Drivers and Brakes of CAR T Cell Efficacy Determined by the Tumor Immune Microenvironment

Informazioni relative al progetto

CAR-TIME

ID dell’accordo di sovvenzione: 101116768

DOI

10.3030/101116768

Data della firma CE 20 Ottobre 2023

Data di avvio 1 Gennaio 2024

Data di completamento 31 Dicembre 2028

Finanziato da

• European Research Council (ERC)

Costo totale

€ 1 499 875,00

Contributo UE

€ 1 499 875,00

Coordinato da

EBERHARD KARLS UNIVERSITAET TUEBINGEN
Germany

Periodic Reporting for period 1 - CAR-TIME (Drivers and Brakes of CAR T Cell Efficacy Determined by the Tumor Immune Microenvironment)

Periodo di rendicontazione: 2024-01-01 al 2026-06-30

Sintesi del contesto e degli obiettivi generali del progetto

Cancer immunotherapies, such as chimeric antigen receptor (CAR) T cells, have transformed the treatment of certain blood cancers. However, many patients do not respond, or their cancer returns after treatment. A key reason lies in the tumor immune microenvironment (TIME) — the complex ecosystem of immune cells, cancer cells, blood vessels, and supporting tissue that surrounds and influences tumors. Understanding how this environment either supports or blocks therapy is essential to improving patient outcomes.

The CAR-TIME project investigates why CAR T cells succeed in some patients but fail in others. Focusing on diffuse large B-cell lymphoma (DLBCL), an aggressive blood cancer, the project aims to identify the “drivers” and “brakes” within the TIME that determine therapy response. By combining advanced imaging, molecular profiling, and innovative tissue culture systems, the project seeks to develop tools that predict treatment outcomes and guide personalized immunotherapy strategies. Ultimately, this work aims to make CAR T cell therapy safer, more effective, and better tailored to individual patients.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

We have assembled a large, well-characterized cohort of 191 DLBCL patients, including both cured patients and those whose disease relapsed or resisted treatment. Using advanced spatial proteomics (CODEX multiplex imaging), we analyzed over 21 million individual cells within tumor tissues. This created one of the most detailed single-cell maps of the DLBCL TIME to date.

In parallel, we performed genetic profiling of tumors to classify molecular subtypes associated with prognosis and therapy response. These molecular features are now being integrated with spatial imaging data and clinical outcomes to build predictive models for treatment success.

A major technological breakthrough was the development of a live 3D perfusion bioreactor system that allows intact human tumor tissues to be cultured outside the body while preserving their structure and immune microenvironment. This system enables us to directly test immunotherapies — including CAR T cells and immune checkpoint inhibitors — in patient-derived tissue samples. A modification of this platform is also compatible with live-cell two-photon microscopy, enabling us to directly visualize immune cell movement and interactions within living tissues in real time. Using the bioreactor, we demonstrated that CAR T cells can infiltrate patient-derived lymphoma tissue and eliminate cancer cells in a realistic 3D setting, and that engineered CAR T cells with enhanced signaling properties show improved tissue penetration and activation.

In addition, a novel microscopy workflow was developed that combines high-dimensional 2D imaging with whole-organ 3D imaging, allowing precise mapping of tumor–immune interactions from the organ level down to individual cells. A patent application has been filed for the bioreactor system.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

The CAR-TIME project advances the field beyond traditional cancer models by preserving the natural lymphoma TIME while allowing functional testing of therapies in living human tissue. This bridges a critical gap between laboratory experiments and clinical reality.

The project introduces:
• A high-resolution spatial atlas of the DLBCL TIME in cured and refractory / relapsed patients
• A live tissue bioreactor compatible with advanced microscopy
• Real-time visualization of immune cell behavior using two-photon microscopy
• Integrated multi-omics approaches linking genetics, spatial biology, and clinical outcomes

These innovations create a foundation for functional precision medicine — where therapies can be tested on a patient’s own tissue before treatment decisions are made.

To ensure further uptake, future steps include expanding validation studies, refining predictive algorithms, optimizing imaging workflows, exploring regulatory pathways for translational implementation, and commercialization of the live imaging-compatible bioreactor platform (patent pending). The bioreactor platform also has potential applications beyond lymphoma, including solid tumors and other immune-based therapies.

Overall, CAR-TIME provides new tools to better understand and improve CAR T cell therapy, bringing us closer to more precise and personalized cancer treatment.