ABSTRACT
As research uncovers the underpinnings of cancer biology, new targeted therapies have been developed. Many of these therapies are small molecules, such as kinase inhibitors, that target specific proteins; however, only 1% of the genome encodes for proteins and only a subset of these proteins has 'druggable' active binding sites. In recent decades, RNA therapeutics have gained popularity due to their ability to affect targets that small molecules cannot. Additionally, they can be manufactured more rapidly and cost-effectively than small molecules or recombinant proteins. RNA therapeutics can be synthesised chemically and altered quickly, which can enable a more personalised approach to cancer treatment. Even though a wide range of RNA therapeutics are being developed for various indications in the oncology setting, none has reached the clinic to date. One of the main reasons for this is attributed to the lack of safe and effective delivery systems for this type of therapeutic. This review focuses on current strategies to overcome these challenges and enable the clinical utility of these novel therapeutic agents in the cancer clinic.
ABSTRACT
BackgroundThe gut microbiome has emerged as a promising innovative therapeutic target for immune-stimulation treatment of solid tumours. MRx0518 is a novel, gut microbiome-derived oral live biotherapeutic. It has potent anti-tumorigenic efficacy in the preclinical setting including murine models of lung (LLC1), kidney (Renca) and breast (EMT6) cancer.1 In these models, a significant reduction in tumour growth has been demonstrated, including induction of immunostimulatory responses with tumour infiltration of NK cells, CD8+ and CD4+ T-cells. MRx0518 is under investigation in various oncological settings, including in combination with immune checkpoint inhibitors (NCT03637803) and radiotherapy (NCT04193904).MethodsTreatment naïve patients were recruited from April 2019 to February 2020. Patients were eligible if they received a histologically confirmed diagnosis of cancer (solid tumours) scheduled for surgical resection. Patients received 1 capsule of MRx0518 (1x1010 to 1x1011 CFU) twice daily from inclusion until the day preceding surgery (maximum 28 days therapy). The primary study outcome is to evaluate safety and tolerability of MRx0518 monotherapy in treatment naïve patients. Additional exploratory outcomes including identifying surrogate biomarkers of efficacy, microbiome analysis, effect on metabonomic markers and identification of histological and genomic alterations in paired pre-treatment (diagnostic biopsy) and post-treatment (surgical specimen) samples.ResultsIn part A, 17 patients received treatment, across tumour groups including breast (n=8), prostate (n=4), uterine (n=3), melanoma (n=1) and bladder (n=1). MRx0518 was well tolerated by all, with no grade 3/4 CTCAE toxicity reported, no severe adverse effects or treatment discontinuations. All patients proceeded to surgery, however the COVID-19 pandemic delayed surgery in 3 cases.Analysis of the first 5* patient paired samples utilising the NanoString Pan Cancer IO 360TM Gene Expression panel has demonstrated significant changes in gene expression profiles in 48 genes (pConclusionsThis study has demonstrated the safety and tolerability of the live biotherapeutic MRx0518 in treatment naïve cancer patients. Exploratory analyses of post-treatment samples has echoed preclinical observations of increased infiltration of immune cells following treatment and will undergo further validation. Part B will focus on investigating efficacy in a further 100 treatment naïve patients with a placebo-controlled arm.Trial RegistrationNCT03934827Ethics ApprovalThe study was approved by East of England - Cambridge East Research Ethics Committee approval number 18/EE/0091ReferenceLauté-Caly DL, Raftis EJ, Cowie P, et al. The flagellin of candidate live biotherapeutic Enterococcus gallinarum MRx0518 is a potent immunostimulant. Scientific Reports 2019;9(1):1-14. doi:10.1038/s41598-018-36926-8*Data analysis has been censored at 18/9/2020, further samples analysis is ongoing and will be updated.