owing to the potential to improve tumour exposure through tissue-tethering and retention of the agent in the tumour microenvironment following intratumoural administration. CEA, carcinoembryonic antigen; DC, dendritic cell; FAP, fibroblast-activation protein; NK, natural killer; T_reg, regulatory T.