"The local administration of anti-CD137 immunostimulant antibodies leads to rejection of tumors without the liver inflammation produced when administered intravenously", explained Dr. Ignacio Melero, a scientist at the Center for Applied Medical Research (CIMA) and the University of Navarra Hospital. The results of this research, carried out in collaboration with researchers at the Immunology Service of the Hospital de la Princesa in Madrid, have been published in the scientific journal Cancer Discovery, of the American Association for Cancer Research (AACR).

In the tumor microenvironment there are simultaneously immunity-system cells which favor tumor growth and others which, potentially, have the capacity to destroy malignant cells. "In the last ten years we have seen an explosion of knowledge on the cell and molecular mechanisms that cause these effects. These mechanisms are therapeutic targets which can be altered by means of monoclonal antibodies and other therapeutic agents", suggested Asís Palazón, a postdoctoral researcher at CIMA and the first of the article's authors.

The micro-environmental conditions in tumoral tissue are different from those of most tissues. Parameters such as the absence of oxygen, intense metabolic activity and high interstitial pressure mark the changes in the cellular functioning of the tumor. "We are aware that the administration of antibodies that activate CD137, a receptor that accelerates the cell functions of the immune system, determines the rejection of transplantable tumors in mice. The pharmaceutical companies Bristol Myers and Pfizer are carrying out clinical trials with antibodies with this specificity. In our work, we realized that the lymphocytes with tumoricidal capacity inside the tumors have CD137 on their surface, whereas this is not so in other parts of the organism. This is due to hypoxia (low oxygen pressure) and the cell mechanisms which adapt the cells to hypoxia. Given that most targets for the anti-CD137 immunostimulant antibodies are in the tumor, we found that local administration of these antibodies maintains the capacity to provoke rejection of the tumors without liver inflammation as a side effect".

Dr. Melero's group is taking part in a clinical trial at the University of Navarra Hospital which is analyzing these action mechanisms in patients. "Moreover, we have used animal models to study the effects of the synergic combination with other immunostimulant antibodies such as those that block PD-1. This receptor acts as an immune system brake, and the antibodies targeting it free the brake.   In the article published in Cancer Discovery we have shown that to provoke the rejection of the tumors in an optimum way we have to release the brake (PD-1) and step on the accelerator (CD137) of the lymphocytes that are present in the carcinoma infiltrates  and have both receptors simultaneously. These combinations of immunotherapy strategies show great clinical promise", explains the lead researcher.