Home-Grown CAR-T Cells: A Blessing or a Threat?

Biotech's pushback against the development of academic CAR-T cell therapy in the Netherlands.

Chimeric Antigen Receptor T-cell therapy (CAR-T) is a new therapy where a patient's cells are harvested, modified, and reintroduced to kill cancer cells. Last week, the Dutch Healthcare Institute's announcement of a €16.5 million grant to the academic hospital of Groningen for developing an in-house CAR-T for the treatment of Multiple Myeloma (MM) sparked strong criticism from HollandBio, the umbrella organisation representing biotech companies in the Netherlands.

In a blog post titled "Government Fails, Not the Market," they argue that investing in the development of homegrown CAR-T therapies is a waste of taxpayers' money, unduly exposes patients to experimental treatments, and insults the biotech ecosystem. They find it particularly concerning because it follows a previous €30 million government subsidy to “cobble together” a CAR-T for non-Hodgkin lymphoma (NHL), which they consider a waste of scarce public funds.

Reading their statement today, several things go through my mind. Why are biotech companies reacting so strongly to a research grant, and why are they suddenly concerned about the waste of public money? Public resources are constantly wasted on authorised drugs with excessively high prices, unfunded lengthy treatment durations and ambiguous effectiveness. I’m also wondering why biotech companies are undermining a research programme with hurtful, damaging words and essentially unfounded allegations, such as “cobbling together” and “exposing vulnerable patients,” when this in-house CAR-T has already undergone a phase 2 trial (providing a similar level of evidence as some commercial products), and the current grant aims to deliver phase 3 data for regulatory approval in the second-line setting.

If anything, the research team deserves to be applauded for their noble mission to enhance accessibility and the steps they are taking to drive future innovations. After all, we shouldn't forget that CAR-T originated as an academic achievement

Limited access and displacement of other care

Currently, six CAR-T cell products are approved in the European Union, but access to these products has been limited. The combination of high costs and limited clinical evidence (typically based on small patient groups in single-arm trials) makes it difficult for HTA bodies to assess cost-effectiveness or negotiate financial agreements with the companies providing these therapies, without negatively impacting other healthcare services.

For the first authorised indication of Cilta-cel for MM patients who have had at least three prior treatments, the Dutch HTA advised the government in 2022 against covering the therapy due to its high costs and the negative impact on the healthcare budget.

To contextualize what is meant by “high costs”, the cost of one infusion bag of Cilta-cel is 420,000 euro based on the report of our HTA from 2022.

The HTA was unable to recommend a cost-effective price because the analysis submitted by the manufacturer was of insufficient quality. Recently, based on a new HTA review, the government has been advised to negotiate a price reduction of at least 35%, as the budget impact of Cilta-cel could cause a significant displacement of other healthcare services, “equivalent to about 800 full-time district nurses”. This is for a country with a population roughly double that of New York City.

While the first authorised indication of Cilta-cel is expected to become available soon following a successful financial arrangement, the reimbursement dossier for the second-line indication of this drug, which was authorised last year, still needs to be submitted by the company to the Dutch HTA body. This indication concerns a much larger patient population and therefore has a higher budget impact.

Many countries are investing in in-House CAR-T production

Worldwide, a growing number of academic centres are establishing the necessary infrastructure and expertise to develop and produce CAR-T therapies. In Europe, the EMA is actively supporting academia and non-profit organisations in developing CAR-T or other advanced therapy medicinal products (ATMPs) to help them meet regulatory requirements. The first CAR-T pilot is ARI-0001, a second-generation CAR developed at Hospital Clínic de Barcelona for Acute Lymphoblastic Leukaemia (ALL) and NHL. A second CAR-T (ARI-0002h) for multiple myeloma (MM) is also being developed through an academic network, including the initiative in the Netherlands.

Building academic networks for collaboration, alongside effective regulatory oversight, is essential for the sustainable development and production of CAR-T therapies.

Six reasons for countries to invest in CAR-T development

Investing in in-house development and production of CAR-T therapies offers several strategic, operational and financial advantages:

• 1. Production of CAR-T at academic facilities can be achieved at a fraction of the commercial cost, making therapies more affordable and accessible.

• 2. There is no need for patient materials to be shipped to a centralised facility, often outside the country, for processing. This reduces the time required to start therapy and potentially has a positive impact on the quality of the cells and the outcome of the therapy.

• 3. Greater flexibility to innovate, like rapid prototyping and testing of new CAR-T modifications, enables better-tailored treatments with improved safety and efficacy.

• 4. Academic centres can prioritise treatments for underserved populations, like paediatrics or rare conditions, as there's no pressure for high financial returns.

• 5. Greater transparency regarding the product characteristics, which is important for the reproducibility of research, predicting efficacy and for investigating long-term effects, such as the potential development of secondary malignancies.

• 6. Manufacturing process between clinical trials and routine treatment is more consistent for in-house CAR-T; this can be a challenge for commercial CAR-T cell therapies, as companies need to significantly scale up production after authorisation. In its assessment report regarding uncertainties and limitations of Cilta-cel, the EMA notes: “Regarding the proposed commercial manufacturing process, comparability of commercial product with clinical trial lots could not be fully established at the quality level. Currently, only few clinical data are available for patients treated with lots from the commercial process, supporting the efficacy of these lots but not excluding slight differences.”

From the Hospital Clínic de Barcelona, where CAR-T products are manufactured, Urbano-Ispizua et al. note that, while it may seem we are competing with pharmaceutical companies, “a symbiotic relationship is plausible.” “ Building Point-of-care manufacturing infrastructure does not have to serve as a competition for pharmaceutical companies but can instead narrow the inequality gap that currently exists with commercial CAR T-cell programs.”