In-gene-ious!

A novel drug delivery system successfully kills cancer cells


Australian biopharmaceutical company, EnGeneIC is poised to make a huge impact in delivering cancer therapies to patients after the recent first clinical trials involving humans (MesomiR-1) recorded “startling” results in end-stage, recurrent malignant pleural mesothelioma (MPM) or asbestos-related lung cancer patients. The findings have since been published in the peer-reviewed American Journal of Respiratory and Critical Care Medicine.
Holding more than 160 patents worldwide for platforms entirely developed in-house by founders and former CSIRO researchers Himanshu Brahmbhatt and Jennifer McDiarmid, EnGeneIc also won the Thomson Reuters Australian Citation & Innovation Award 2015 in recognition of its proprietary EnGeneIC Delivery Vehicle (EDV). The award is based on patent innovation, jurisdiction and global importance.
“This innovation award is a wonderful surprise, and we are very excited to be recognised as it follows the outcome of trials that dosing with the targeted EDV nanocell has enabled a near complete response in an end-stage mesothelioma patient,” Dr McDiarmid said.
EDV, a nanocell technology platform, is a novel but potent, bacterially-derived nanoparticle drug delivery system, designed to directly target and effectively kill tumour cells with minimal toxicity, while at the same time stimulating the immune system’s natural anti-tumour response.
The multi-centre world first trials, conducted in conjunction with Asbestos Diseases Research Institute (ADRI), Chris O’Brien Lifehouse, Northern Cancer Institute, Royal Prince Alfred Hospital, Concord Repatriation General Hospital and the University of Sydney, delivered microRNA (miRNA), a genetic material. ADRI scientists Glen Reid and Nico van Zandwijk identified these as missing in MPM patients.
Cancer can spread when microRNAs, which regulate a number of cell functions, are abnormal or missing. It is the first time a targeted nanotherapeutic approach to microRNA replacement is being tested in patients with MPM.
The trial is an exploratory Phase 1 study of ‘TargomiRs’, administered in escalating doses by intravenous infusion in patients with MPM who failed to respond to standard therapy. It aims to establish the optimal dose of TargomiRs and to detect early signs of disease stabilisation.

TargomiRs consist of EnGeneIC’s antibody-guided EDV nanocells packaged with miR-16-based microRNAs. To deliver the missing microRNAs, the EDV nanocells are designed to specifically target the epidermal growth factor receptor found on MPM cells.
After failing three chemotherapy regimens, 51-year-old plumber Bradley Selmon entered the MesomiR-1 study, along with five others. The cohort received eight weekly infusions and was assessed in Week 9.
At the end of the study period at the Chris O’Brien Lifehouse, under the care of medical oncologist Dr Steven Kao, a near-complete response was evident on Selmon’s PET and CT scans, with improved respiratory function. More significantly, he only experienced minor toxicities, including shivers, transient chills, low-grade fever, fatigue and headache.
Of the five additional patients in the first cohort, four have achieved stable disease levels and one progressive disease.

“We are particularly pleased with the improvement in quality of life for the patients, given the dose was at its lowest strength. In addition to showcasing the potential of TargomiRs in MPM, the results also serve to demonstrate the platform nature and versatility of EnGeneIC’s targeted EDV nanocells. In previous Phase 1 clinical studies, the EDV nanocells have been used to also deliver cytotoxic drugs,” Dr Brahmbhatt told Indian Link.
How does EDV work where other therapies or drugs have failed before?
Intended to sidestep major drawbacks of standard chemotherapy such as lack of cell specificity, substantial side effects and resistance developed by cancer cells, the EnGeneIC method uses minicells generated from mutant bacteria unlike its synthetic counterparts, to deliver a variety of agents to tumor cells, including both anticancer toxins and mechanisms for suppressing the genes that make tumours resistant to toxins.
Coated with antibodies that direct them towards tumour, the mini-cells pinch off small bubbles of cell membrane each time they divide. The tumour cells engulf and destroy the minicells, a standard defence against bacteria, and in doing so are exposed to whatever cargo the minicells carry.

The blood vessels around tumours tend to be leaky, allowing minicells to enter, explained Dr Brahmbhatt. The minicells do not seem to be highly provocative to the immune system, even though they are made of bacterial cell membrane. The reason may be that antibodies with which they are coated mask the aggravating parts of the membrane, he added.
The method of attacking cancer cells has previously proved surprisingly effective in animal tests involving lab rats and later monkeys and dogs with advanced brain cancer. This method is also extremely cost effective.
Buoyed by the success, EnGeneIC is in talks with oncologists and regulators worldwide and plans to undertake clinical trials in several cancer indications in Australia and USA with its lead drug ^EGFREDV_DOX.
“Fourteen years ago, we embarked on this ambitious journey with just an idea,” Dr Brahmbhatt said. “Nature had all the answers; we only harnessed its potential. This has been ENGeneIC’s biggest asset.”