Tumor cells are able to evade immune responses by activating negative regulatory pathways, also known as immune checkpoints, that block cytotoxic T-cell activation and thus, the immune system cannot kill cancer. Despite the promise of immunotherapy, which boosts the patients immune response, the absence of dramatic immunotherapeutic responses has been attributed to a variety of factors, including hindering of immune cell delivery and activity in the tumor owing to the hypo-perfused tumor microenvironment (TME). Perfusion rates (i.e. blood flow), in some regions of a tumor can be significantly lower than that in the peri-tumor normal tissue, leading to inadequate delivery of medicines, which in turn, compromises the efficacy of cancer therapies, including immunotherapy. Particularly, hypo-perfusion can reduce the number of immune cells that infiltrate into the tumor and induce hypoxia (i.e. lack of oxygen). Hypoxia in turn renders TME immunosuppressive and attenuates the killing potential of immune cells.
There is evidence that improving perfusion in tumors by restoring abnormalities of the tumor vessels can improve the efficacy of cancer therapies. In ImmunoMECH, we tested experimentally and with the use of mathematical modeling the hypothesis that re-purposing safe and well tolerated drugs with the aim to repair vascular abnormalities in tumors and restore normal blood flow, namely tumor normalization strategy, can optimize the efficacy of immunotherapy in murine tumor models.
The overall objectives of the project are: the development of innovative data driven algorithms leading to realistic biomechanical modeling for immune cell/anti-angiogenic agents and tumor evolution that will harness the power of High Performance Computing environments, the experimental investigation of the normalization/immunotherapy efficiency with in vivo experiments in animal tumor models and the experimental validation and verification of model parameters to optimize the therapeutic strategy in terms of immunotherapeutic and normalization agents dosage.
A biomechanical model was extended to study the effects of immunotherapy and normalization therapy on tumor growth, based on previous work of the host Cancer Biophysics Laboratory. The MSolve Finite Element numerical solution platform, developed in the Fellow’s former laboratory at the National Technical University of Athens, was implemented to tackle the computational cost. The hypothesis of the project was tested experimentally. Orthotopic syngeneic models for sarcoma tumors were generated by implantation of MCA205 and K7M2wt cancer cells in mice. Using these two murine sarcoma models, we demonstrated that normalization of the tumor microenvironment by re-purposing an approved antihistamine drug can effectively modulate tumor stiffness and mechanical stresses, improving vascular perfusion and promote immunostimulation. Furthermore, we found the optimal dose of the normalization agent that most effectively improves perfusion and showed that normalization treatment can optimize the efficacy of immune checkpoint inhibition in both tumor models.
We concluded that modulating the tumor micro-environment to restore vascular abnormalities is an effective therapeutic strategy to improve immunotherapy.
