Tumor Microenvironment Modulating Microspheres to Augment Tumor Infiltrating Lymphocyte Therapy Against Solid Tumors

The tumor infiltrating lymphocyte (TIL) therapy, in which TILs are collected from a patient's tumor, expanded ex vivo, and infused back, is the first ever T cell therapy approved for treating solid tumors. However, the limited numbers and activities of TILs collected in the first place result in a time consuming preparation process and suboptimal treatment efficacy. The dense extracellular matrix and immunosuppressive tumor microenvironment are critical barriers that hamper the infiltration and function of TILs inside tumors. Herein, we developed alginate-based hydrogel microspheres coloaded with hyaluronidase and chemokine CXCL9. With the released hyaluronidase to degrade the extracellular matrix and CXCL9 to recruit lymphocyte infiltration, such microspheres after intratumoral injection enable effective tumor microenvironment modulation, leading to greatly enhanced numbers of TILs in tumors. TILs collected from these pre-treated tumors not only show much faster proliferation that allows significantly shortened expansion time, but also exhibit markedly improved activity and anti-exhaustion capacity. These TILs, after reinfusion, significantly inhibit tumor growth and suppress metastasis, achieving greatly improved therapeutic outcomes in different tumor models. Our work demonstrates that modulating the tumor microenvironment prior to TIL harvest may be an effective and clinically practical strategy to enhance current TIL therapies.