Aprīlis 2022: Saskaņā ar provizoriskiem datiem no I/II fāzes klīniskā pētījuma, kas tika prezentēts 2022. gada AACR ikgadējā sanāksmē, kas notika no 8. līdz 13. aprīlim, jaunam himērisko antigēnu receptoru (CAR) T-šūnu produktam bija pieņemams drošības profils un tas parādīja agrīnas efektivitātes pazīmes monoterapijā un kombinācijā ar mRNS vakcīnu pacientiem ar norobežotiem audzējiem. Šī informācija tika sniegta aprīlī.
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.
Saskaņā ar prezentācijas vadītāju Džons Hānens, MD, PhD, medicīnas onkologs Nīderlandes Vēža institūtā (NKI), Amsterdamā, Nīderlandē, sacīja: "Ir grūti īpaši novirzīt CAR T šūnas pret audzēja šūnām, vienlaikus saudzējot veselās, jo lielākā daļa olbaltumvielas, kas atrodas uz cietajiem audzējiem, kuras varētu izmantot kā mērķi, ir arī zemā līmenī normālās šūnās. "Citas problēmas ietver ierobežoto CAR T šūnu noturību, kas novērota cietos audzējos", kā arī "viņu grūtības sasniegt audzējus un iekļūt masas centrā", teikts rakstā.
Dr Džons Hannens
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-šūna 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 klīniskā pētījuma 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-šūnu terapija 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-šūna 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 citokīnu atbrīvošanās sindroms 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.
"Tas ir pārsteidzoši, ka lielākajai daļai pacientu ar sēklinieku vēzi tika novērots klīnisks ieguvums 2. devas līmenī," sacīja Haanens. "Novērotās atbildes var būt dziļas, ieskaitot vienu nepārtrauktu pilnīgu remisiju."
Pēc Hānana teiktā, "CLDN6 CAR T infūzija atsevišķi vai kombinācijā ar CARVac ir droša un sola pacientiem ar CLDN6 pozitīvu vēzi." “CLDN6 nekad iepriekš nebija mērķēts ar šūnu terapiju; tomēr mūsu pētījumā šī pieeja jau uzrāda efektivitāti, kas var būt labāka nekā dati no citiem CAR T pētījumiem cieto audzēju gadījumā," sacīja pētnieki.
Tomēr Haanens brīdināja, ka šie dati ir ļoti agrīni, un tāpēc, ka līdz šim ir ārstēts tikai neliels skaits pacientu, ir pāragri izdarīt nozīmīgus secinājumus.
Izmeklēšanu finansēja BioNTech SE meitas uzņēmums, kas pazīstams kā BioNTech Cell & Gene Therapies GmbH. BioNTech sniedza finansiālu atbalstu NKI tās pētījumiem. Uzņēmuma BioNTech zinātniskajā konsultatīvajā padomē darbojas Hāns. Finansiālā kompensācija tiek saņemta NKI.
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