Április 2022: Az április 2022-8-án megtartott AACR Annual Meeting 13 során bemutatott I/II. fázisú klinikai vizsgálat előzetes adatai szerint egy új kiméra antigénreceptor (CAR) T-sejt-terméknek elfogadható biztonsági profilja volt, és a hatékonyság korai jelei monoterápiaként és mRNS vakcinával kombinálva szolid daganatos betegeknél. Ezt az információt áprilisban ismertették.
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.
Az előadó, John Haanen, MD, PhD, az amszterdami Holland Cancer Institute (NKI) orvosi onkológusa szerint „nehéz specifikusan irányítani a CAR T-sejteket a tumorsejtek ellen, miközben megkíméljük az egészségeseket, mert a legtöbb a szolid tumorokon jelenlévő fehérjék, amelyek célpontként használhatók, alacsony szinten megtalálhatók a normál sejtekben is”. „Egyéb kihívások közé tartozik a CAR T-sejtek szolid daganatokban megfigyelt korlátozott perzisztenciája”, valamint „nehezükre jutni a daganatokhoz és behatolni a tömeg közepébe” – áll a cikkben.
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-cella 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 klinikai vizsgálat 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-sejt terápia 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-cella 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 citokin felszabadulás szindróma 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.
„Elképesztő, hogy a hererákos betegek többsége klinikai előnyt mutatott a 2-es dózisszint mellett” – mondta Haanen. "Az általunk megfigyelt válaszok mélyrehatóak lehetnek, beleértve a folyamatban lévő teljes remissziót is."
Haanen szerint „A CLDN6 CAR T infúziója, akár önmagában, akár CARVac-cal kombinálva, biztonságos, és ígéretes a CLDN6-pozitív rákban szenvedő betegek számára.” „A CLDN6-ot korábban soha nem célozták meg a sejtterápiával; tanulmányunkban azonban ez a megközelítés már olyan hatékonyságot mutat, amely jobb lehet, mint más CAR T-vizsgálatok adatai szolid daganatokban” – mondták a kutatók.
Haanen azonban felhívta a figyelmet arra, hogy ezek az adatok nagyon koraiak, és mivel eddig csak kis számú beteget kezeltek, még korai lenne jelentős következtetéseket levonni.
A vizsgálatot a BioNTech SE BioNTech Cell & Gene Therapies GmbH néven ismert leányvállalata finanszírozta. A BioNTech anyagi támogatást nyújtott az NKI-nek kutatásaihoz. A BioNTech cég tudományos tanácsadó testületében Haanen dolgozik. Az anyagi ellentételezés az NKI-t kapja.
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