New procedure to reduce costs for cancer therapy

Frankfurt For ten years, Emily Whitehead has celebrated her birthday twice a year. Once on the anniversary of her birth and once because she has been cancer-free for another year. The young American was saved by CAR-T therapy. This involves reprogramming the patient's immune cells so that they successfully fight the aggressive blood cancer cells.

The procedure is a milestone in the history of medicine

The CAR-T therapy from the Swiss pharmaceutical company Novartis was first approved in the USA in 2017. In the meantime, countless previously incurable blood cancer patients owe their lives to innovative cell therapies.

But there could be many more lives to be saved. Therapies such as the one for Emily Whitehead are still largely produced in clean rooms. This is time-consuming and makes them expensive – the costs are more than a quarter of a million euros.

Will mRNA technology make Car-T cell therapy cheaper?

A greater use of such therapies would not only overburden healthcare systems financially, it is hardly technically feasible.

says Ulrike Köhl, Director of the Fraunhofer Institute IZI, which produced the CAR-T therapy Kymriah for Novartis for some time.

The RNAuto project aims to change this: seven Fraunhofer Institutes are developing a process based on mRNA technology, which was made famous by the coronavirus vaccines. mRNA technology has been researched in cancer medicine for decades, and development pioneer Biontech also has its roots here. This „messengerRNA“ is a messenger substance that carries the genetic information, the blueprint for a protein. And can thus reprogramme cells.

The end result should be an automated, multi-module production technology that can reduce costs by 90 per cent – and produce therapies in just a few days instead of four to six weeks.

„In my opinion, the lead project RNAuto has really great potential to significantly advance individualised therapies“, says Lutz Uharek, expert in cell and gene therapies and founder of the biotech start-up Xencura.

Car T-cell therapy: A billion-dollar market for gene therapies is emerging

There are currently six CAR-T therapies approved worldwide and hundreds are currently being researched. The need is great: every year, more than 917,000 people worldwide are diagnosed with blood cancer alone. And even beyond oncology, more and more novel gene and cell therapies are being developed for infectious diseases, hereditary diseases and autoimmune diseases.

The FDA and EMA expect more than ten of these innovative therapies, known in the industry as ATMPs (Advanced Therapy Medicinal Products), to come onto the market every year from 2025 onwards.

The market is still in its infancy. According to estimates by market researchers at the Business Research Company, sales of gene and cell therapies are expected to triple from just under 8.6 billion dollars last year to more than 26 billion dollars in 2027. And then continue to grow at a significant double-digit rate.

This estimate is probably still conservative, as according to the industry association Alliance for Regenerative Medicine, there are currently 2220 clinical studies on these innovative therapies worldwide. Of these, 43 per cent are in the USA, 38 per cent in the Asia-Pacific region and 18 per cent in Europe.

Car T-cell therapy: faster, cheaper, safer

In CAR-T therapy, an inactive virus is introduced into the immune cells (T cells) whose genetic material has been expanded to include a special gene. The cells produce a protein called CAR (chimären antigen receptor) with the help of the präparised gene. This becomes something like an antenna on the surface of the cell and ensures that the CAR-T cells that have now been built recognise the patient's cancer cells and bind them according to the lock-and-key principle.

In the Fraunhofer project, gene transfer is to be carried out using mRNA instead of viruses. The idea is to use mRNA to reprogramme immune cells in such a way that they destroy cancer cells, for example. Because mRNA technology is very flexible, the active substances can be adapted to a new target and produced comparatively quickly," says Köhl.

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Andreas Herrmann, Chair of Macromolecular Materials and Systems at RWTH Aachen University, sees the main advantage of non-viral gene transfer as being significantly higher patient safety: „With mRNA, there is no risk of DNA integrating into the genome of the patient's cells. In contrast, this can certainly occur with viral gene transfer.“

And mRNA has further advantages: it can be produced more cheaply and quickly. In addition to mRNA-induced therapeutics, Fraunhofer intends to develop a production process for manufacturing an mRNA-based vaccine against the West Nile virus in a second project.

Binding the individual parts together

The four-year lead project is headed by immuno-oncologist Köhl. The various Fraunhofer Institutes are pooling their expertise in vaccine development, cell and gene therapy, bioprocess development, smart sensor technology and the automation and digitalisation of production processes.

The broad expertise is necessary. The risk of contamination is high in cleanrooms, and every manufacturing process must meet the highest standards. And until now, this has practically come from workshops, not factories: „We want to bring the work and expertise of the pharmacist, so to speak, who previously did the process by hand, into an automated process“, says Peter Liggesmeyer, Institute Director of Fraunhofer IESE in Kaiserslautern.

There are already devices from companies such as the Swiss company Lonza or the German biotech firm Miltenyi, which carry out cell separation, cell cultivation and cell formulation (i.e. the reprogramming of the T cell to CAR-T) through to the finished product in the clean room. However, the transition from one production step to the next is still carried out manually.

In addition, quality control, which makes up a large part of the process, has so far only been automated to a limited extent. Here we need a digitally controlled monitoring process that works without human intervention as far as possible," says Köhl. We need to investigate how well the killer cells have been reprogrammed, how well they multiply and whether they also destroy the cancer cells.

„Entirely new players are emerging“

Uharek believes that the RNAuto project is a pioneering approach. The entrepreneur established the production of individualised cell therapeutics at the Charité University Hospital in Berlin. Two years ago, he founded his own company Xencura, which offers a digitally controlled platform for the production of gene and cell therapies, also individualised.

It is important that different disciplines are brought together so that more companies can map the entire process for the production of such therapies in one, says the oncologist.

In the USA, for example, there are more and more treatment centres specialising in the production of individual gene and cell therapies, reports Uharek. „Entirely new players are emerging that are also competing with the pharmaceutical industry to a certain extent.“

However, the pharmaceutical industry is not idle either: Novartis has set up production facilities for its gene and cell therapies in the USA, France and Switzerland. And Biontech - the company has been focussing on the support of artificial intelligence (AI) in drug development for a few years now - acquired its cooperation partner Instadeep from the UK in January of this year. The technology company specialises in AI and machine learning.

Biontech intends to deploy these technologies across the company to build large-scale capabilities in AI-driven drug discovery and the development of next-generation immunotherapies and vaccines.

First discussions with companies

The Fraunhofer Institute IESE in Kaiserslautern is responsible for automated production in the lead project RNAuto. In an earlier consortium project with industrial partners, the institute developed a virtual middleware called BaSyS4 for applications in the field of Industry 4.0, i.e. the networked factory. The software platform controls production digitally and with the help of AI. This system is able to automatically plan and reschedule production processes, for example if a machine breaks down," says Liggesmeyer.

Digital twins will also be used to virtualise production and quality control. Fraunhofer wants to make the modules, software packages and production processes developed as part of the project accessible to industry via process patents.

As they are working with modules of different sizes, they are of interest to both large pharmaceutical companies and smaller biotech companies, as well as for research at universities, says Liggesmeyer: "We are already holding initial discussions with industry.

Car T-cell therapy: cheaper, but still expensive

Molecular expert Andreas Herrmann from the University of Aachen believes that the applications of the lead project are particularly interesting for smaller biotech companies. They would then have the opportunity to continue to concentrate on their core medical expertise and can leave the topic of production to Fraunhofer. And then perhaps licence in the technology later on,

he says.

Liggesmeyer, meanwhile, cites a decisive factor: „Our model calculations have shown that in the medium term, the price of such innovative therapies could be reduced to a tenth or less.“ This would bring the project roughly in line with the price level of conventional therapies for cancer therapeutics, the professor explains.

This would mean that the new cell therapies would cost a five-figure sum instead of a six-figure sum in future: conventional chemotherapies currently cost up to 20,000 euros, while cancer immunotherapies cost at least 80,000 euros. That is still a lot of money for a CAR-T therapy - but far closer to medical practice.

More: These could be the biontechs of tomorrow– Five German biotech hopes of investors

Article from the "Handelsblatt" of 27 March 2023