“Minicells” Safely Deliver Targeted Drugs

A new form of targeted drug delivery via “minicells” proved generally tolerable in its first trial in humans. The minicells are derived from mutated bacteria that divide at the poles, producing a nonliving sphere with no nucleus that can be loaded with chemotherapeutic drugs and coated with antibodies that target specific tumor cells.

The 400-nm-wide spheres are large enough to be contained by normal blood vessels but small enough to slip out of the leaky vessels found inside tumors, says Benjamin Solomon, MBBS, PhD, the trial's principal investigator and a medical oncologist at the Peter MacCallum Cancer Centre in Melbourne, Australia. Once inside the tumor, targeted antibodies bind to receptors on the tumor cell. When the minicell is ingested by the tumor cell, it breaks down and the drug is released.

Twenty-eight patients with end-stage solid tumors participated in the phase I multicenter trial, reported on November 9 at the 2012 Symposium on Molecular Targets and Cancer Therapeutics, hosted in Dublin by the European Organisation for Research and Treatment of Cancer, the National Cancer Institute, and the American Association for Cancer Research.

“Minicells” derived from mutated bacteria are nonliving spheres that can be loaded with chemotherapeutic drugs and coated with antibodies that target specific tumor cells.

The patients received 5 weekly infusions of minicells filled with paclitaxel and coated with antibodies targeting the epidermal growth factor receptor (EGFR) protein found on the surface of many tumor cells.

Ten of the patients showed stable disease after 6 weeks, and some continued on minicell therapy for months, with 1 patient receiving 45 doses in 15 months. Side effects included short-lived fevers and, in some cases, chills, typically an hour after dosing. At the highest dose, some patients showed signs of liver function changes.

Minicell developers Himanshu Brahmbhatt, PhD, and Jennifer MacDiarmid, PhD, of EnGeneIC, in Sydney, Australia, hope to reduce side effects by minimizing the presence of endotoxins in the minicell membranes.

The team plans a phase I/II trial to test minicells in patients with gliomas, again targeting EGFR but delivering doxorubicin. Dogs with brain cancer showed promising results with this treatment, notes Solomon.

“The success of the phase I trial allows us to begin to look at efficacy,” says Solomon. “But the real potential is packaging drugs that are impossible to give systemically.” For instance, the team is exploring the possibility of using minicells to deliver siRNA to silence drug-resistant genes.