The needs of cancer patients are clear – chemotherapies that are as gentle as possible, associated with minimal adverse effects and have a rapid effect. This is often difficult to achieve because the drug that stops tumour growth needs to remain in the body for a certain amount of time during which time it damages cancerous as well as healthy structures.
Dr. Gerhard Pütz and Dr. Jürgen Eckes founded the company TellTargeting Medical GmbH & Co. KG and worked in cooperation with the Freiburg University Medical Centre to develop CARL®, a chemotherapy principle in which around half of the drug is removed from the body as soon as it has done its job.
In order to combat a tumour effectively, chemotherapy treatment requires the application of disproportionately high amounts of drugs that remain in the entire body for a relatively long time. The concentration of the drug, doxorubicin is one example, in the target tissue itself is negligibly low while the remainder circulates in the blood. While the long-term circulation of a harmless drug in the blood might be tolerable, a toxic drug such as doxorubicin can have many adverse effects. Doxorubicin has been used since 1960, notably in the treatment of breast and lung cancer. It is a red dye that interacts with DNA by intercalation, thereby inhibiting the division of tumour cells. While doxorubicin is able to prevent tumours from growing, it is highly cytotoxic and affects both tumour and healthy cells. It is particularly toxic to heart muscle cells, and can lead to severe, irreversible myocardial diseases.
Chemist Dr. Gerhard Pütz, co-founder of the company TellTargeting and scientist at the Freiburg University Medical Centre, compares doxorubicin therapy with flying blind: “Once the drug has been administered, we are no longer able to affect pharmacokinetics, i.e. what happens in the body.” A number of years ago, Pütz came up with the idea of packaging the drug in a form that can be better tolerated by the body. He used liposomes, i.e. nanocarriers, just one hundred nanometres in size, to encapsulate the drug.
Heart damage is the most dangerous adverse effect of doxorubicin. As the heart is unable to take up liposomes, the liposome-encapsulated drug remains in the blood for longer than usual, which reduces its cardiotoxicity. Once the tumour is saturated with the chemotherapy drug, around 70 percent of the toxic drug continues circulating in the blood and exerting its cytotoxic effect on healthy cells. Although the liposome-encapsulated form of doxorubicin lessens the substance’s cardiotoxicity, it still results in a side effect known as hand-foot syndrome. “This is severe skin damage that, although not life-threatening, is very painful,” said Pütz referring to the extensive redness and swelling which resemble severe burns.
In 2001, Pütz and his colleague Dr. Jürgen Eckes founded the company TellTargeting as a private partnership (German: GbR) and in 2002 they filed a patent for their invention. Six years later, they were joined by oncologist Dr. Oliver Schmah and pharmacist Dr. Martin Hug, both at the Freiburg University Medical Centre. The interdisciplinary group of researchers then turned TellTargeting into a limited liability company (German GmbH) and initiated a pilot study with the Department of Gynaecology and Gynaecological Oncology at Freiburg University to test the efficiency and effect of the proposed therapy. The study progressed smoothly thanks to the already approved liposome-encapsulated drug and the availability of required equipment.
Inspired by the desire to reduce the adverse effects of chemotherapy, Pütz and Eckes decided to stop focusing on the active drug ingredient itself and turn their attention to the temporal aspect of the chemotherapy. “We found that liposome-encapsulated doxorubicin accumulates very rapidly in the tumour, but less quickly in other tissues such as the skin,” said Pütz highlighting the key aspect of the treatment concept. “We realised that we had a kinetic advantage that we had to put to good use.” The drug accumulates in the tumour due to the so-called EPR (enhanced permeation and retention) effect: “The blood vessels in the tumour grow very quickly; this leads to holes between the endothelial cells of the blood vessel walls through which the liposomes can enter the tumour.” Such holes do not occur in healthy tissue. As the cells are arranged like a fish trap and as the blood pressure in the blood vessels is quite high, the liposomes are unable to leave the tumour and remain trapped inside,” said the researcher.
In order to take advantage of this aspect, the researchers decided to start apheresis as early as 48 hours after the application of doxorubicin, the goal being to remove more than 50% of the liposomal drug from the blood. CARL® stands for “Controlled Application and Removal of Liposomal Therapeutics” and is TellTargeting’s key product. It is an efficient method for reducing the toxicity of chemotherapy by directly affecting the drug’s pharmacokinetics. After the enrichment of the drug in the tumour, apheresis is able to rapidly and efficiently reduce the toxicity of the drug that is circulating in the blood.
CARL® is based on a method known as cascade filtration, a filtering process that takes place in several stages. During the first stage, the blood is passed through a filter to separate the plasma from the blood. In the second stage, the plasma components pass through a second filter and recombine with the patient’s blood cells. The second filter retains and removes molecules of high-molecular weight, i.e. liposomal doxorubicin.
In 2010, TellTargeting concluded a pilot trial in which 50 patients underwent CARL® treatment. The trial was carried out in cooperation with the Freiburg University Medical Centre and the Breast Centre in Offenburg and came up with promising results: since this procedure is not associated with adverse effects and is much better tolerated by patients than standard chemotherapy, CARL® has the potential to intensify cancer therapy by using a higher initial drug dose.
“With our innovation we are able to offer patients the possibility of undergoing cancer treatment without the large number of adverse effects that are normally associated with chemotherapy,” said Pütz highlighting that the procedure is quite costly and not yet reimbursed by health insurance companies. Patients therefore have to pay for the treatment themselves. The high costs are due to the fact that the liposomal version of the drug is more expensive than the active substance itself. It is marketed by an American company and price reductions are not likely to occur in the foreseeable future. Treatment involves four to five apheresis cycles that cost 2000 euros each. “CARL® is therefore unable to generate high sales volumes, at least at present, which is why we have decided to remain in our current jobs rather than working full time for our company,” said Pütz. The company owners are continuing their research and hope that CARL® will at some stage become standard cancer therapy. Last year, Pütz and his colleagues filed a new patent for a method that enables the more rapid and patient-friendly determination of doxorubicin content in the body during infusion using a lab-on-a-chip device. In analogy to the CARL® method, this innovation is also aimed at discontinuing the administration of drugs as soon as sufficient quantities of drugs are present in the organism.
Further information:Dr. Gerhard Pütz University of Freiburg Medical CentreDepartment of Clinical ChemistryHugstetterstr. 5579106 FreiburgTel.: +49 (0)761/270-32070E-mail: gerhard.puetz(at)uniklinik-freiburg.de