INCLIVA provides new clinical evidence on the role of the gut microbiota in cancer therapies
The INCLIVA Health Research Institute – University Clinical Hospital of Valencia has explored in a study the impact of the gut microbiota, or intestinal flora, on the prognosis of lymphoma patients receiving CAR-T cell therapy, a cancer treatment in which the patient's own cells are genetically modified to recognize and destroy specific tumor cells.
The study was led by the Hematology Department of the University Clinical Hospital and the Hematopoietic Transplantation and Molecular Microbiology and Microbial Pathogenesis research groups at INCLIVA, with the participation of the Precision Medicine and Bioinformatics Units at INCLIVA and the University of Valencia in the statistical analysis and machine learning.
“The interaction between gut flora and immune system cells is now well understood, and there is strong scientific evidence linking the presence of certain bacteria to a greater response to antineoplastic drugs. However, not all bacterial species in the digestive tract play a beneficial role. Some, for example, are associated with inflammatory bowel diseases or treatment failure. There is practically no information on the influence of the microbiota on CAR-T cell therapy. For this reason, in this study we focused on investigating which bacteria influence the response to or toxicity of the treatment, as this is a crucial issue for improving patient prognosis. If, for example, a beneficial species were identified, it could be added as a probiotic to the treatment,” says Dr. Rafael Hernani, from the Hematopoietic Transplantation Research Group at INCLIVA and the Hematology Department of the Hospital Clínico de València, and principal investigator of the study.
About CAR-T Therapy
CAR-T (chimeric antigen receptor T) therapy offers results that significantly improve the efficacy of conventional cancer treatment and prolong survival in these patients. A CAR-T cell is a lymphocyte (a type of white blood cell in the immune system that recognizes and fights infections and cancer cells) genetically modified to specifically recognize a membrane protein (antigen) on the cancer cell.
To produce a CAR-T cell, the patient undergoes apheresis, a procedure similar to dialysis, which filters part of the blood. Once the lymphocytes have been collected, they are sent to the laboratory for genetic modification. Using a virus, the information that will allow the lymphocyte to express a receptor on its membrane is inserted into its DNA. This receptor specifically and precisely recognizes a particular antigen on the tumor cell. After the genetic modification is complete, a series of substances are added to the lymphocytes to enable them to multiply. Once a sufficient number of lymphocytes have been collected, they are frozen and returned to the hospital, at which point they can be infused into the patient in a process similar to a blood transfusion, requiring only one administration.
The patient typically remains hospitalized for 10 to 14 days. During this period, the CAR-T lymphocytes are expected to recognize the tumor cells, multiply, and attack them. As a result of this battle between the lymphocyte and the cancer cell, a series of substances known as cytokines can be released into the bloodstream. These cytokines are responsible for two of the most characteristic complications of CAR-T therapy: cytokine release syndrome and neurotoxicity. It is possible to develop one or more of these complications, which can range from a simple fever or headache to seizures or the need for medication to raise blood pressure. After these first few weeks, the probability of developing these complications is very low, and the patient can be discharged.
A complex study to analyze the gut microbiota
In this study, fecal samples were collected from 30 patients at the Hospital Clínico de València and from healthy household members using special kits that preserve the microbiota unaltered until frozen. Bacterial DNA was extracted and analyzed using shotgun metagenomics sequencing, which allows for detailed identification of each bacterial species in the sample. Furthermore, in collaboration with Carlos Hernani Morales, a researcher at the University of València, machine learning studies were conducted, enabling the creation of response models by analyzing the presence or absence of a few bacterial species.