Aprile 2022: Secondo i dati preliminari di uno studio clinico di fase I/II presentato durante l'AACR Annual Meeting 2022, che si è tenuto dall'8 al 13 aprile, un nuovo prodotto a base di cellule T del recettore dell'antigene chimerico (CAR) aveva un profilo di sicurezza accettabile e ha mostrato primi segni di efficacia come monoterapia e in combinazione con un vaccino a mRNA in pazienti con tumori solidi. Queste informazioni sono state presentate ad aprile.
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.
Secondo il presentatore, John Haanen, MD, PhD, medico oncologo presso il Netherlands Cancer Institute (NKI), Amsterdam, Paesi Bassi, ha dichiarato: “è difficile dirigere in modo specifico le cellule T CAR contro le cellule tumorali risparmiando quelle sane perché la maggior parte delle le proteine presenti sui tumori solidi che potrebbero essere usate come bersagli si trovano a bassi livelli anche sulle cellule normali”. "Altre sfide includono la persistenza limitata delle cellule T CAR osservate nei tumori solidi", così come "la loro difficoltà a raggiungere i tumori e a penetrare nel centro della massa", secondo l'articolo.
Il dottor 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 Cella CAR-T 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 sperimentazione clinica 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 Terapia con cellule T CAR 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 Cella CAR-T 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 sindrome da rilascio di citochine 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.
"È sorprendente che la maggior parte dei pazienti con cancro ai testicoli abbia mostrato benefici clinici al livello di dose 2", ha affermato Haanen. "Le risposte che abbiamo osservato possono essere profonde, inclusa una remissione completa in corso".
Secondo Haanen, "L'infusione di CLDN6 CAR T, da solo o in combinazione con CARVac, è sicura e promettente per i pazienti con tumori CLDN6-positivi". “CLDN6 non è mai stato preso di mira prima con la terapia cellulare; tuttavia, nel nostro studio, questo approccio sta già dimostrando un'efficacia che potrebbe essere migliore rispetto ai dati di altri studi CAR T su tumori solidi", hanno affermato i ricercatori.
Tuttavia, Haanen ha avvertito che questi dati sono molto precoci e poiché solo un piccolo numero di pazienti è stato trattato fino a questo punto, è prematuro trarre conclusioni importanti.
L'indagine è stata finanziata dalla società controllata di BioNTech SE nota come BioNTech Cell & Gene Therapies GmbH. BioNTech ha fornito supporto finanziario a NKI per la sua ricerca. La società BioNTech ha Haanen nel suo comitato consultivo scientifico. La compensazione finanziaria va a NKI.
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