Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric receptors enhance T cell-mediated cancer targeting.
• HER2 is a validated target in several human cancers.

Purpose of the Study:

• To develop and evaluate the therapeutic efficacy of T cells engineered with a HER2-specific chimeric receptor (N29gamma chR).
• To assess the impact of T cell dose and interleukin-2 (IL-2) on treatment outcomes in murine tumor models.

Main Methods:

• Engineered murine breast (MT901) and fibrosarcoma (MCA207) cancer cell lines to express human HER2.
• Administered primary T cells engineered to express N29gamma chimeric receptor (chR) targeting HER2.
• Evaluated treatment efficacy against pulmonary micrometastases and established macrometastases.

Main Results:

• N29gamma chR-expressing T cells eradicated established HER2-positive micrometastases but not parental cells.
• A 5-8 fold higher dose of N29gamma T cells was required for macrometastases regression.
• Interleukin-2 (IL-2) administration enhanced efficacy for advanced macrometastases but was not essential for micrometastases.
• CD8 T cells expressing N29gamma chR mediated tumor suppression independently of CD4+ cells.

Conclusions:

• Genetically modified T cells with a HER2-targeting chimeric receptor can mediate antigen-specific regression of metastatic cancers.
• Treatment efficacy is dose-dependent and can be augmented by IL-2 in advanced disease.
• These findings support the clinical potential of genetically redirected T cells in cancer immunotherapy.