Periodic Reporting for period 4 - H2020MM04 (DC-based immunotherapy to treat Malignant Mesothelioma)
Okres sprawozdawczy: 2020-07-01 do 2021-12-31
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 ‘training’ of the patients’ 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 patients’ 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 ‘cell lines’: 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 patients’ mesothelioma tumors. After the exposure to PheraLys, the patients’ 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.
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 ‘training’ of the patients’ 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 patients’ 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 ‘cell lines’: 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 patients’ mesothelioma tumors. After the exposure to PheraLys, the patients’ 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.
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. Obtaining approvals for the clinical study was more time consuming and complex than anticipated based on previous studies.
Patients were randomized to receive either dendritic cell-based immunotherapy or standard care. Inclusion of patients in the first centers started mid 2018, and more centers started including subsequently. From early 2020, COVID-19 has had a tremendous impact on the project. Inclusion was temporarily stopped between mid-March and mid-May 2020, while treatment, care and follow-up of already included patients continued as much as possible, taking into account local (travel)restrictions and hospital visit policies. Continuously changing travel restrictions and hospital policies throughout 2020 and 2021 made it extremely challenging to complete the inclusion of patients for this project, as patients randomized to the dendritic cell-based immunotherapy had to travel to The Netherlands to undergo leukapheresis. Also, even when travel restrictions were lifted slightly, hospital policies still made it difficult to facilitate inclusion of the study, as non-urgent care was scaled down to facilitate COVID-19 related care and other urgent care. However, since the consortium was committed to complete the study, a strategy was developed to complete inclusion. This involved decreasing the sample size. The original sample size was based on a specific number of events that would be required to draw firm conclusions from the study. As the study was taking longer than expected, the follow up of included patients could be extended and more events took place with a lower number of patients. This meant that the sample size could be decreased to a total of 176, while maintaining the statistical power of the study. This made it feasible to complete inclusion, despite the challenging COVID-19 situation. The final patient was included in June 2021.This means that follow up has been completed, and that follow up is still ongoing. Once the follow up of all patients has been completed, the database will be closed and final analyses will be performed. These data will be used to complete the registration files, which will be submitted to the EMA and FDA in order to request approval for registration of this dendritic cell-based immunotherapy for treatment for malignant mesothelioma.
Patients were randomized to receive either dendritic cell-based immunotherapy or standard care. Inclusion of patients in the first centers started mid 2018, and more centers started including subsequently. From early 2020, COVID-19 has had a tremendous impact on the project. Inclusion was temporarily stopped between mid-March and mid-May 2020, while treatment, care and follow-up of already included patients continued as much as possible, taking into account local (travel)restrictions and hospital visit policies. Continuously changing travel restrictions and hospital policies throughout 2020 and 2021 made it extremely challenging to complete the inclusion of patients for this project, as patients randomized to the dendritic cell-based immunotherapy had to travel to The Netherlands to undergo leukapheresis. Also, even when travel restrictions were lifted slightly, hospital policies still made it difficult to facilitate inclusion of the study, as non-urgent care was scaled down to facilitate COVID-19 related care and other urgent care. However, since the consortium was committed to complete the study, a strategy was developed to complete inclusion. This involved decreasing the sample size. The original sample size was based on a specific number of events that would be required to draw firm conclusions from the study. As the study was taking longer than expected, the follow up of included patients could be extended and more events took place with a lower number of patients. This meant that the sample size could be decreased to a total of 176, while maintaining the statistical power of the study. This made it feasible to complete inclusion, despite the challenging COVID-19 situation. The final patient was included in June 2021.This means that follow up has been completed, and that follow up is still ongoing. Once the follow up of all patients has been completed, the database will be closed and final analyses will be performed. These data will be used to complete the registration files, which will be submitted to the EMA and FDA in order to request approval for registration of this dendritic cell-based immunotherapy for treatment for malignant mesothelioma.
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. As mentioned, follow up is currently still ongoing. The consortium as a whole has committed to completing the follow up of all patients included in the study, to facilitate the registration of PheraLys/MesoPher at EMA and FDA for treatment of malignant mesothelioma, and to communicate the final results in the scientific community and among patients and their representatives to change the perspectives for (future) patients diagnosed with malignant mesothelioma. The company involved in the consortium, Amphera, will ensure the registration procedures at EMA and FDA will be completed and they will also take all necessary steps to make the treatment widely available once approved.