| Autor: |
Nief CA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.; Stanford School of Medicine, Stanford University, Stanford, CA 94205, USA., Gonzales A; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA., Chelales E; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA., Agudogo JS; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.; Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.; Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA 02115, USA., Crouch BT; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA., Nair SK; Department of Surgery, Duke University School of Medicine, Durham, NC 27708, USA.; Department of Pathology, Duke University School of Medicine, Durham, NC 27708, USA.; Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27708, USA., Ramanujam N; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA.; Duke Global Health Institute, Duke University, Durham, NC 27708, USA. |
| Abstrakt: |
Triple-negative breast cancer (TNBC) is an immunologically heterogenous disease that lacks clinically actionable targets and is more likely to progress to metastatic disease than other types of breast cancer. Tumor ablation has been used to increase response rates to checkpoint inhibitors, which remain low for TNBC patients. We hypothesized that tumor ablation could produce an anti-tumor response without using checkpoint inhibitors if immunosuppression (i.e., Tregs, tumor acidosis) was subdued. Tumors were primed with sodium bicarbonate (200 mM p.o.) to reduce tumor acidosis and low-dose cyclophosphamide (100-200 mg/kg i.p.) to deplete regulatory T cells, as has been shown independently in previous studies. A novel injectable ablative was then used to necrose the tumor, release tumor antigens, and initiate an immune event that could create an abscopal effect. This combination of bicarbonate, cyclophosphamide, and ablation, called "BiCyclA", was tested in three syngeneic models of TNBC: E0771 (C57BL/6), 67NR (BALB/c), and 4T1-Luc (BALB/c). In E0771 and 67NR, BiCyclA therapy significantly reduced tumor growth and cured 5/7 and 6/10 mice 50 days after treatment respectively. In the metastatic 4T1-Luc tumors, for which surgery and checkpoint inhibitors fail, BiCyclA cured 5/10 mice of primary tumors and lung metastases. Notably, CD4+ and CD8+ T cells were found to be crucial for the anti-metastatic response, and cured mice were able to resist tumor rechallenge, suggesting production of immune memory. Reduction of tumor acidity and regulatory T cells with ablation is a simple yet effective therapy for local and systemic tumor control with broad applicability as it is not limited by expensive supplies. |
