2022 de abril: Según los datos preliminares de un ensayo clínico de fase I/II que se presentó durante la Reunión Anual de la AACR de 2022, que se llevó a cabo del 8 al 13 de abril, un nuevo producto de células T del receptor de antígeno quimérico (CAR) tuvo un perfil de seguridad aceptable y mostró primeros signos de eficacia como monoterapia y en combinación con una vacuna de ARNm en pacientes con tumores sólidos. Esta información fue presentada en abril.
La aplicación de la terapia de células T con CAR a los tumores sólidos ha demostrado ser difícil, a pesar de que ha alterado fundamentalmente las opciones de tratamiento disponibles para los cánceres hematológicos.
Según el presentador, John Haanen, MD, PhD, oncólogo médico del Instituto del Cáncer de los Países Bajos (NKI), Ámsterdam, Países Bajos, dijo: "es difícil dirigir específicamente las células CAR T contra las células tumorales y evitar las sanas porque la mayoría de las proteínas presentes en los tumores sólidos que podrían usarse como dianas también se encuentran en niveles bajos en las células normales”. “Otros desafíos incluyen la persistencia limitada de las células CAR T observadas en los tumores sólidos”, así como “su dificultad para llegar a los tumores y penetrar el centro de la masa”, según el artículo.
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 COCHE de células T 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 ensayo 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 con 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 COCHE de células T 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 liberación 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.
“Es sorprendente que la mayoría de los pacientes con cáncer de testículo mostraran un beneficio clínico con el nivel de dosis 2”, dijo Haanen. “Las respuestas que hemos observado pueden ser profundas, incluida una remisión completa en curso”.
Según Haanen, "la infusión de CLDN6 CAR T, ya sea sola o en combinación con CARVac, es segura y prometedora para los pacientes con cánceres CLDN6 positivos". “CLDN6 nunca antes había sido el objetivo de la terapia celular; sin embargo, en nuestro estudio, este enfoque ya muestra una eficacia que puede ser mejor que los datos de otros ensayos CAR T en tumores sólidos”, dijeron los investigadores.
Sin embargo, Haanen advirtió que estos datos son muy preliminares, y debido a que hasta este momento solo se ha tratado a un pequeño número de pacientes, es prematuro sacar conclusiones importantes.
La investigación fue financiada por la empresa subsidiaria de BioNTech SE conocida como BioNTech Cell & Gene Therapies GmbH. BioNTech brindó apoyo financiero a NKI para su investigación. La empresa BioNTech tiene a Haanen en su consejo asesor científico. La compensación financiera va a NKI.
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