April 2022: I følge foreløpige data fra en fase I/II klinisk studie som ble presentert under AACR Annual Meeting 2022, som ble holdt fra 8. til 13. april, hadde et nytt kimærisk antigenreseptor (CAR) T-celleprodukt en akseptabel sikkerhetsprofil og viste tidlige tegn på effekt som monoterapi og i kombinasjon med en mRNA-vaksine hos pasienter med solide svulster. Denne informasjonen ble presentert i april.
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.
I følge foredragsholderen, John Haanen, MD, PhD, en medisinsk onkolog ved Netherlands Cancer Institute (NKI), Amsterdam, Nederland sa, "det er vanskelig å spesifikt rette CAR T-cellene mot tumorceller mens man sparer friske fordi de fleste av proteinene som er tilstede på solide svulster som kan brukes som mål, finnes også i lave nivåer på normale celler”. "Andre utfordringer inkluderer den begrensede persistensen av CAR T-celler observert i solide svulster," så vel som "vanskelighetene deres med å nå svulstene og trenge gjennom midten av massen," ifølge artikkelen.
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 klinisk studie 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 C-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 flertallet av pasienter med testikkelkreft viste klinisk fordel ved dosenivå 2," sa Haanen. "Responsene vi har observert kan være dyptgripende, inkludert en pågående fullstendig remisjon."
Ifølge Haanen, "Infusjonen av CLDN6 CAR T, enten alene eller i kombinasjon med CARVac, er trygg og lover for pasienter med CLDN6-positive kreftformer." "CLDN6 ble aldri målrettet før med cellulær terapi; I vår studie viser imidlertid denne tilnærmingen allerede en effekt som kan være bedre enn dataene fra andre CAR T-studier i solide svulster,» sa forskerne.
Haanen advarte imidlertid om at disse dataene er veldig tidlige, og fordi bare et lite antall pasienter har blitt behandlet frem til dette punktet, er det for tidlig å trekke noen store konklusjoner.
Undersøkelsen ble finansiert av datterselskapet til BioNTech SE kjent som BioNTech Cell & Gene Therapies GmbH. BioNTech ga økonomisk støtte til NKI for sin forskning. Selskapet BioNTech har Haanen i sitt vitenskapelige rådgivende styre. Økonomisk kompensasjon går til NKI.
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