Mechanical Immunoengineering for Enhanced T-cell Immunotherapy

Descripción del proyecto

Inmunoterapia celular avanzada contra los tumores sólidos

Los linfocitos T modificados para expresar receptores de antígenos quiméricos (linfocitos T-CAR) han mostrado resultados alentadores contra las neoplasias hemáticas. Sin embargo, el entorno inmunodepresor de los tumores sólidos impide que los linfocitos T-CAR lleguen al lugar del tumor, lo que hace necesario utilizar estrategias de potenciación. El proyecto financiado con fondos europeos MechanoIMM propone explotar señales biofísicas y mecánicas para modular la inmunidad antitumoral. Los investigadores diseñarán nanopartículas que respondan a las señales mecánicas de los tumores y suministren fármacos de apoyo a los linfocitos T. Además, diseñarán linfocitos T que sean capaces de distinguir entre la rigidez del tumor y los tejidos sanos, mejorando así la especificidad de la terapia celular.

Objetivo

Cancer immunotherapy harnessing the power of a patient’s immune system to fight cancer is transforming the standard-of-care for cancer. Adoptive cell therapy (ACT), a potent immunotherapy that directly infuses a large number of tumour-reactive T cells into patients, has elicited dramatic clinical responses in leukaemia patients recently. However, solid tumour remains a major challenge as tumour employs a number of strategies to prevent effector T cells reaching the tumour sites and attacking cancer by generating a highly immunosuppressive microenvironment. Current strategies are focused on controlling the immune system or the microenvironment using biochemical immunomodulatory reagents to enhance T cell based immunotherapy. Approaches exploiting biophysical and mechanical cues for immunomodulation are largely underappreciated. In this proposal, we aim to exploit mechanical immunoengineering strategies through biophysical cues to develop novel immune related treatments to enhance the efficacy and safety of adoptive T cell therapy for cancer. We will first develop a mechano-training approach to promote the T cell infiltration into tumour tissues using engineered microfluidic system for controlled force application on T cells in a high through-put manner. Second, we will develop a mechano-responsive nanoparticle delivery system to selectively deliver T-cell-supporting drugs in tumour to overcome the immune suppression in the microenvironment and enhance T cell functions for killing cancer. Third, we will develop mechano-inducible cytokine-secreting T cell therapies to augment the efficacy and minimize the toxicity of ACT by exploiting and targeting the difference in tissue stiffness between tumour and healthy tissues. This proposed project will open a new horizon for immunoengineering through biomechanical modulation of immunity for enhanced cancer immunotherapy and provide insight into the fundamentals of mechanotransduction in immune system in health and disease.