April 2022: Glede na predhodne podatke iz kliničnega preskušanja faze I/II, ki so bili predstavljeni med letnim srečanjem AACR 2022, ki je potekalo od 8. do 13. aprila, je imel nov T-celični izdelek himernega antigenskega receptorja (CAR) sprejemljiv varnostni profil in je pokazal zgodnji znaki učinkovitosti kot monoterapije in v kombinaciji s cepivom mRNA pri bolnikih s solidnimi tumorji. Te informacije so bile predstavljene aprila.
Uporaba CAR T-celične terapije pri solidnih tumorjih se je izkazala za težavno, kljub dejstvu, da je bistveno spremenila možnosti zdravljenja, ki so na voljo za hematološke rake.
John Haanen, MD, PhD, medicinski onkolog na Nizozemskem inštitutu za raka (NKI), Amsterdam, Nizozemska, je povedal, da je »težko specifično usmeriti CAR T celice proti tumorskim celicam, hkrati pa prihraniti zdrave, ker večina beljakovine, prisotne na solidnih tumorjih, ki bi jih lahko uporabili kot tarče, najdemo tudi v nizkih ravneh na normalnih celicah. "Drugi izzivi vključujejo omejeno obstojnost celic CAR T, opaženih v solidnih tumorjih," kot tudi "njihove težave pri doseganju tumorjev in prodiranju v središče mase," piše v 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 CAR T-celica 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 klinično preskušanje 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-celična 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 CAR T-celica 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 sproščanja citokinov 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.
"Osupljivo je, da je večina bolnikov z rakom testisov pokazala klinično korist pri odmerku 2," je dejal Haanen. "Odzivi, ki smo jih opazili, so lahko globoki, vključno z eno stalno popolno remisijo."
Po besedah Haanena je "infuzija CLDN6 CAR T, bodisi sama bodisi v kombinaciji s CARVac, varna in obetavna za bolnike s CLDN6 pozitivnimi vrstami raka." »CLDN6 še nikoli ni bil ciljno usmerjen s celično terapijo; vendar v naši študiji ta pristop že kaže učinkovitost, ki je lahko boljša od podatkov iz drugih preskušanj CAR T pri solidnih tumorjih,« so povedali raziskovalci.
Vendar je Haanen opozoril, da so ti podatki zelo zgodnji in ker je bilo do te točke zdravljenih le majhno število bolnikov, je prezgodaj za kakršne koli večje zaključke.
Preiskavo je financiralo hčerinsko podjetje BioNTech SE, znano kot BioNTech Cell & Gene Therapies GmbH. BioNTech je NKI finančno podprl raziskave. Družba BioNTech ima Haanena v svojem znanstvenem svetovalnem odboru. Finančno nadomestilo gre NKI.
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