“We wanted to use nanotechnology in cancer therapy and change the way we treat this disease,” said Lawrence Tamarkin, Ph.D., president and CEO of CytImmune. The approach that Dr. Tamarkin and colleagues developed relies on 27 nm gold nanoparticles that have been used since the 1930s to treat psoriatic arthritis and present an established history of safety.
The surface of the colloidal gold nanoparticles was simultaneously bound to covalently linked thiolyated PEG, to avoid immune detection, and recombinant human tumor necrosis factor (TNF). Clinically, TNF has been successfully used in Europe to treat tumors of the extremities, in a procedure known as isolated limb perfusion. Infusing high-dose TNF prior to chemotherapy can achieve 15–25-fold higher concentrations as compared to systemic administration, without the same risks of adverse effects. With this strategy, several studies found up to 95% response rates after one treatment in patients with melanoma and sarcoma. “We wanted to mimic this clinical experience systemically,” said Dr. Tamarkin.
The 27 nm-diameter gold nanoparticles are small enough to travel through the blood vessels, and the 2–4 nm gaps between endothelial cells in healthy blood vessels are too small to allow them to cross into tissues, due to the presence of the tight junctions. “But at the site of the tumor, where the neovasculature fenestrations are 200–400 nm, the blood pressure forces them into the tumor bed, where TNF molecules bind to TNF receptors on the endothelial cells and start causing vascular disruption,” he added.
In a Phase I clinical trial, CYT-6091, the nanotherapeutic that Dr. Tamarkin and colleagues developed, delivered up to 1.2 mg TNF, as compared to 0.4 mg, which is the maximum tolerated human dose, without any signs of dose-limiting toxicity. “The promise of nanotechnology is that we can reduce or eliminate toxicity and improve the therapeutic index,” he said. Moreover, the drug accumulated at tumor sites, and very few gold nanoparticles were seen in healthy tissues.
“We intended not simply to reformulate an already approved drug, but to create a safe and effective therapeutic by using nanotechnology,” he said. Two patients, one with inoperable breast cancer and another one with pancreatic cancer, neither of them having previously undergone surgical treatment, showed the most nanoparticles accumulating in the tumor, as compared to the adjacent healthy tissue. “This indicated that perhaps treating patients surgically so quickly might not be a good idea, because it tears up the roadway that nanoparticles use to reach their targets,” he commented.
Gold nanoparticles accumulated in malignant tissues even at the lowest doses, but accumulation was not increasing in a dose-dependent manner. Reducing the tumor burden in situ offers the possibility to reduce the need for sophisticated surgery and the hospitalization time.
“We have the promise to dramatically improve healthcare because of decreased treatment costs,” he concluded.