In Vitro and In Vivo Tumor Models for the Evaluation of Anticancer Nanoparticles.

Multiple studies about tumor biology have revealed the determinant role of the tumor microenvironment in cancer progression, resulting from the dynamic interactions between tumor cells and surrounding stromal cells within the extracellular matrix. This malignant microenvironment highly impacts the efficacy of anticancer nanoparticles by displaying drug resistance mechanisms, as well as intrinsic physical and biochemical barriers, which hamper their intratumoral accumulation and biological activity.Currently, two-dimensional cell cultures are used as the initial screening method in vitro for testing cytotoxic nanocarriers. However, this fails to mimic the tumor heterogeneity, as well as the three-dimensional tumor architecture and pathophysiological barriers, leading to an inaccurate pharmacological evaluation.Biomimetic 3D in vitro tumor models, on the other hand, are emerging as promising tools for more accurately assessing nanoparticle activity, owing to their ability to recapitulate certain features of the tumor microenvironment and thus provide mechanistic insights into nanocarrier intratumoral penetration and diffusion rates.Notwithstanding, in vivo validation of nanomedicines remains irreplaceable at the preclinical stage, and a vast variety of more advanced in vivo tumor models is currently available. Such complex animal models (e.g., genetically engineered mice and patient-derived xenografts) are capable of better predicting nanocarrier clinical efficiency, as they closely resemble the heterogeneity of the human tumor microenvironment.Herein, the development of physiologically more relevant in vitro and in vivo tumor models for the preclinical evaluation of anticancer nanoparticles will be discussed, as well as the current limitations and future challenges in clinical translation.

Current challenges and emerging opportunities of CAR-T cell therapies.

Infusion of chimeric antigen receptor (CAR)-genetically modified T cells (CAR-T cells) have led to remarkable clinical responses and cancer remission in patients suffering from relapsed or refractory B-cell malignancies. This is a new form of adoptive T cell therapy (ACT), whereby the artificial CAR enables the redirection of T cells endogenous antitumor activity towards a predefined tumor-associated antigen, leading to the elimination of a specific tumor. The early success in blood cancers has prompted the US Food and Drug Administration (FDA) to approve the first CAR-T cell therapies for the treatment of CD19-positive leukemias and lymphomas in 2017. Despite the emergence of CAR-T cells as one of the latest breakthroughs of cancer immunotherapies, their wider application has been hampered by specific life-threatening toxicities, and a substantial lack of efficacy in the treatment of solid tumors, owing to the strong immunosuppressive tumor microenvironment and the paucity of reliable tumor-specific targets. Herein, besides providing an overview of the emerging CAR-technologies and current clinical applications, the major hurdles of CAR-T cell therapies will be discussed, namely treatment-related life-threatening toxicities and the obstacles posed by the immunosupressive tumor-microenvironment of solid tumors, as well as the next-generation strategies currently designed to simultaneously improve safety and efficacy of CAR-T cell therapies in vivo.