آوریل 2022: بر اساس داده های اولیه از یک کارآزمایی بالینی فاز I/II که در جلسه سالانه AACR 2022 که از 8 تا 13 آوریل برگزار شد، ارائه شد، یک محصول جدید گیرنده آنتی ژن کایمریک (CAR) سلول T دارای مشخصات ایمنی قابل قبولی بود و نشان داد علائم اولیه اثربخشی به عنوان یک تک درمانی و در ترکیب با واکسن mRNA در بیماران مبتلا به تومورهای جامد. این اطلاعات در ماه آوریل ارائه شده است.
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.
به گفته مجری، جان هانن، MD، PhD، انکولوژیست پزشکی در موسسه سرطان هلند (NKI)، آمستردام، هلند، گفت: «هدایت کردن سلول‌های CAR T در مقابل سلول‌های تومور در حالی که از سلول‌های سالم صرفه‌جویی می‌کند، دشوار است، زیرا بسیاری از پروتئین های موجود در تومورهای جامد که می توانند به عنوان هدف مورد استفاده قرار گیرند نیز در سطوح پایین در سلول های طبیعی یافت می شوند. بر اساس این مقاله، «چالش‌های دیگر عبارتند از تداوم محدود سلول‌های CAR T مشاهده‌شده در تومورهای جامد» و همچنین «مشکل آنها در رسیدن به تومورها و نفوذ به مرکز توده».
دکتر جان هانن
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-cell 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 کارآزمایی بالینی 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 سلول درمانی T با 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-cell 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 سندرم رهش سیتوکین 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.
هانن گفت: «تعجب آور است که اکثر بیماران مبتلا به سرطان بیضه مزایای بالینی را در سطح دوز 2 نشان دادند. پاسخ‌هایی که مشاهده کرده‌ایم می‌توانند عمیق باشند، از جمله یک بهبودی کامل مداوم.»
به گفته هانن، "تزریق CLDN6 CAR T، چه به تنهایی یا در ترکیب با CARVac، ایمن است و برای بیماران مبتلا به سرطان های CLDN6 مثبت نویدبخش است." CLDN6 قبلا هرگز با سلول درمانی مورد هدف قرار نگرفت. با این حال، در مطالعه ما، این رویکرد در حال حاضر کارایی را نشان می دهد که ممکن است بهتر از داده های دیگر کارآزمایی های CAR T در تومورهای جامد باشد.
با این حال، هانن هشدار داد که این داده‌ها بسیار زود است، و از آنجایی که تنها تعداد کمی از بیماران تا این مرحله تحت درمان قرار گرفته‌اند، نتیجه‌گیری اساسی زود است.
این تحقیقات توسط شرکت تابعه BioNTech SE معروف به BioNTech Cell & Gene Therapies GmbH تأمین مالی شد. BioNTech برای تحقیقات خود از NKI حمایت مالی کرد. شرکت BioNTech دارای Haanen در هیئت مشاوره علمی خود است. غرامت مالی به NKI می رود.
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