Ignacio Melero
Professor of Immunology at the University of Navarra, CIMA researcher and co-director of the Department of Immunology and Immunotherapy at the Clínica Universidad de Navarra.
Estos artículos presentan investigaciones preclínicas extraordinariamente interesantes. Describen la prueba de concepto sobre cómo poner un control remoto a los linfocitos que se utilizan en terapia celular adoptiva. La idea es poder controlar farmacológicamente la expresión de factores que aumentan su función pero que suponen un riesgo, puesto que pueden ser tóxicos.
En uno de los artículos la técnica consiste en controlar la función de genes clave con factores de transcripción artificiales. El diseño se basa en partes de controladores conocidos de la expresión génica, pero se han modificado sus propiedades para hacerlos sensibles a la modulación con fármacos de uso clínico. Se trata un mecano de piezas inteligente y controlable desde el exterior con fármacos para controlar con precisión el nivel de la expresión de algunos genes que son beneficiosos para la función antitumoral. Incluso algunas piezas se han optimizado y cambiado su encaje con genes de interés. Es un precioso ejemplo de virtuosismo tecnológico.
El segundo sistema se basa en receptores de membrana que, al encontrar su ligando, activan un factor de transcripción (proteína que controla en el núcleo la expresión de genes que responden a ese factor de transcripción). Como ejemplo controlan la expresión del gen de la de interleukina-2 y comprueban que, sorprendentemente, funciona mucho mejor en estos sistemas cuando la producen los propios linfocitos T de forma controlada.
These articles present extraordinarily interesting preclinical research. They describe the proof of concept of how to remotely control lymphocytes used in adoptive cell therapy. The idea is to be able to pharmacologically control the expression of factors that enhance their function but pose a risk, as they can be toxic.
In one paper, the technique involves controlling the function of key genes with artificial transcription factors. The design is based on parts of known controllers of gene expression, but their properties have been modified to make them sensitive to modulation by drugs in clinical use. It is an intelligent, externally drug-controllable mechano of parts to precisely control the level of expression of some genes that are beneficial for anti-tumour function. Some parts have even been optimised and re-matched to genes of interest. It is a beautiful example of technological virtuosity.
The second system is based on membrane receptors that, when they find their ligand, activate a transcription factor (a protein that controls the expression of genes in the nucleus that respond to that transcription factor). As an example, they control the expression of the interleukin-2 gene and find that, surprisingly, it works much better in these systems when it is produced by the T cells themselves in a controlled manner.
The experimentally proven concept is very promising. These papers conclude that it can be done. The ideas are patented but the translation to the clinic needs a lot of development and optimisation. The availability of remote pharmacological monitoring is certainly useful. Until now the only thing available in this regard was to put in pharmacologically controlled suicide genes to eliminate CAR lymphocytes if something went terribly wrong in the patient. Modulating function to increase function, but in a controlled way, is one avenue that could lead to effective adoptive cell therapies for solid tumours, taking treatment efficacy beyond haematological tumours (CAR therapies are often effective in the clinic only for leukaemias and B-lymphomas, as well as multiple myeloma).