Clinical protocol phase II study of tumor infiltrating lymphocytes in advanced tumors with alterations in the SWI/SNF complex: the TILTS study.

The SWI/SNF complex is a chromatin remodeling complex comprised by several proteins such as SMARCA4 or SMARCB1. Mutations in its components can lead to the development of aggressive rhabdoid tumors such as epithelioid sarcoma, malignant rhabdoid tumor or small cell carcinoma of the ovary hypercalcemic type, among others. These malignancies tend to affect young patients and their prognosis is poor given the lack of effective treatments. Characteristically, these tumors are highly infiltrated by TILs, suggesting that some lymphocytes are recognizing tumor antigens. The use of those TILs as a therapeutic strategy is a promising approach worth exploring. Here, we report the clinical protocol of the TILTS study, a Phase II clinical trial assessing personalized adoptive cell therapy with TILs in patients affected by these tumor types.Clinical Trial Registration: 2023-504632-17-00 (www.clinicaltrialsregister.eu) (ClinicalTrials.gov).

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Driver mutations in GNAQ and GNA11 genes as potential targets for precision immunotherapy in uveal melanoma patients.

Uveal melanoma (UM) is the most common ocular malignancy in adults. Nearly 95% of UM patients carry the mutually exclusive mutations in the homologous genes GNAQ (amino acid change Q209L/Q209P) and GNA11 (aminoacid change Q209L). UM is located in an immunosuppressed organ and does not suffer immunoediting. Therefore, we hypothesize that driver mutations in GNAQ/11 genes could be recognized by the immune system. Genomic and transcriptomic data from primary uveal tumors were collected from the TCGA-UM dataset (n = 80) and used to assess the immunogenic potential for GNAQ/GNA11 Q209L/Q209P mutations using a variety of tools and HLA type information. All prediction tools showed stronger GNAQ/11 Q209L binding to HLA than GNAQ/11 Q209P. The immunogenicity analysis revealed that Q209L is likely to be presented by more than 73% of individuals in 1000 G databases whereas Q209P is only predicted to be presented in 24% of individuals. GNAQ/11 Q209L showed a higher likelihood to be presented by HLA-I molecules than almost all driver mutations analyzed. Finally, samples carrying Q209L had a higher immune-reactive phenotype. Regarding cancer risk, seven HLA genotypes with low Q209L affinity show higher frequency in uveal melanoma patients than in the general population. However, no clear association was found between any HLA genotype and survival. Results suggest a high potential immunogenicity of the GNAQ/11 Q209L variant that could allow the generation of novel therapeutic tools to treat UM like neoantigen vaccinations.

Bases moleculares de la resistencia a cisplatino en cáncer de testículo / Molecular basis of platinum-resistance in testicular cáncer

El cisplatino ha sido, desde su introducción hace algo más de 30 años, la piedra angular del tratamiento de los tumores germinales testiculares y parte fundamental en los esquemas administrados en múltiples tumores de origen ovárico, pulmón, cabeza y cuello, vejiga, entre otros. Algunos tumores presentan resistencia primaria a este fármaco, otros la desarrollarán a pesar de una buena respuesta inicial. En el caso de los tumores germinales testiculares la gran mayoría son exquisitamente sensibles a esta droga pero hasta un 20% de los pacientes con enfermedad metastásica presentarán resistencia, la mayor parte secundaria tras una muy buena respuesta inicial. El cisplatino actúa uniéndose al ADN para así activar los mecanismos de reconocimiento de daño genético y activar apoptosis por la vía mitocondrial. Los mecanismos de resistencia a cisplatino han sido clasificados en (1) mecanismos que suceden antes de la unión al ADN, y (2) una vez se ha unido al ADN. La mayoría de los avances en el descubrimiento de los mismos han utilizado como modelos otras neoplasias, mayoritariamente tumores de ovario y pulmón. En esta revisión describiremos los mecanismos biológicos que hay detrás de la resistencia al cisplatino desde la perspectiva global pero intentándonos centrar en los tumores germinales testiculares (AU)

Cisplatin has been the cornerstone of germ cell testicular tumors therapy since its introduction more tan 30 years ago, and a basic part of the schemes given to multiple ovarian, lung, head and neck, and bladder tumors among others. Some tumors present primary resistance to this drug, others will develop it despite good initial response. In the case of testicular germ cell tumors most of them are very sensitive to this drug but up to 20% of patients with metastatic disease will present resistance, most of them secondary after a very good initial response. Cisplatin acts by binding to DNA to activate genetic damage recognition mechanisms and apoptosis through the mitochondrial pathway. Resistance mechanisms to cisplatin have been classified in those that happen (1) before its binding to DNA and (2) once it binds to DNA. Most advances in their discovery have used other neoplasias as models, mainly ovarian and lung tumors. In this review we will describe the biological mechanisms behind resistance to cisplatin from the global perspective but trying to focus in testicular germ cell tumors (AU)

Seguimiento del cáncer colorrectal / Folow-up of colorectal cancer

El seguimiento del cáncer colorrectal forma parte de nuestra práctica clínica, pese a existir una importante controversia sobre el número de visitas, qué pruebas utilizar y si estas estrategias tienen un impacto sobre la supervivencia. Todas estas preguntas se han intentado responder mediante varios estudios que incluyen metaanálisis, ensayos aleatorios y estudios de cohortes. Estos resultados han llevado al desarrollo de unas guías de práctica clínica por las sociedades oncológicas más importantes. En este capítulo revisaremos estos estudios y guías de práctica clínica para a continuación exponer nuestra experiencia con una cohorte de 399 pacientes seguidos de forma homogénea en nuestro centro (AU)