April 2022: Ifølge foreløbige data fra et fase I/II klinisk forsøg, der blev præsenteret under AACR Annual Meeting 2022, som blev afholdt fra 8.-13. april, havde et nyt kimærisk antigenreceptor (CAR) T-celleprodukt en acceptabel sikkerhedsprofil og viste tidlige tegn på effekt som monoterapi og i kombination med en mRNA-vaccine hos patienter med solid tumor. Disse oplysninger blev præsenteret i april.
Anvendelsen af CAR T-celleterapi til solide tumorer har vist sig at være vanskelig, på trods af at det fundamentalt har ændret de tilgængelige behandlingsmuligheder for hæmatologiske kræftformer.
Ifølge oplægsholderen, John Haanen, MD, PhD, en medicinsk onkolog ved det nederlandske kræftinstitut (NKI), Amsterdam, Holland sagde, "det er vanskeligt specifikt at rette CAR T-cellerne mod tumorceller, mens man skåner sunde, fordi de fleste af de proteiner, der findes på solide tumorer, der kan bruges som mål, også findes i lave niveauer på normale celler". "Andre udfordringer inkluderer den begrænsede persistens af CAR T-celler observeret i solide tumorer," såvel som "deres vanskeligheder med at nå tumorerne og trænge ind i midten af massen," ifølge artiklen.
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 CAR T-celle 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 kliniske forsøg 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 BIL T-cellebehandling 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 CAR T-celle 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 cytokinfrigivelsessyndrom 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.
"Det er forbløffende, at størstedelen af patienter med testikelkræft viste klinisk fordel ved dosisniveau 2," sagde Haanen. "De reaktioner, vi har observeret, kan være dybtgående, inklusive en igangværende fuldstændig remission."
Ifølge Haanen er "Infusionen af CLDN6 CAR T, enten alene eller i kombination med CARVac, sikker og lover for patienter med CLDN6-positive kræftformer." "CLDN6 var aldrig målrettet før med cellulær terapi; Men i vores undersøgelse viser denne tilgang allerede en effekt, der kan være bedre end data fra andre CAR T-forsøg i solide tumorer,” sagde forskerne.
Haanen advarede dog om, at disse data er meget tidlige, og fordi kun et lille antal patienter er blevet behandlet indtil dette punkt, er det for tidligt at drage nogen større konklusioner.
Undersøgelsen blev finansieret af datterselskabet af BioNTech SE kendt som BioNTech Cell & Gene Therapies GmbH. BioNTech ydede økonomisk støtte til NKI til sin forskning. Virksomheden BioNTech har Haanen i sit videnskabelige rådgivende udvalg. Økonomisk kompensation går til NKI.
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