April 2022: Enligt preliminära data från en fas I/II klinisk prövning som presenterades under AACR Annual Meeting 2022, som hölls 8-13 april, hade en ny chimär antigenreceptor (CAR) T-cellsprodukt en acceptabel säkerhetsprofil och visade tidiga tecken på effekt som monoterapi och i kombination med ett mRNA-vaccin hos patienter med solida tumörer. Denna information presenterades i april.
Tillämpningen av CAR T-cellsterapi på solida tumörer har visat sig vara svår, trots att det i grunden har förändrat de tillgängliga behandlingsalternativen för hematologiska cancerformer.
Enligt presentatören, John Haanen, MD, PhD, en medicinsk onkolog vid Dutch Cancer Institute (NKI), Amsterdam, Nederländerna sa, "det är svårt att specifikt rikta CAR T-cellerna mot tumörceller samtidigt som man skonar friska eftersom de flesta av de proteiner som finns på solida tumörer som skulle kunna användas som mål finns också i låga nivåer på normala celler”. "Andra utmaningar inkluderar den begränsade persistensen av CAR T-celler som observerats i solida tumörer", såväl som "deras svårighet att nå tumörerna och penetrera massans centrum", enligt artikeln.
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-cell 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 prövning 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 CAR T-cellterapi 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-cell 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 cytokinfrisättningssyndrom 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 är häpnadsväckande att majoriteten av patienter med testikelcancer visade klinisk nytta vid dosnivå 2", sa Haanen. "Reaktionerna vi har observerat kan vara djupgående, inklusive en pågående fullständig remission."
Enligt Haanen är "Infusionen av CLDN6 CAR T, antingen ensam eller i kombination med CARVac, säker och lovar för patienter med CLDN6-positiva cancerformer." "CLDN6 var aldrig målinriktad tidigare med cellulär terapi; Men i vår studie visar detta tillvägagångssätt redan en effekt som kan vara bättre än data från andra CAR T-studier på solida tumörer, säger forskarna.
Haanen varnade dock för att dessa data är mycket tidiga och eftersom endast ett litet antal patienter har behandlats fram till denna punkt är det för tidigt att dra några större slutsatser.
Undersökningen finansierades av BioNTech SE:s dotterbolag, känt som BioNTech Cell & Gene Therapies GmbH. BioNTech gav ekonomiskt stöd till NKI för dess forskning. Företaget BioNTech har Haanen i sitt vetenskapliga råd. Ekonomisk ersättning går till NKI.
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