Intracavitary 'T4 immunotherapy' of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Malignant mesothelioma is an aggressive and incurable cancer.
• Dysregulation of the ErbB receptor tyrosine kinase family is implicated in mesothelioma pathogenesis.
• EGFR, ErbB4, and HER2 are expressed in a high percentage of mesothelioma tumors, presenting therapeutic targets.

Purpose of the Study:

• To develop and evaluate a novel immunotherapy targeting the ErbB family in malignant mesothelioma.
• To engineer patient T-cells to express a chimeric antigen receptor (CAR) targeting panErbB and a chimeric cytokine receptor for IL-4 mediated proliferation (T4 immunotherapy).

Main Methods:

• Mesothelioma tumor samples were analyzed for ErbB family member expression.
• Patient T-cells were genetically modified using retroviral transduction to express the T4 construct.
• In vitro assessment of T4 T-cell activation, cytotoxicity, and cytokine release against mesothelioma cell lines.
• In vivo efficacy study using SCID Beige mice bearing mesothelioma xenografts treated with T4 immunotherapy.

Main Results:

• 88% of mesothelioma tumors expressed at least one ErbB family member.
• Patient T-cells were successfully engineered and expanded using IL-4.
• Patient-derived T4+ T-cells exhibited potent anti-tumor activity (cytotoxicity and cytokine release) against mesothelioma cell lines.
• Adoptive transfer of T4 immunotherapy led to significant tumor regression or eradication in a preclinical mesothelioma xenograft model.
• T4 immunotherapy was well-tolerated in vivo, despite inducing cytokine release.

Conclusions:

• T4 immunotherapy effectively targets ErbB-expressing mesothelioma.
• Preclinical data strongly support the clinical evaluation of intracavitary T4 immunotherapy for mesothelioma treatment.