Generation of a Transgenic BALB/c Mouse Line With Selective Expression of Human Mesothelin in Thyroid Gland:...

Area of Science:

• Oncology
• Immunology
• Transgenic Animal Models

Background:

• Immunotherapies show promise but have high failure rates.
• Effective preclinical models are needed to test antitumor drugs targeting human tumor antigens like mesothelin (MSLN).
• MSLN is a cell-surface glycoprotein highly expressed in various human cancers, making it a valuable therapeutic target.

Purpose of the Study:

• To establish an immunocompetent transgenic mouse model expressing human MSLN (hMSLN) for preclinical cancer immunotherapy research.
• To evaluate the efficacy of a combination therapy targeting MSLN in this novel mouse model.

Main Methods:

• Development of a transgenic mouse model using a thyroid peroxidase (TPO) promoter to express hMSLN specifically in the thyroid gland.
• Utilizing the TPO-MSLN mouse model to assess the response to combination treatment with LMB-100 (an MSLN-targeted immunotoxin) and anti-CTLA-4 (an immune checkpoint inhibitor).
• Evaluating tumor regression, survival rates, and the development of long-term antitumor immunity upon rechallenge.

Main Results:

• The TPO-MSLN mice tolerated hMSLN-expressing tumor cells and high doses of hMSLN-targeted immunotoxin.
• Combination therapy with LMB-100 and anti-CTLA-4 resulted in complete tumor regression in 91% of treated mice.
• The combination therapy significantly improved survival compared to monotherapy and induced long-term immunity, evidenced by rejection of rechallenged tumor cells.

Conclusions:

• The novel TPO-MSLN transgenic mouse model is a valuable tool for preclinical screening of immunotherapies targeting MSLN.
• This model can help predict tumor responses to immunomodulatory therapies and accelerate the development of effective cancer treatments.
• Combination therapy targeting MSLN shows significant potential for inducing complete tumor regression and durable antitumor immunity.