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Updated: Dec 26, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
T-cells expressing a chimeric-PD1-Dap10-CD3zeta receptor reduce tumour burden in multiple murine syngeneic models of
Geoffrey Parriott1, Kelsey Deal1, Shane Crean1
1Department of Biological and Environmental Sciences, Longwood University, Farmville, VA, USA.
Abstract:
Adoptive transfer of T-cells is a promising therapy for many cancers. To enhance tumour recognition by T-cells, chimeric antigen receptors (CARs) consisting of signalling domains fused to receptors that recognize tumour-associated antigens can be expressed in T-cells. While CAR T-cells have shown clinical success for treating haematopoietic malignancies, using CAR T-cells to treat solid tumours remains a challenge. We developed a chimeric PD1 (chPD1) receptor that recognizes the ligands for the PD1 receptor that are expressed on many types of solid cancer. To determine if this novel CAR could target a wide variety of tumour types, the anti-tumour efficacy of chPD1 T-cells against syngeneic murine models of melanoma, renal, pancreatic, liver, colon, breast, prostate and bladder cancer was measured. Of the 14 cell lines tested, all expressed PD1 ligands on their cell surface, making them potential targets for chPD1 T-cells. ChPD1 T-cells lysed the tumour cells and secreted pro-inflammatory cytokines [interferon (IFN)γ, tumour necrosis factor (TNF)α, interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-17 and IL-21], but did not secrete the anti-inflammatory cytokine IL-10. Furthermore, T-cells expressing chPD1 receptors reduced an established tumour burden and led to long-term tumour-free survival in all types of solid tumours tested. ChPD1 T-cells did not survive longer than 14 days in vivo; however, treatment with chPD1 T-cells induced protective host anti-tumour memory responses in tumour-bearing mice. Therefore, adoptive transfer of chPD1 T-cells could be a novel therapeutic strategy to treat multiple types of solid cancer.
Insights
Chimeric PD1 (chPD1) T-cells target solid tumors by recognizing PD1 ligands. This novel therapy effectively reduces tumor burden and induces long-term anti-tumor memory in various cancer models.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Adoptive T-cell therapy shows promise for cancer treatment.
- Chimeric antigen receptors (CARs) enhance T-cell tumor recognition.
- CAR T-cells are effective against hematologic malignancies but face challenges in solid tumors.
Purpose of the Study:
- To develop a novel CAR, chimeric PD1 (chPD1), targeting PD1 ligands on solid tumors.
- To evaluate the anti-tumor efficacy of chPD1 T-cells against a wide range of solid cancers.
- To assess the potential of chPD1 T-cell therapy for treating diverse solid tumor types.
Main Methods:
- Developed a chimeric PD1 (chPD1) receptor.
- Tested chPD1 T-cell efficacy in syngeneic murine models of melanoma, renal, pancreatic, liver, colon, breast, prostate, and bladder cancer.
- Measured tumor cell lysis, cytokine secretion, tumor burden reduction, and host anti-tumor memory.
Main Results:
- All 14 tested solid tumor cell lines expressed PD1 ligands, indicating chPD1 T-cell targetability.
- chPD1 T-cells effectively lysed tumor cells and secreted pro-inflammatory cytokines (IFNγ, TNFα, IL-2, GM-CSF, IL-17, IL-21).
- chPD1 T-cell treatment reduced established tumor burden, achieved long-term tumor-free survival, and induced protective anti-tumor memory.
Conclusions:
- chPD1 T-cells represent a novel therapeutic strategy for multiple solid cancers.
- The ability to target PD1 ligands broadens the potential application of CAR T-cell therapy.
- Induction of host anti-tumor memory suggests durable therapeutic benefits.
