Periodic Reporting for period 2 - Immuno-Predictor (Mechanical Biomarkers for Prediction of Cancer Immunotherapy)
Periodo di rendicontazione: 2021-10-01 al 2023-03-31
Immunotherapy has revolutionized the treatment of multiple cancers and has already become a standard of care for some tumor types. However, a majority of patients do not benefit from current immunotherapeutics and many develop severe toxicities. Therefore, the identification of biomarkers to classify patients as likely responders or nonresponders to immunotherapy is a timely and of tremendous impact task. My hypothesis is that biomechanical aspects of the tumor microenvironment mediate resistance to immunotherapy. Specifically, many tumors stiffen as they grow and also, tumor growth within the host tissue generates mechanical forces, termed solid stress. Tumor stiffening and solid stress are distinct mechanical abnormalities that compress intratumoral blood vessels, causing hypo-perfusion and hypoxia. Systemic administration of immunotherapeutics requires a well-perfused vasculature, whereas hypo-perfusion and hypoxia promote immunosuppression, helping cancer cells to evade immune responses. The objective of the proposed research is the identification of novel Mechanical Biomarkers related to tumor stiffness, solid stress, perfusion and hypoxia for prediction of immunotherapy. Tumor-bearing mice will be developed and treated with immunotherapeutic drugs and clinically used methods will be combined with computational biomechanical modeling for measuring the Mechanical Biomarkers, making the research transferable to the clinic. The biomarkers will be benchmarked against tumor normalization strategies aiming to restore/normalize mechanical abnormalities and optimize immunotherapy. Finally, the clinical utility of the selected biomarkers will be evaluated in human tumors. Only few tumor-specific biomarkers are used in the clinic - based mainly on genomic analysis. This project is expected to lead to the first biomarkers for immunotherapy prediction exploiting tumor mechanics.
We have successfully repurposed approved antihistamine and anti-hypertensive drugs to reduce stiffness and improve perfusion in preclinical tumor models, which resulted in improved efficacy of immunotherapy. We have further verified the ability of ultrasound shear wave elastography and contrast-enhanced ultrasound, two clinically applied ultrasound methods in oncology, to monitor changes in tumor stiffness and perfusion during treatment. In addition, we have found that stiffness of the tumor and the degree of perfusion before the initiation of immunotherapy can act as markers for the prediction of the efficacy of immunotherapy.
We have provided the first evidence that biomarkers based on the mechanical properties of tumors (i.e. stiffness and perfusion) can be used for the prediction of cancer immunotherapy. We will work further within the project to solidify our findings and expand the research to additional tumor types.