Trial TILs001, which is open to patients with metastatic triple-negative breast cancer, is the first study to assess the safety and efficacy of TILs selected in accordance with their PD-1 protein expression levels.

On 15 July 2022, trial TILs001 started at the Hospital Clínic de Barcelona, a trial led by Dr. Aleix Prat and funded by the Spanish Association Against Cancer (AECC). This trial, involving eight patients with metastatic triple-negative breast cancer, will include the participation of three other Spanish centres: the Hospital Universari Vall d'Hebron in Barcelona, the Clínica Universidad de Navarra and the Hospital Universitario 12 de Octubre in Madrid. The study will be coordinated by SOLTI, an academic oncology research group that carries out both national and international clinical trials.

"We are very happy to announce that we have opened our first academic clinical trial TILs001 for patients with metastatic triple-negative breast cancer", says Dr. Prat, head of the IDIBAPS Translational genomics and targeted therapies in solid tumours research group. "This procedure has already shown promising results in patients with metastatic melanoma and other types of tumour, and we are now starting to test its viability in this type of aggressive breast cancer", he adds.

Metastatic triple-negative breast cancer (mTNBC) is the most aggressive type of breast cancer and accounts for about 10-15% of all breast cancer cases. It is a poorly known disease that affects around 5,000 women in Spain each year. Among women with metastatic TNBC, the five-year survival rate is 12%, compared with 28% in those with other types of metastatic breast cancer. Due to the nature of TNBC, treatment options are far more limited.

Cell-based immunotherapy using tumour-infiltrating lymphocytes (TILs) is a heterogeneous mixture made up of T-lymphocytes, mainly targeting tumour cells. There are two types of T-cells in the immune system, CD4+ and CD8+ T-cells, which are at different stages of cell differentiation. “Lymphocytes are cells of the immune system involved in its functioning and regulation and are responsible for destroying cancer or infected cells. TILs are found naturally in the inflammatory infiltrates of some solid tumours", explains Dr. Manel Juan, head of the Hospital Clínic Immunology Service and of the Immunogenetics and immunotherapy in the immune and autoinflammatory response group.

The adoptive T-lymphocyte transfer or TIL therapy in solid tumours is a programme that was launched jointly by the Medical Oncology and Immunology Services at the Hospital Clínic. It is a type of cell therapy that is conceptually similar to CAR T-cell therapy. However, instead of genetically manipulating T-lymphocytes, it selects the anti-tumour T-lymphocytes present in the tumour. The Hospital Clínic-IDIBAPS has already developed CAR T-cell therapies to treat acute lymphoblastic leukaemia, already authorized for use by the Spanish Agency of Medicines and Medical Devices (AEMPS), or for multiple myeloma, which is currently being assessed by this agency.

The process consists of three parts. First of all, molecular pre-selection is performed to select the tumours most likely to be enriched by TILs by determining the PD-1 expression in the tumour. Next, those T-lymphocytes most capable of acting against cancer cells (PD-1-positive TILs) are isolated and selected, and many copies are produced in the laboratory. Finally, these lymphocytes are injected back into the patient intravenously. The final infusion product is manufactured by the Hospital Clínic de Barcelona under the name NUMARZU-001 and, thanks to the validation and structuring work by Núria Chic, Marta Español, Azucena González and Eulàlia Olesti, it has been shown that it is possible to obtain it from patients in a reproducible way, a fundamental step towards obtaining authorization from the AEMPS to start this trial.

Dr. Gonzalo Calvo, head of the Clinical Pharmacology Service in the Medicines Area of the Hospital Clínic, led a group of professionals in his department, who prepared the dossier to obtain approval for the clinical trial. According to Dr. Calvo, “the approval process was complex, due to the nature of the study, and it was possible thanks to the great professionals who contributed to the preparation of the application dossier”.

SOLTI will be the organization responsible for managing the development of the trial, coordinating all the activities in the four participating hospitals, where for the first time in Spain treatment of this type of immunotherapy for breast cancer will be administered. Tomás Pascual, scientific director of SOLTI and oncologist at the Hospital Clínic, explains that the trial TILs001 “represents a new therapeutic option for patients with metastatic triple-negative breast cancer. As a cooperative group, which bases its research on networking with hospitals, being part of an academic trial is our raison d'être. All this makes us proud and reaffirms the important work we do as cooperative groups.

In addition to being supported by the AECC, the trial has received funding from the Fero Foundation and from other campaigns and anonymous donations through the Hospital Clínic-IDIBAPS Immunotherapy against cancer project. The Hospital Clínic-IDIBAPS Immunotherapy Research Unit is supported by “la Caixa” Foundation, thanks to a strategic alliance established between the institutions.

Image: From lesft to right: Tomás Pascual, Azucena González, Manel Juan, Eulalia Olesti, Mariona Pascal y Aleix Prat (Foto: Francisco Avia)

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