Researchers from CNIO and Hospital 12 de Octubre take part in two international trials to expand the indications of CAR-T cell immunotherapy

Immunotherapy with CAR-T cells is one of the biggest recent advances in cancer treatment, although for now it has only been approved for use in patients with certain haematological tumours who have not responded well to previous treatments. Researchers from CNIO and Hospital 12 de Octubre have participated in an international trial that will help to expand the indications of this therapy, and the results of which have been published in New England Journal of Medicine.

As haematologist Joaquin Martinez, director of the H12O-CNIO Haematological Malignancies Clinical Research Unit, explains, the fact that Spanish hospitals and research centres are collaborating significantly in these trials means, above all, that “we are drawing up alongside other European countries in the development of CAR-T therapies”.

The new trial is focusing on tisagenlecleucel, currently approved for the treatment of some second-relapse patients with diffuse large B-cell lymphoma and  relapsed childhood lymphoblastic leukaemia. 

The BELINDA trial is focusing on diffuse large B-cell lymphoma. Together with the ZUMA-7 trial – which uses the drug axi-cel to fight the same lymphoma– this is the first phase III trial for CAR-T therapy, in other words, its aim is to study whether the new treatment is safe and works well compared to the standard protocol in patients with first-relapsed lymphoma. Participants are randomly assigned to separate groups, allowing for more impartial analysis of the results. The findings from the BELINDA trial, published in the New England Journal of Medicine, in principle show no improvement over conventional treatment.

The study have been promoted by Novartis Pharmaceuticals Corporation, the manufacturer of tisagenlecleucel.

Ultra-personalised therapies

The application of CAR-T lymphocyte immunotherapy requires specific experience and expertise. It is a personalised therapy that involves an autologous transplant of T-lymphocytes, one of the types of cells that make up the immune system.

Specifically, the patient’s own T lymphocytes are genetically modified to strengthen their ability to fight the tumour. The modification takes place outside the body: Lymphocytes are removed, manipulated, and cultured in the laboratory, and finally infused into the patient, like an ultra-personalised medication. 

Genetic modification causes T lymphocytes to recognise a type of molecule present in cancer cells, specific to each type of cancer; the modified T lymphocytes target tumour cells and destroy them. Around 15 Spanish hospitals are already accredited to administer CAR-T immunotherapies, approved for the first time in Spain in 2018.

Need for more evidence against diffuse large B-cell lymphoma

The the H12O-CNIO Haematological Malignancies Clinical Research Unit is involved in the BELINDA trial, which tests the same CAR-T therapy in diffuse large B-cell lymphoma.

The use of tisagenlecleucel had already been approved for this disease, but only after a phase II trial without a comparison branch and for patients who have relapsed after two previous third-line treatments. The BELINDA trial is studying its application in patients following their first relapse and has found no improvement over standard treatment.

However, the aforementioned ZUMA-7 trial with another CAR-T in the same indication, published in the same journal, has seen positive results. “These studies should be continued in order to explore possible regulatory agency approval of CAR-T therapies in diffuse large B-cell lymphoma,” Martínez concludes.

Reference articles: Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. Michael R. Bishop et al. (New England Journal of Medicine). DOI:10.1056/NEJMoa2116596