Multimodal profiling of CAR T cells against glioblastoma using a microengineered 3D tumor-on-a-chip model

Area of Science:

• Oncology
• Biotechnology
• Immunotherapy

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows promise for hematological cancers but faces challenges in solid tumors like glioblastoma (GBM).
• Developing effective CAR T-cell therapies for GBM is limited by the lack of preclinical models that accurately represent the tumor microenvironment (TME).
• Physiologically relevant models are crucial for optimizing CAR constructs and enhancing therapeutic efficacy in GBM.

Purpose of the Study:

• To develop and utilize a microengineered glioblastoma-on-a-chip (GOC) model with a vascular network to assess the efficacy and selectivity of IL-13 mutein CAR T cells (TV-13).
• To investigate CAR T-cell interactions with U87 GBM cells expressing IL13Rα2 and IL13Rα1 within a biomimetic TME.
• To evaluate CAR T-cell responses under conditions mimicking locoregional administration for GBM treatment.

Main Methods:

• A microengineered GOC model with a functional vascular network was created to recapitulate the GBM TME.
• The model was used to evaluate the efficacy of IL-13 mutein CAR T cells (TV-13) against U87 GBM cells expressing IL13Rα2.
• CAR T-cell mediated inhibition of GBM invasion, real-time cell interactions, and cytokine release were quantified.

Main Results:

• CAR T cells demonstrated a density-dependent reduction in U87 GBM cell migration.
• TV-13 CAR T cells showed specificity for the IL13Rα2 tumor antigen over IL13Rα1.
• The GOC model successfully evaluated CAR T-cell efficacy against patient-derived GBM cells.

Conclusions:

• The GOC platform serves as a powerful preclinical tool for optimizing cancer immunotherapies, particularly for GBM.
• This model facilitates dynamic evaluation of CAR T-cell responses within a physiologically relevant TME.
• The study validates the potential of IL-13 mutein CAR T cells for targeting IL13Rα2-expressing GBM.