The promise of immunotherapy for transplantation

The team of Julien Zuber, researcher in the Human Lymphohematopoiesis Laboratory at the Imagine Institute and transplanter at the Hôpital Necker-Enfants malades AP-HP, has identified the most promising candidate for future anti-rejection treatments based on immunotherapy.

Published on 20.12.2021

Research Acceleration

Over the past ten years, a new class of drugs has revolutionised cancer treatment: Chimeric Antigen Receptor T cells (CAR-T). These are immune cells, called T cells, which are educated to destroy tumour cells. This education consists of genetically modifying them by inserting into their nucleus a DNA sequence coding for a "chimeric" receptor which is capable of specifically recognising the antigen of tomoral cells. This innovative therapy has already produced spectacular results in patients with blood cancers.

Thanks to a new study published in the journal Nature Communications by the team of Julien Zuber, specialising in renal transplants at the Hôpital Necker-Enfants malades and researcher in the human lymphohaematopoiesis laboratory at the Institut Imagine, this approach could eventually be extended to another field of application: organ transplants and autoimmune diseases [1].

Using regulatory cells to prevent rejection

"Rather than targeting a tumour to destroy it, our approach consists of targeting the transplanted organ to protect it from the recipient's immune response and thus avoid rejection," explains Julien Zuber. To achieve this, researchers are developing so-called 'regulatory' CAR-T cells (CAR-Treg). These cells act like orchestra conductors : they are capable of selectively controlling the immune response in order to avoid rejection while preserving anti-infectious and anti-tumour responses. This is a valuable property that makes up for the main shortcoming of immunosuppressive treatments which, over time, weaken the entire immune system of transplant patients and increase the likelihood of developing cancer. "The risk of skin cancer in transplant patients is multiplied by a factor of 60 to 250 compared with the general population," emphasises Julien Zuber.

"Our approach is to target the transplanted organ to protect it from the recipient's immune response"

However, CAR-Treg cells still need to be investigated before they reach the bedside. Indeed, these cells tend to lose their regulatory identity if they are over-stressed. A whole field of research therefore consists of finding the best 'recipe' to make them more stable. In their new study, Julien Zuber and his team have made a significant advance in identifying one of the main ingredients of this recipe.

A first step towards future clinical trials

By studying in detail the influence of different chimeric receptor designs on the biology of the cell, they were able to identify the most appropriate one for future clinical studies. These chimeric receptors actually consist of several stages or 'domains', each involved in different stages of cell activation. There are two main candidate receptors : one involves a domain called CD28, the other a domain called 4-1BB. "Without going into detail, we have shown that the receptor with the CD28 domain is more effective and, above all, confers greater stability on CAR-Tregs than the one with 4-1BB in the context of transplantation, which had never been demonstrated before," explains Julien Zuber.

This important result is a first step towards future clinical investigations. However, researchers still need to accumulate a lot of data before they can get the green light from the French National Agency for the Safety of Medicines and Health Products (ANSM). This is precisely the ambition of Julien Zuber's team. "We are currently developing a new model that allows us to monitor the stability of the cell over a much longer period, precisely to be able to provide proof of safety to the regulatory authorities," he says. A promising work(*) which gives hope.

(1) B. Lamarthée et al., Nature Communications, doi.org/10.1038/s41467-021-26844-1, 2021

(*) This research project was financed by the DIM (Domaine d'intérêt majeur) 'Gene Therapy', a research support programme of the Île-de-France Region.