A bioengineered immunocompetent human leukemia chip for preclinical screening of CAR T cell immunotherapy.

Chimeric antigen receptor (CAR) T cell immunotherapy is promising for treatment of blood cancers; however, clinical benefits remain unpredictable, necessitating development of optimal CAR T cell products. Unfortunately, current preclinical evaluation platforms are inadequate due to their limited physiological relevance to humans. We herein engineered an organotypic immunocompetent chip that recapitulates microarchitectural and pathophysiological characteristics of human leukemia bone marrow stromal and immune niches for CAR T cell therapy modeling.

Spatiotemporal dissection of tumor microenvironment via in situ sensing and monitoring in tumor-on-a-chip.

Real-time monitoring in the tumor microenvironment provides critical insights of cancer progression and mechanistic understanding of responses to cancer treatments. However, clinical challenges and significant questions remain regarding assessment of limited clinical tissue samples, establishment of validated, controllable pre-clinical cancer models, monitoring of static versus dynamic markers, and the translation of insights gained from in vitro tumor microenvironments to systematic investigation and understanding in clinical practice. State-of-art tumor-on-a-chip strategies will be reviewed herein, and emerging real-time sensing and monitoring platforms for on-chip analysis of tumor microenvironment will also be examined.

Computational model of CAR T-cell immunotherapy dissects and predicts leukemia patient responses at remission, resistance, and relapse.

Background: Adaptive CD19-targeted chimeric antigen receptor (CAR) T-cell transfer has become a promising treatment for leukemia. Although patient responses vary across different clinical trials, reliable methods to dissect and predict patient responses to novel therapies are currently lacking. Recently, the depiction of patient responses has been achieved using in silico computational models, with prediction application being limited.

A Computational Model of Cytokine Release Syndrome during CAR T-cell Therapy.

Cytokine release syndrome (CRS) is a lethal adverse event in chimeric antigen receptor (CAR) T-cell therapy, hindering this promising therapy for cancers, such as B-cell acute lymphoblastic leukemia (B-ALL). Clinical management of CRS requires a better understanding of its underlying mechanisms. In this study, a computational model of CRS during CAR T-cell therapy is built to depict how the cellular interactions among CAR T-cells, B-ALL cells, and bystander monocytes, as well as the accompanying molecular interactions among various inflammatory cytokines, influence the severity of CRS.

An glioblastoma microenvironment model dissects the immunological mechanisms of resistance to PD-1 checkpoint blockade immunotherapy.

The PD-1 immune checkpoint-based therapy has emerged as a promising therapy strategy for treating the malignant brain tumor glioblastoma (GBM). However, patient response varies in clinical trials due in large to the tumor heterogeneity and immunological resistance in the tumor microenvironment. To further understand how mechanistically the niche interplay and competition drive anti-PD-1 resistance, we established an model to quantitatively describe the biological rationale of critical GBM-immune interactions, such as tumor growth and apoptosis, T cell activation and cytotoxicity, and tumor-associated macrophage (TAM) mediated immunosuppression.