LONDON – Amphera BV is coming out of stealth mode to look for potential partners and routes to commercialization for its Mesopher dendritic cell cancer vaccine, after launching a pivotal phase II/III trial in pleural mesothelioma.

The 230-patient study began recruiting in May 2018 and is due to conclude in December 2020. That will lead to submission to the EMA for marketing approval by the end of 2021, Rob Meijer, Amphera CEO, told BioWorld.

If it can deliver on that, Amphera will have cracked two seemingly intractable problems, of developing a dendritic cell cancer vaccine that can be cost-effectively manufactured at scale, and showing a meaningful effect in an extremely aggressive cancer that has sunk numerous other products in clinical trials.

The only treatment for malignant mesothelioma, a combination of pemetrexed and cisplatin, was approved as far back as 2003. The therapy improves survival by a mere three months, in a cancer that is usually fatal within 12 months of diagnosis.

Mesothelioma is thought to be caused exclusively by exposure to asbestos fibers and, although banned in the U.S. and Europe for some time, there remains much of the fireproof material in the built environment. That, combined with a 20- to 40-year gap between exposure to asbestos and development of mesothelioma, means the incidence of that cancer, and the unmet medical need, is increasing.

In the U.S. there are around 3,000 cases per year, in Europe about 5,000. High-risk groups include shipyard workers, sailors, oil refinery workers, plumbers, welders and electricians. As Meijer noted, that means there is a relatively high incidence of mesothelioma in the industrialized region around Rotterdam, the largest port in Europe. Rotterdam also is home to the Erasmus University Medical Center, the largest cancer center in the Netherlands, where Mesopher originated.

Researchers at Erasmus led by Joachim Aerts, professor of pulmonary oncology, began with the traditional approach to dendritic cancer vaccines, extracting monocytes through electrophoresis and maturing them ex-vivo to immature dendritic cells, before adding antigens from the patient's tumor and injecting the vaccine.

In two early stage trials, a cytotoxic T-cell response against the tumor was induced, with objective responses seen in X-rays and promising survival rates. A major drawback was a relatively high dropout rate of patients that was caused by a lack of adequate tumor tissue from which to generate tumor antigens. (See BioWorld Today, March 15, 2010.)

That hurdle was overcome by developing five clinical-grade stable mesothelioma cell lines, ensuring a constant source of cells from which to produce an antigen-rich lysate.

It takes 10 days from isolating a patient's monocytes, culturing them to immature dendritic cells and pulsing those with the tumor cell lysate, to generating activated, mature dendritic cells.

Promising efficacy so far

On injection into the patient, Mesopher goes to the lymph nodes, where antigen-specific T-cell activation takes place. Tumor-directed T cells enter the bloodstream and traffic to the tumor.

All nine patients in the phase I/II trial of Mesopher had a T-cell response. Median survival stood at 26 months in August 2017, when seven patients were still alive. "It was perfectly safe, with just vaccination-type reactions. We also saw promising efficacy as well," Meijer said.

Mesopher has EMA advanced therapy medicinal product designation and has EMA and FDA orphan drug status.

In the phase II/III open-label trial, each patient will receive three injections, administered fortnightly from nine to 13 weeks after the last dose of chemotherapy. A further two booster doses will be given at weeks 10 and 30, in patients who respond to the first three doses. The control arm will receive best supportive care. The endpoint is overall survival.

The phase II/III trial is taking place at six mesothelioma referral centers in five countries in Europe, allowing Hertogenbosch, the Netherlands-based Amphera to stress test its supply chain. Monocytes extracted from the patients will be processed centrally in the Netherlands and frozen before being shipped back for administration. One cycle will produce enough of the product for all five doses for each patient.

The etiology of mesothelioma renders it particularly unreceptive to immunotherapies. When normal mesothelial cells are infiltrated by asbestos fibers, it causes release of inflammatory cytokines, attracting immune stimulatory macrophages. However, the macrophages cannot digest the asbestos fibers, and the ongoing inflammatory response turns normal cells cancerous, attracting immune suppressor cells and sheltering the tumor from immune surveillance.

Meijer said the evidence from the phase I/II trial is that Mesopher turns the tumor microenvironment from cold to hot. "In mesothelioma, dendritic cells are impaired from the outset by the immune-suppressive tumor environment," he said. "After adding the activated dendritic cells, the immune system is started again."

In addition to pleural mesothelioma, Amphera has a phase I/II trial in peritoneal mesothelioma ongoing. The company also is planning to start another phase I/II study in an undisclosed indication.

The phase II/III study is partly funded by a €5.8 million (US$6.6 million) grant from the EU's Horizon 2020 research program. Other than that, Amphera has not disclosed any funding, but Meijer said the company has the money to complete the three trials. "Now that the studies are started, communication to a wider audience becomes important to identify potential partners," he said.

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