An experimental drug that eliminates senescent cells from tumors can improve the effectiveness of chemotherapy, according to research led by the Barcelona Biomedical Research Institute (IRB), which opens the way to improving the treatment of different types of cancer.
Research clarifies why tumors become resistant to chemotherapy and how to remedy it. The drug has demonstrated treatment potential in mice with breast cancer and in human cells from patients with melanoma, endometrial, and head and neck cancer. A similar drug has been designed to be administered to people and has begun to be tested in non-human primates, reports José Alberto López-Domínguez, IRB researcher and co-author of the work.
Although chemotherapy reduces the size of tumors, it does not usually eliminate them completely. According to the results of the research presented today in the journal Nature Cancer, the cause - or one of the main causes - is that chemotherapy causes the appearance of senescent cells in tumors that paradoxically limit their effectiveness.
The key is in the PD-L2 protein, which senescent cells display on their membrane as a white flag so that the immune system does not attack them. Using PD-L2, senescent cells entrench themselves in the tumor and secrete proteins that help the cancer grow again.
But if the PD-L2 protein is blocked with an antibody, as the researchers have done, then the cytotoxic T lymphocytes of the immune system rush into the tumor, eliminate the senescent cells and the chemotherapy causes a rapid regression of the tumor. cancer.
“By blocking PD-L2 we have seen that chemotherapy is more effective,” says Manuel Serrano, who led the research at the IRB and currently works at the company Altos Labs in the United Kingdom, in a statement. Researchers have proven that the combination of chemotherapy and immunotherapy against PD-L2 is more effective than either of the two alone, which opens the way to changing the way chemotherapies are administered in the future. First, however, clinical trials will have to be carried out in people to make sure that chemotherapy improves if a PD-L2 inhibitor is added.
Currently, there are already approved antibodies against the PD-L1 protein, PD-L2's cousin, on which cancer immunotherapy treatments are based. But PD-L2 "has received less attention" than PD-L1, write in Nature Cancer the authors of the research, in which the Vall d'Hebron Institute of Oncology (VHIO), the Research Institute of the hospital of the Mar (the former IMIM) and the National Cancer Research Center (CNIO).
The company Rejuveron Senescence Therapeutics, of which Serrano is a co-founder and scientific advisor, is developing an antibody against PD-L2 for use in people. The antibody has begun to be tested in non-human primates and the first results indicate “good antitumor activity without obvious side effects,” report the IRB researchers. The company is preparing to test the antibody in people with “different types of cancer, including breast cancer,” although it has not yet specified when they will start.
“In this research we have seen that, when we block PD-L2, the tumor's floodgates to the immune system open and chemotherapy becomes much more effective,” highlights Joaquín Arribas, director of the Hospital del Mar Research Institute and co-author of the work. . This discovery, Arribas points out, suggests that “senescent cells are a determining mechanism of the resistance of many tumors to chemotherapy.”
This phenomenon has been clearly observed in mice with a type of breast cancer, the main animal model used in research, making triple negative breast cancer a candidate for starting clinical trials in people.
It is possible that acting against senescent cells reduces the side effects of chemotherapy, points out José Alberto López-Domínguez, since “some side effects of chemo in the medium and long term may have to do with the appearance of senescence in healthy tissues, that are also damaged by the treatment.”
