Travanj 2022: Prema preliminarnim podacima iz kliničkog ispitivanja faze I/II koji su predstavljeni tijekom godišnjeg sastanka AACR-a 2022., koji je održan od 8. do 13. travnja, novi T-stanični proizvod himernog antigenskog receptora (CAR) imao je prihvatljiv sigurnosni profil i pokazao rani znakovi učinkovitosti kao monoterapija i u kombinaciji s mRNA cjepivom u bolesnika sa solidnim tumorima. Ova informacija je predstavljena u travnju.
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.
Prema voditelju, Johnu Haanenu, MD, PhD, medicinskom onkologu na Nizozemskom institutu za rak (NKI), Amsterdam, Nizozemska, rekao je, "teško je specifično usmjeriti CAR T stanice protiv tumorskih stanica, a poštedjeti zdrave jer većina proteini prisutni na solidnim tumorima koji bi se mogli koristiti kao mete također se nalaze u niskim razinama na normalnim stanicama”. "Drugi izazovi uključuju ograničenu postojanost CAR T stanica uočenih u solidnim tumorima", kao i "njihove poteškoće u dosezanju tumora i probijanju središta mase", navodi se u članku.
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 AUTO T-stanica 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 kliničko ispitivanje 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 Terapija T-stanicama CAR-a 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 AUTO T-stanica 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 sindrom oslobađanja citokina 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.
"Zapanjujuće je da je većina pacijenata s rakom testisa pokazala kliničku korist pri razini doze 2", rekao je Haanen. "Odgovori koje smo primijetili mogu biti duboki, uključujući jednu potpunu remisiju koja je u tijeku."
Prema Haanenu, "Infuzija CLDN6 CAR T, bilo sama ili u kombinaciji s CARVacom, sigurna je i obećava za pacijente s CLDN6-pozitivnim karcinomima." “CLDN6 nikada prije nije bio ciljano staničnom terapijom; međutim, u našoj studiji, ovaj pristup već pokazuje učinkovitost koja bi mogla biti bolja od podataka iz drugih CAR T ispitivanja na solidnim tumorima,” rekli su istraživači.
Međutim, Haanen je upozorio da su ti podaci vrlo rani, a budući da je samo mali broj pacijenata liječen do ove točke, prerano je donositi bilo kakve veće zaključke.
Istragu je financirala tvrtka kćer BioNTech SE poznata kao BioNTech Cell & Gene Therapies GmbH. BioNTech je NKI-ju pružio financijsku potporu za njegovo istraživanje. Tvrtka BioNTech ima Haanena u znanstvenom savjetodavnom odboru. Novčana naknada ide NKI-ju.
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