Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human...

Area of Science:

• Oncology
• Immunology
• Preclinical Cancer Models

Background:

• Immunotherapies have transformed cancer treatment but benefit only a subset of patients.
• Over 1500 clinical trials investigate immunotherapy combinations to improve efficacy.
• Preclinical models are crucial for cost-effective combination drug testing.

Purpose of the Study:

• To evaluate human immune system (HIS) mice as a preclinical model for testing cancer immunotherapy combinations.
• To characterize the human immune system reconstitution and its response to immunotherapy in HIS mice bearing human tumors.
• To compare immune cell phenotypes in lymph tissues and tumors to treatment responses.

Main Methods:

• Utilized a cord blood-derived HIS-BALB/c-Rag2nullIl2rgnullSIRPαNOD (BRGS) mouse model.
• Engrafted BRGS mice with human tumor cell lines and patient-derived xenografts.
• Administered immune checkpoint blockade combinations and analyzed immune cell kinetics, subsets, activation, cytokine production, and receptor expression via flow cytometry.

Main Results:

• HIS-BRGS mice supported human tumor growth and allowed testing of immunotherapy combinations.
• The human immune system reconstitution and tumor-infiltrating leukocyte phenotype were variable and tumor-dependent.
• Responding tumors exhibited human T cells with a more inflammatory signature compared to non-responding tumors.

Conclusions:

• HIS mice serve as a valuable preclinical model for evaluating combination immunotherapies in diverse human cancers.
• Careful attention to protocol details and data analysis is essential for reliable results.
• The model recapitulates key aspects of human immunotherapy responses observed in clinical trials.