Avril 2022: Selon les données préliminaires d'un essai clinique de phase I/II qui ont été présentées lors de la réunion annuelle 2022 de l'AACR, qui s'est tenue du 8 au 13 avril, un nouveau produit de lymphocytes T à récepteur d'antigène chimérique (CAR) avait un profil d'innocuité acceptable et a montré premiers signes d'efficacité en monothérapie et en association avec un vaccin à ARNm chez les patients atteints de tumeurs solides. Cette information a été présentée en avril.
The application of CAR T-cell therapy to solid tumours has proven to be difficult, despite the fact that it has fundamentally altered the treatment options available for hematologic cancers.
Selon le présentateur, John Haanen, MD, PhD, oncologue médical à l'Institut néerlandais du cancer (NKI), à Amsterdam, aux Pays-Bas, a déclaré : "il est difficile de diriger spécifiquement les cellules CAR T contre les cellules tumorales tout en épargnant les cellules saines car la plupart des les protéines présentes sur les tumeurs solides qui pourraient servir de cibles se retrouvent également à de faibles niveaux sur les cellules normales ». "D'autres défis incluent la persistance limitée des cellules CAR T observées dans les tumeurs solides", ainsi que "leur difficulté à atteindre les tumeurs et à pénétrer le centre de la masse", selon l'article.
Dr John Hannen
Haanen and colleagues are conducting a first-in-human, open label, multicenter clinical trial to evaluate the safety and preliminary efficacy of a previously developed Cellule T CAR product that targets CLDN6. CLDN6 is a tumor-specific antigen that is widely expressed in a variety of solid tumours but is silenced in healthy adult tissues. The purpose of this essai clinique is to determine whether or not the product is safe to use in humans and to determine whether or not it has preliminary therapeutic potential. This treatment was evaluated in preclinical models in conjunction with a CLDN6-encoding mRNA vaccine known as CARVac, which promotes the growth of CAR T cells. According to Haanen’s explanation, this combined treatment, which is known as BNT211, led to an increase in the transferred CAR T cells’ capacity to multiply and their persistence in the blood, which, in turn, led to an improvement in the ability to kill tumour cells.
Patients with relapsed or refractory advanced CLDN6-positive solid tumours were sought out by the researchers in order to test the effectiveness of the CLDN6 Thérapie par cellules CAR T both on its own and in conjunction with CARVac.
Following lymphodepletion to reduce the total number of T cells present in the body and make room for the transferred CAR T cells, the clinical trial was divided into two parts. In the first part, increasing doses of CLDN6 CAR T cells were administered as monotherapy. In the second part, the same treatment was administered in combination with CARVac. In Part 2, CARVac was given to the patient every two to three weeks for the first one hundred days after the Cellule T CAR transfer. Additionally, one patient received maintenance vaccinations every six weeks. When this report was written, a total of 16 patients had been treated up to that point.
A manageable syndrome de libération de cytokines developed in approximately forty percent of patients, but there was no evidence of neurotoxicity in any of these patients. Cytopenia, also known as a low blood cell count, and abnormal immune responses were some of the other adverse events that occurred, but they all went away on their own. After receiving CARVac, some people experienced fleeting symptoms similar to the flu that lasted for up to 24 hours. According to Haanen, “CLDN6 CAR T treatment and CARVac seemed to be safe, with only a limited number of adverse events that were easily manageable.”
Four patients with testicular cancer and two patients with ovarian cancer experienced a partial response (PR) at six weeks after infusion, resulting in an overall response rate of nearly 43 percent. The patients who were evaluable for efficacy were divided into two groups: those who had testicular cancer and those who had ovarian cancer. Among the people who took part in the research and had a PR, there were two patients who were treated with the combination of CAR T cells and CARVac and four patients who received CAR T cells as a monotherapy. There was an 86% success rate in eradicating the disease. At 12 weeks after the infusion, it was found that initial partial responses had improved in all of the patients who could be evaluated. This led to a single complete response, which is still present six months after the infusion was given.
"Il est étonnant que la majorité des patients atteints d'un cancer des testicules aient montré un bénéfice clinique au niveau de dose 2", a déclaré Haanen. "Les réponses que nous avons observées peuvent être profondes, y compris une rémission complète continue."
Selon Haanen, "La perfusion de CLDN6 CAR T, seule ou en association avec CARVac, est sûre et prometteuse pour les patients atteints de cancers CLDN6-positifs." « CLDN6 n'a jamais été ciblé auparavant par la thérapie cellulaire ; cependant, dans notre étude, cette approche montre déjà une efficacité qui pourrait être meilleure que les données d'autres essais CAR T dans les tumeurs solides », ont déclaré les chercheurs.
Cependant, Haanen a averti que ces données sont très précoces, et comme seul un petit nombre de patients ont été traités jusqu'à présent, il est prématuré de tirer des conclusions majeures.
L'enquête a été financée par la filiale de BioNTech SE connue sous le nom de BioNTech Cell & Gene Therapies GmbH. BioNTech a fourni un soutien financier à NKI pour ses recherches. La société BioNTech a Haanen siégeant à son conseil consultatif scientifique. La compensation financière va à NKI.
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