Novel Zebrafish Model Allows Assessment of T-Cell–based Immunotherapies at Single-Cell Resolution
Key findings
- Researchers at Massachusetts General Hospital have improved on a previous model of immunodeficient zebrafish such that the animals now stably engraft both human cancers and T cells
- Using the new model, the researchers were able to quantify responses to T-cell immunotherapies across a wide range of tumor types
- Experiments with the zebrafish also validated the efficacy of antibody–peptide epitope conjugates, a new approach to immunotherapy, showing they are highly specific for killing only epitope-expressing tumor cells
- Xenograft studies with both the zebrafish and immunocompromised mice identified epidermal growth factor receptor T-cell immunotherapy as a promising new treatment strategy for pediatric rhabdomyosarcoma
In 2019, Massachusetts General Hospital researchers reported in Cell on the creation of the first immune deficient zebrafish that can grow human cancers. These animals are transparent, which allows direct visualization of tumor growth and response to cancer therapy.
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Now, David M. Langenau, PhD, associate chair for Research in the Department of Pathology, Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program at the Mass General Cancer Center, and colleagues have improved the model to enable the engraftment of human T cells. This facilitates in vivo testing of T-cell–based immunotherapies, as detailed in the Journal of Experimental Medicine.
The New Model
The zebrafish are severely immunodeficient but live into adulthood. They can stably engraft a wide range of human cancer cells and T cells, which can be imaged in real-time at the single-cell level.
The zebrafish allowed assessment of responses to chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engagers (BiTEs), including dynamic single cell imaging of T-cell infiltration and tumor cell engagement and killing.
Assessing Antibody–peptide Epitope Conjugates
Antibody–peptide epitope conjugates (APECs), a modified class of antibody–drug conjugates, are a new approach to personalized cancer therapy. They pair a tumor-specific viral epitope with a tumor-specific protease cleavage site. After viral peptide cleavage by the proteases, the epitope is delivered to the tumor surface for presentation by human leukocyte antigen (HLA)-I, which leads to recruitment of CD8+ T cells and tumor cell killing.
Experiments with the zebrafish showed APECs are highly specific to killing epitope-expressing tumor cells in an array of cancer types. This work provides a strong foundation for moving APECs into human studies.
Assessing EGFR Immunotherapies for Rhabdomyosarcoma
Dr. Langenau's lab has a special focus on pediatric muscle tumors, called rhabdomyosarcoma (RMS). Pediatric RMS is common, and patients with metastatic or refractory/relapsed disease have an abysmal five-year survival rate.
The researchers identified epidermal growth factor receptor (EGFR) as a suitable antigen for pediatric RMS, then examined how EGFR-targeted CAR T-cells, BiTEs and APECs affected RMS cells engrafted into the zebrafish.
The team observed significant reductions in tumor burden with all three therapies. EGFR CAR T-cells showed the greatest efficacy and were also effective in suppressing RMS xenograft growth in immunocompromised mice. These studies provide a preclinical rationale for assessing EGFR-targeted immunotherapies in RMS. They also suggest the zebrafish could help explore T-cell–based therapies for other solid tumors.
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