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.

The Impact of m1A Methylation Modification Patterns on Tumor Immune Microenvironment and Prognosis in Oral Squamous Cell Carcinoma

“…The survival analyses between the groups of patients were performed using the Kaplan-Meier method and log-rank tests. The optimal cutoff values for gene expression were determined using the survminer package in R. The tumor mutation burden analysis for OSCC patients in high and low m1A score clusters was performed using the maftools package in R. Spearman correlation analysis was performed to calculate the correlation coefficient of gene expression and correlation between m1A score and known biological gene signatures using previously reported gene sets [8,9]. Student's t-test was used to estimate the statistical differences between two groups, while one-way ANOVA and Kruskal-Wallis tests were performed when more than two groups were considered.…”

“…In recent years, ICIs, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) blockades, have been frequently applied in clinical oncotherapy. Inspiring therapeutic outcomes, such as improved overall survival (OS) and tumor shrinkage, have been verified in the head and neck squamous cell carcinoma (HNSCC) [9,10]. However, only a few patients with HNSCC/OSCC can benefit from Int.…”

Systematic investigation of the aza-Cope reaction for fluorescence imaging of formaldehyde in vitro and in vivo

“…The fast in vivo kinetics may be due to high local concentrations of FA and the probe that was directly injected into the tumor region, as also noted in intratumoral drug administration. 42 These high locoregional concentrations could accelerate the reaction between the probe and FA. Similarly, a faster in vivo response, relative to in vitro , was previously observed for a nitroreductase fluorescent probe during in vivo fluorescence imaging.…”

Intratumoural Treatment of 18 Cytologically Diagnosed Canine High-Grade Mast Cell Tumours With Tigilanol Tiglate

“…In Australian studies there has been no detection of reduced efficacy related to the number of treatment cycles on a location or the subsequent use on de novo tumours arising at a distant location. There is a low likelihood of the development of resistance to TT given the host's immune response plays a role in TT mode of action and may improve patient survival (27,44,45). The beneficial effect of the combination of TT for local tumour control with adjunctive systemic chemotherapy protocols or tyrosine kinase therapy is unknown and prospective studies are necessary to provide the answer.…”