April 2022: Menurut data awal daripada percubaan klinikal fasa I/II yang dibentangkan semasa Mesyuarat Tahunan AACR 2022, yang diadakan dari 8-13 April, produk sel T reseptor antigen chimeric (CAR) baharu mempunyai profil keselamatan yang boleh diterima dan menunjukkan tanda-tanda awal keberkesanan sebagai monoterapi dan digabungkan dengan vaksin mRNA pada pesakit dengan tumor pepejal. Maklumat ini dibentangkan pada bulan April.
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.
Menurut penyampai, John Haanen, MD, PhD, pakar onkologi perubatan di Institut Kanser Belanda (NKI), Amsterdam, Belanda berkata, "sukar untuk secara khusus mengarahkan sel T CAR terhadap sel tumor sambil menyelamatkan yang sihat kerana kebanyakan protein yang terdapat pada tumor pepejal yang boleh digunakan sebagai sasaran juga didapati pada tahap rendah pada sel normal”. "Cabaran lain termasuk kegigihan terhad sel T CAR yang diperhatikan dalam tumor pepejal," serta "kesukaran mereka mencapai tumor dan menembusi pusat jisim," menurut artikel itu.
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 Sel T KERETA 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 percubaan klinikal 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 Terapi sel T KERETA 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 Sel T KERETA 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 pelepasan sitokin 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.
"Sungguh mengejutkan bahawa majoriti pesakit dengan kanser testis menunjukkan manfaat klinikal pada tahap dos 2," kata Haanen. "Tanggapan yang kami perhatikan boleh menjadi sangat mendalam, termasuk satu pengampunan lengkap yang berterusan."
Menurut Haanen, "Infusi CLDN6 CAR T, sama ada secara bersendirian atau digabungkan dengan CARVac, adalah selamat dan menjanjikan untuk pesakit dengan kanser positif CLDN6." “CLDN6 tidak pernah disasarkan sebelum ini dengan terapi selular; bagaimanapun, dalam kajian kami, pendekatan ini sudah menunjukkan keberkesanan yang mungkin lebih baik daripada data daripada ujian CAR T lain dalam tumor pepejal, "kata penyelidik.
Bagaimanapun, Haanen memberi amaran bahawa data ini adalah sangat awal, dan kerana hanya sebilangan kecil pesakit telah dirawat sehingga tahap ini, adalah terlalu awal untuk membuat sebarang kesimpulan utama.
Siasatan itu dibiayai oleh anak syarikat BioNTech SE yang dikenali sebagai BioNTech Cell & Gene Therapies GmbH. BioNTech menyediakan sokongan kewangan kepada NKI untuk penyelidikannya. Syarikat BioNTech mempunyai Haanen berkhidmat di lembaga penasihat saintifiknya. Pampasan kewangan diberikan kepada NKI.
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