2022 de abril: De acordo com dados preliminares de um ensaio clínico de fase I/II apresentado durante o AACR Annual Meeting 2022, realizado de 8 a 13 de abril, um novo produto de células T de receptor de antígeno quimérico (CAR) tinha um perfil de segurança aceitável e mostrou sinais precoces de eficácia como monoterapia e em combinação com uma vacina de mRNA em pacientes com tumores sólidos. Esta informação foi apresentada em abril.
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.
De acordo com o apresentador, John Haanen, MD, PhD, oncologista médico do Netherlands Cancer Institute (NKI), Amsterdã, Holanda, disse: “é difícil direcionar especificamente as células CAR T contra as células tumorais, poupando as saudáveis porque a maioria das as proteínas presentes em tumores sólidos que poderiam ser usadas como alvos também são encontradas em níveis baixos em células normais”. “Outros desafios incluem a persistência limitada de células CAR T observadas em tumores sólidos”, bem como “sua dificuldade em atingir os tumores e penetrar no centro da massa”, de acordo com o artigo.
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 Célula T CAR 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 ensaio clínico 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 Terapia de células T 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 Célula T CAR 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 síndrome de liberação de citocinas 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.
“É surpreendente que a maioria dos pacientes com câncer testicular tenha apresentado benefício clínico no nível de dose 2”, disse Haanen. “As respostas que observamos podem ser profundas, incluindo uma remissão completa contínua”.
De acordo com Haanen, “A infusão de CLDN6 CAR T, isoladamente ou em combinação com CARVac, é segura e promissora para pacientes com cânceres positivos para CLDN6”. “CLDN6 nunca foi direcionado antes com terapia celular; no entanto, em nosso estudo, essa abordagem já está mostrando eficácia que pode ser melhor do que os dados de outros ensaios CAR T em tumores sólidos”, disseram os pesquisadores.
No entanto, Haanen alertou que esses dados são muito iniciais e, como apenas um pequeno número de pacientes foi tratado até o momento, é prematuro tirar conclusões importantes.
A investigação foi financiada pela empresa subsidiária da BioNTech SE conhecida como BioNTech Cell & Gene Therapies GmbH. A BioNTech forneceu apoio financeiro à NKI para sua pesquisa. A empresa BioNTech tem Haanen servindo em seu conselho consultivo científico. A compensação financeira vai para a NKI.
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