Apríl 2022: Podľa predbežných údajov z klinickej štúdie fázy I/II, ktorá bola prezentovaná počas výročného stretnutia AACR 2022, ktoré sa konalo od 8. do 13. apríla, nový produkt T-buniek s chimérickým antigénovým receptorom (CAR) mal prijateľný bezpečnostný profil a preukázal skoré známky účinnosti ako monoterapie a v kombinácii s mRNA vakcínou u pacientov so solídnymi nádormi. Táto informácia bola prezentovaná v apríli.
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.
John Haanen, MD, PhD, lekársky onkológ z Holandského onkologického inštitútu (NKI), Amsterdam, Holandsko povedal, že „je ťažké špecificky nasmerovať CAR T bunky proti nádorovým bunkám a zároveň šetriť zdravé, pretože väčšina proteíny prítomné na pevných nádoroch, ktoré by mohli byť použité ako ciele, sa nachádzajú v nízkych hladinách aj na normálnych bunkách“. "Ďalšie výzvy zahŕňajú obmedzené pretrvávanie CAR T buniek pozorované v solídnych nádoroch", ako aj "ich ťažkosti dostať sa k nádorom a preniknúť do stredu hmoty," podľa článku.
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-bunka 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 Klinická štúdia 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 Liečba T-bunkami CAR 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-bunka 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 syndróm uvoľnenia cytokínov 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.
"Je ohromujúce, že väčšina pacientov s rakovinou semenníkov preukázala klinický prínos pri dávke 2," povedal Haanen. "Odpovede, ktoré sme pozorovali, môžu byť hlboké, vrátane jednej prebiehajúcej úplnej remisie."
Podľa Haanena „Infúzia CLDN6 CAR T, buď samostatne alebo v kombinácii s CARVac, je bezpečná a sľubuje pacientov s CLDN6-pozitívnymi rakovinami. „CLDN6 nebol nikdy predtým cielený bunkovou terapiou; v našej štúdii však tento prístup už ukazuje účinnosť, ktorá môže byť lepšia ako údaje z iných štúdií CAR T u solídnych nádorov,“ uviedli vedci.
Haanen však varoval, že tieto údaje sú veľmi skoré, a keďže sa doteraz liečil len malý počet pacientov, je predčasné robiť nejaké zásadné závery.
Vyšetrovanie financovala dcérska spoločnosť BioNTech SE známa ako BioNTech Cell & Gene Therapies GmbH. BioNTech poskytol finančnú podporu NKI na jej výskum. Spoločnosť BioNTech má Haanen, ktorý pôsobí v jej vedeckom poradnom zbore. Finančná kompenzácia ide NKI.
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