Evaluating Next-Generation CAR-T Cells in Complex Tumor-Immune Models
Naiara Martínez-Vélez
Stanford University
Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, yet its clinical efficacy in solid tumors remains limited. Key barriers include poor tumor trafficking, antigen heterogeneity, and profound immunosuppression driven by myeloid cells and other stromal components within the tumor microenvironment (TME). In response, nextgeneration CAR-T strategies have been developed to incorporate cell-intrinsic enhancements or engineered cargos designed to sustain T-cell function under the hostile conditions of solid tumors.
However, most immunotherapies, including CAR-T cells, are routinely developed and tested using simplified in vitro systems and xenograft models in immunodeficient mice, which fail to capture the full complexity of the native TME. Importantly, correlative analyses from clinical trials increasingly suggest that myeloid cells within the TME play a central role in limiting CAR-T cell persistence and antitumor activity. A deeper understanding of the dynamic interplay between CAR-T cells and the TME is therefore essential for the rational design of more effective cellular therapies for solid cancers.
To address this challenge, we have established murine immunocompetent models that more faithfully recapitulate T cell–TME interactions observed in patients. These novel models have revealed that distinct intrinsic CAR-T cell enhancements differentially remodel the tumor microenvironment, affecting their potency. To further recapitulate and understand these interactions in a human tumor setting, we have also developed and optimized patient-derived tumor immune organoids that preserve neoplastic, stromal, and immune compartments while maintaining the native architecture and cellular crosstalk of the original tumor. These platforms provide a physiologically relevant autologous model in which matched patient-derived CAR T and tumors can be studied under native TME conditions, allowing a more faithful assessment of therapeutic efficacy and the immunosuppressive barriers that limit CAR-T cell function in solid
tumors.
By integrating immunocompetent in vivo models with patient-derived tumor immune organoids, this work aims to improve the preclinical evaluation and provide a better understanding of CART cell performance in patients, ultimately accelerating the development of next-generation cellular immunotherapies effective against solid tumors.