MADRID—Moderna and BioNTech have quite a few things in common, one being that both are trying to chart their post-COVID course by reinventing cancer modalities. And both, it seems, have run into the reality of manufacturing challenges.
BioNTech presented data from a rejigged formula for the CAR-T therapy BNT211 at the European Society for Medical Oncology (EMSO) Monday, showing that the therapy had signs of clinical efficacy with an overall response rate of 45% in 38 of 44 evaluable patients.
BioNTech’s Benjamin Rengstl, M.D., director of clinical development and immunoreceptor therapy, told Fierce Biotech on the sidelines of the conference that the presentation was the debut of a new manufacturing process that is more automated, robust and scalable. It also created a more potent product—which also meant more toxicities. The new stronger formula led BioNTech to redo dose escalation.
“Everyone wants to develop protocols with a short turnaround time,” Rengstl said.
This new protocol will form BioNTech’s next generation of products, which will move away from retroviral vectors to virus-free versions of gene editing, Rengstl explained. “I'm pretty sure this will be the future.”
Rengstl insists that the only delay to the BNT211 program is the redo for the dose-optimization portion of the phase 1/2 trial. Because of the higher potency, they had to ensure the dosing schedule was appropriate to mitigate risk.
“Because you do not want to risk the patient, so we take a delay into account,” Rengstl said.
BioNTech is also expanding its manufacturing capabilities globally, which will help serve a worldwide network of clinical trials for BNT211. Rengstl said the company needs at least 100 patients to show how effective the therapy is, with 44 already enrolled in the early-stage portion of the phase 1/2 trial.
Moderna, meanwhile, is working with Big Pharma Merck & Co., known as MSD here in Spain, on a personalized cancer vaccine called mRNA-4157 that is soon to enter phase 3. While the companies didn’t have major news to reveal at ESMO, both had a presence.
“No patient's tumor has the same mutational profile as the next patient's tumor,” said Merck’s Jane Healy, M.D., Ph.D., vice president of early clinical development, in an interview. “Every single patient gets this drug manufacturer just for them.”
The companies sequence the tumor and identify the unique mutations to select which ones are likely to be immunogenic or recognizable to the immune system, Healy explained. These neoantigens are not expressed in normal healthy tissue.
“We generate this vaccine for them and then we give it to them as part of their treatment regimen, and this is really cool because we don't know exactly what which tumor types will work best in,” Healy said.
Sounds simple, right? Of course it’s not. Healy admits that the manufacturing process will likely have similar challenges to those that have snarled the CAR-T space.
“There will be a lot of parallels to the CAR-T space in terms of the individualized nature of the therapy but what's different compared to CAR-T is the complexity,” Healy said. Moderna and Merck’s single mRNA molecule, encapsulated within a lipid nanoparticle, is simpler to manufacture than a live cell-based therapy, she said. That process requires genetic engineering and more.
“But there will be significant logistical challenges with these patient trials, because we're not used to having large studies where you have individualized therapy that you have to develop for every single patient and then get it to them, and so that can lead to bottlenecks in terms of manufacturing,” Healy said.
The current turnaround time is six to eight weeks, a time period that may only be suitable for earlier “micro-metastatic” cancers where patients get initial treatment, have surgery, and then, while waiting for the cancer to recur or not, the vaccine is manufactured. MRNA-4157 could also be administered in combination with other therapies, which could start even before the vaccine is ready.
“It's a vaccine so it takes time to work. So if a disease is just really taken off and progressing really fast, this is probably not a great therapy for those types of cancers because you have to train the immune system, and the immune system has to ramp up to be able to take care of the disease,” Healy explained.
The demand for these therapies is still unknown. Moderna and Merck have a lot of work to do to resolve those logistical challenges to support the therapy in a commercial setting if the phase 3 data are positive. Healy suspects that some of the process could be automated, but, ultimately, she hopes the easier process will help the therapy succeed where CAR-Ts have struggled.
“It will be a challenge, but I think that the advantage here is that it's associated with less complexity than CAR-T based therapies so I think that could be a real benefit,” Healy said.