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A Novel Mice Model for Studying the Efficacy and IRAEs of Anti-CTLA4 Targeted Immunotherapy
Shengchao Xu1, Xi Yan2, Gan Dai3
1Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, China.
Background:
Patient-derived orthotopic xenograft (PDOX) is a popular animal model for translational cancer research. Immunotherapy is a promising therapy against glioblastoma (GBM). However, the PDOX model is limited to evaluating immune-related events. Our study aims to establish GBM humanized PDOX (HPDOX) mice models to study the mechanism of anti-CTLA4 immunotherapy and immune-related adverse events (IRAEs).
Methods:
HPDOX models were established by culturing GBM tissues and intracranially implanting them in NSG mice. Meanwhile, peripheral blood mononuclear cells (PBMCs) were separated from peripheral blood and of GBM patients and administrated in corresponding mice. The population of CD45+, CD3+, CD4+, CD8+, and regulatory T (Treg) cells was estimated in the peripheral blood or tumor.
Results:
T cells derived from GBM patients were detected in HPDOX mice models. The application of anti-CTLA4 antibodies (ipilimumab and tremelimumab) significantly inhibited the growth of GBM xenografts in mice. Moreover, residual patient T cells were detected in the tumor microenvironment and peripheral blood of HPDOX mice and were significantly elevated by ipilimumab and tremelimumab. Additionally, Treg cells were decreased in mice with IRAEs. Lastly, the proportion of CD4+/CD8+ T cells dramatically increased after the administration of ipilimumab. And the degree of IRAEs may be related to CD56+ expression in HPDOX.
Conclusions:
Our study established HPDOX mice models for investigating the mechanism and IRAEs of immunotherapies in GBM, which would offer a promising platform for evaluating the efficacy and IRAEs of novel therapies and exploring personalized therapeutic strategies.
Insights
This study established humanized patient-derived orthotopic xenograft (HPDOX) mice models for glioblastoma (GBM). These models effectively evaluate anti-CTLA4 immunotherapy, showing significant tumor inhibition and aiding in understanding immune-related adverse events.
Area of Science:
- Oncology
- Immunology
- Translational Research
Background:
- Patient-derived orthotopic xenograft (PDOX) models are crucial for cancer research but have limitations in evaluating immune responses.
- Immunotherapy, particularly targeting CTLA-4, shows promise for glioblastoma (GBM) treatment.
- Existing PDOX models do not adequately assess immune-related events or adverse events associated with immunotherapy.
Purpose of the Study:
- To establish glioblastoma humanized PDOX (HPDOX) mice models.
- To investigate the mechanisms of anti-CTLA4 immunotherapy in GBM.
- To study immune-related adverse events (IRAEs) associated with GBM immunotherapies.
Main Methods:
- HPDOX models were created by implanting patient-derived GBM tissues into NSG mice.
- Peripheral blood mononuclear cells (PBMCs) from GBM patients were administered to the mice.
- Immune cell populations (CD45+, CD3+, CD4+, CD8+, Treg) were analyzed in peripheral blood and tumors.
Main Results:
- Human T cells were successfully engrafted and detected in HPDOX mice.
- Anti-CTLA4 antibodies (ipilimumab, tremelimumab) significantly inhibited GBM xenograft growth.
- Therapy increased T cell infiltration in tumors and peripheral blood, while decreasing regulatory T cells in mice experiencing IRAEs.
- Increased CD4+/CD8+ T cell ratios and potential correlation of IRAEs with CD56+ expression were observed.
Conclusions:
- Established HPDOX mice models provide a viable platform for studying GBM immunotherapy mechanisms.
- These models are suitable for evaluating the efficacy and IRAEs of novel immunotherapies for GBM.
- The HPDOX platform can facilitate the exploration of personalized therapeutic strategies for GBM.
