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GD2-Specific CAR T Cells Demonstrate Potent and Targeted Anti-Tumor Efficacy Against Melanoma In Vitro and In Vivo
Julia Philippova1, Julia Shevchenko1, Alaa Alsalloum1
1Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia.
Background:
Disialoganglioside (GD2) is a tumor-associated antigen that is highly expressed in various neuroectodermal cancers, including melanoma. While chimeric antigen receptor (CAR) T-cell immunotherapy has demonstrated remarkable success in treating hematologic neoplasms, the identification of suitable targets remains a major obstacle in translating this approach to solid tumors.
Methods:
Peripheral blood T lymphocytes from six healthy donors were used to generate GD2-specific CAR T cells via retroviral transduction. The resulting GD2.CAR T cells were characterized by NanoString transcriptome profiling, flow cytometry with hierarchical stochastic neighbor embedding (HSNE) dimensionality reduction, and in vitro cytotoxicity assays against GD2+ and GD2- melanoma cell lines. In vivo experiments were also performed using GD2+ xenograft models and a single intratumoral dose of 8 × 106 GD2.CAR T cells.
Result:
The GD2.CAR T cell population exhibited a predominantly naive phenotype (CD8+CD40L+CD69‒CD107a+4-1BB+FasL+) and effective anti-tumor mechanisms involving the granzyme A/B axis, the Fas/FasL axis, and cytokine release. Transcriptome analysis revealed transduction-related effects on proliferation and a shift towards an effector phenotype during early co-culture with tumor cells, accompanied by upregulation of interferon-gamma (IFN-γ) and cytokine signaling genes. GD2.CAR T cells demonstrated robust cytotoxicity against GD2+ melanoma cells in vitro, while significant in vivo tumor control was observed in xenograft models.
Conclusion:
GD2.CAR T cells demonstrate potent anti-tumor activity against melanoma in vitro and in vivo, highlighting their therapeutic potential and warranting further clinical investigation.
Insights
Chimeric antigen receptor (CAR) T-cells targeting disialoganglioside (GD2) show potent anti-melanoma activity. These GD2.CAR T-cells effectively eliminate tumors in vitro and in vivo, indicating significant therapeutic potential for melanoma treatment.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Disialoganglioside (GD2) is a tumor-associated antigen highly expressed in neuroectodermal cancers like melanoma.
- Chimeric antigen receptor (CAR) T-cell immunotherapy shows promise for hematologic cancers, but solid tumor applications face target identification challenges.
Purpose of the Study:
- To develop and evaluate GD2-specific CAR T-cells for melanoma treatment.
- To assess the anti-tumor efficacy of GD2.CAR T-cells in preclinical models.
Main Methods:
- Generated GD2-specific CAR T-cells from healthy donor lymphocytes via retroviral transduction.
- Characterized GD2.CAR T-cells using NanoString transcriptome profiling, flow cytometry, and in vitro cytotoxicity assays.
- Evaluated in vivo anti-tumor activity in GD2+ melanoma xenograft models.
Main Results:
- GD2.CAR T-cells exhibited a naive phenotype with effective anti-tumor mechanisms including granzyme and Fas/FasL axes, and cytokine release.
- Transcriptome analysis indicated proliferation effects and a shift to an effector phenotype with IFN-γ upregulation upon tumor cell co-culture.
- Demonstrated robust in vitro cytotoxicity against GD2+ melanoma cells and significant in vivo tumor control in xenograft models.
Conclusions:
- GD2.CAR T-cells exhibit potent in vitro and in vivo anti-melanoma activity.
- These findings highlight the therapeutic potential of GD2.CAR T-cells for melanoma.
- Further clinical investigation is warranted for this promising immunotherapy approach.
