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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - H2020MM04 (DC-based immunotherapy to treat Malignant Mesothelioma)

Teaser

Summary

Malignant mesothelioma is a form of cancer that in most cases is caused by inhalation of asbestos fibers. It is a fatal disease with a very poor prognosis; survival after diagnosis is generally around 12 months. Chemotherapy provides a very modest increase in life expectancy of around 3 months. In 2010, 8,100 deaths caused by mesothelioma were registered by IARDC. Although use of asbestos has already been banned for many years, the incidence of mesothelioma is still rising. This is mainly due to the long period between exposure to asbestos and manifestation of the disease: this can vary from a couple of years to as long as 30 years after initial exposure. Most mesothelioma patients have been exposed to asbestos during their jobs e.g. as construction worker, before asbestos was banned from use. It is obvious that there is an urgent medical need for a therapy that can increase life expectancy of mesothelioma patients significantly.

In Erasmus MC University Medical Center Rotterdam (ERA), a unique personalized form immunotherapy has been developed from the earliest laboratory experiments up to phase I clinical studies. This therapy is based on â€˜trainingâ€™ of the patientsâ€™ own immune system to equip it to work against the mesothelioma tumors. For this purpose, a specific type of immune cells, so-called dendritic cells, are obtained from the patientsâ€™ plasma. Subsequently the cells are treated in the laboratory by exposing them to PheraLys. PheraLys is a cocktail of factors prepared out of a so-called mesothelioma â€˜cell linesâ€™: cells originating from a variety of mesothelioma tumors, which have been cultured and characterized extensively in the laboratory. This equips the dendritic cells with a broad spectrum of capacities to attack the patientsâ€™ mesothelioma tumors. After the exposure to PheraLys, the patientsâ€™ own cells, now named MesoPher, are given back to the patient in a series of injections. The safety and tolerability of this PheraLys/MesoPher treatment has been demonstrated in a phase I clinical trial performed at ERA. Median survival of the 9 patients participating in this trial is 26 months and rising, since 7 of these patients are still alive in August 2017.

The objective of the H2020MM04 consortium is to demonstrate the efficacy of this dendritic cell-based immunotherapy in a randomized phase II/III clinical trial. For this purpose, a consortium has been composed of 6 mesothelioma expert centers in Europe, complemented with the company Amphera, which is responsible for the potential exploitation of the therapy, and the European Cancer Patient Coalition.

Work performed

Mesothelioma was designated as orphan disease by both the EMA and the FDA, a designation that has the goal to speed up the developmental process from laboratory to patient treatment. This phase III clinical trial aims to serve as final registration study, which is the last step to be taken before dendritic cell immunotherapy can be made available to mesothelioma patients worldwide. Since it is of outmost importance that the European Medicine Agency (EMA) and Food and Drug Authority (FDA) will accept the results of this study, the consortium has made tremendous effort to perfect the study protocol to ensure that it will meet all criteria of EMA and FDA. The first approvals packages for starting the study have been submitted to the respective authorities, a procedure that has to be done for each participating country individually. Obtaining approvals for the clinical study was more time consuming and complex than anticipated based on previous studies. Currently, approval has been granted in the Netherlands, Belgium, France and the UK. Approval is still pending in Italy. In total 230 patients will be participating, who will be randomized to receive either dendritic cell-based immunotherapy or standard care. After the initial delay, mainly caused by an exceptionally lenghty approvals procedure, inclusion started mid 2018 and is running smoothly: up to early May 2019, almost 20% of the total study population has been included (44/230 patients). Another 33 patients are prescreened prior to their enrolment in spring/summer 2019, which makes a total of over 30% of the study population. The involved PIs have advertised the project in many (invited)lectures and presentations on multiple conferences and other occasions.

Final results

When this phase III clinical trial confirms the promising results from the phase I study, it is foreseen that dendritic cell-based immunotherapy will be registered at the EMA and the FDA as treatment for mesothelioma. Once this is achieved, the treatment can be marketed for mesothelioma patients all over the world. The phase I clinical trial resulted in a massive increase in survival of mesothelioma patients. When this phase III clinical trial meets the expectations arisen from the phase I trial, the introduction of PheraLys/MesoPher treatment to the market could result in a dramatic increase of life expectancy for mesothelioma patients. The consortium is determined to perform this clinical trial according to the highest standards and together they aim to make a real difference for future mesothelioma patients.