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Tumor Immunotherapy

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.

The Tumor Microenvironment

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...

The Tumor Microenvironment

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...

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Dual-modular-nanobody CAR-T cell technical platform against the solid tumor microenvironment.

Yangzi Li^1,2, Xuan Wang³, Shangkun Zhang⁴

¹Guangxi Key Laboratory of Nanobody Research, Guangxi Nanobody Engineering Research Center, College of Stomatology, Guangxi Medical University, Nanning, 530021, China.

Journal of Hematology & Oncology

|July 3, 2026

Summary

This study introduces a novel dual-modular nanobody-based CAR-T therapy targeting fibroblast activation protein (FAP) and CTLA-4. This approach shows promise in overcoming the immunosuppressive tumor microenvironment in solid tumors.

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Area of Science:

Immunotherapy
Oncology
Biotechnology

Background:

CAR-T therapy faces challenges in solid tumors due to antigen heterogeneity and immunosuppressive tumor microenvironments (TME).
Systemic CTLA-4 blockade can cause severe adverse events.
A dual-modular nanobody-based CAR-T platform was developed to target fibroblast activation protein (FAP) and locally release anti-CTLA-4 within the tumor stroma.

Purpose of the Study:

To develop and evaluate a novel CAR-T therapy for solid tumors.
To overcome the immunosuppressive TME by targeting FAP and localizing CTLA-4 blockade.
To assess the efficacy and safety of this dual-modular CAR-T platform in preclinical models and a glioblastoma patient.

Main Methods:

Generation and in vitro assessment of FAP/CTLA-4 dual-module CAR-T cells for cytotoxicity and cytokine release.
In vivo evaluation in xenograft models for antitumor efficacy, survival, and T-cell infiltration.
Intrathecal administration in a refractory glioblastoma patient, monitoring clinical response, CSF cytokines, and safety.
Analysis of TME changes using transcriptomic sequencing and multiplex immunofluorescence staining.

Main Results:

Engineered CAR-T cells demonstrated potent in vitro cytotoxicity and cytokine production with reduced exhaustion.
In vivo studies showed significant tumor regression, prolonged survival, and increased T-cell infiltration.
The glioblastoma patient experienced disease stabilization, elevated CSF cytokines, and a favorable safety profile post-treatment.
TME analysis revealed a shift towards an immunologically active state.

Conclusions:

FAP/CTLA-4 dual-modular CAR-T therapy effectively overcomes the immunosuppressive solid tumor microenvironment via localized immunomodulation.
This approach shows promising preclinical efficacy and a favorable safety profile in a patient with refractory glioblastoma.