A humanized mouse model allows for the study of long-term immunotherapy combinations.

Researchers at Cima University of Navarra have optimized the use of humanized mice (in vivo) with the goal to reproduce the anti-tumor immune response of cancer patients. This model allows the testing of long-term immunotherapy combinations, thus overcoming the limitations of cellular (in vitro) models.

Immunotherapy has become a treatment of reference letter in different types of cancer and has also revolutionized the preclinical drug development . "The fundamental difference with other cancer drugs is that immunotherapy does not target molecules present in tumor cells, but proteins present in immune cells. This implies that we must include immune cells in preclinical models for the results to be reliable. This process leads to an increase B of its complexity and makes replicating the human immune system in models of laboratory a challenge", explains Dr. Iñaki Eguren, researcher of the group of Applied and Translational Onco-Immunology at Cima.

An alternative to rejection

Since cellular models (in vitro) are limited by their short duration and after a few days of culture the sample usually loses viability, for longer term experiments it is necessary to have an animal model (in vivo) that provides the tumor with a balanced environment of nutrients and metabolites to sustain its growth. However, the incorporation of human immune cells into mice leads to recognition of the mouse tissue as foreign, with subsequent rejection. 

"In our laboratory at Cima we have explored a mouse model genetically modified to prevent rejection, in which we have tested two types of immunotherapy. In both treatment modalities, we have found that this model mouse Exempt for 'severe graft-versus-host' disease allows for long-term experiments," says Dr. Eguren. The results have been published in the Journal for Immunotherapy of Cancer.

Specifically, this study highlights the use of compounds that directly activate T cells (the effector arm of our immune system), known as "T-cell engagers". This strategy has recently been approved for the treatment of uveal melanoma and small cell lung cancer. "These compounds make it possible to activate T-cells that are close to the tumor cell, achieving very striking responses. However, we still have a lot to learn about their mechanism of action and, above all, about the mechanisms of tumor resistance to this therapy. These models can help us to resolve some of these questions," says Dr. Miguel Fernández de Sanmamed. Dr. Miguel Fernández de Sanmamedresearcher principal of the group of Applied and Translational Onco-Immunology of the Cima and specialistof the Lung Cancerarea of the Cancer Center Clínica Universidad de Navarra.

The models developed have some limitations that will require further advances in the future. "The research advances in order to reproduce on the laboratory the complex interaction between tumor cells and the patient's immune system, with the goal ultimate goal of developing tools that allow us to reliably reproduce the patient's response to treatment," the researchers conclude.

The study, carried out at the framework of the Institute of research Sanitaria de Navarra (IdiSNA) and the research center Biomedica en network Cáncer (CIBERONC), was supported by partnership of public and private institutions such as the Ministry of Science, Innovation and Universities, the association Española contra el Cáncer, the CRIS contra el Cáncer Foundation and the FERO Foundation. 

Bibliographical references

- J Immunother Cancer. 2024 Sep 6;12(9):e008516. doi: 10.1136/jitc-2023-008516. MHC class I and II-deficient humanized mice are suitable tools to test the long-term antitumor efficacy of immune checkpoint inhibitors and T-cell engagers.