Luzie A Doemel1,2, Jessica G Santana1, Lynn J Savic1,2,3, Fabian M Laage Gaupp1, Tabea Borde1,4, Alexandra Petukhova-Greenstein1,2, Ahmet S Kucukkaya1,2, Isabel T Schobert1,2, Charlie A Hamm2,5, Bernhard Gebauer2, John J Walsh6, Irvin Rexha1,2, Fahmeed Hyder1,6,7, MingDe Lin1,8, David C Madoff1,7,9,10,11, Todd Schlachter1, Julius Chapiro12,13, Daniel Coman1,7. 1. Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. 2. Department of Diagnostic and Interventional Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, 10117, Berlin, Germany. 3. Berlin Institute of Health, 10178, Berlin, Germany. 4. Department of Diagnostic and Interventional Radiology, Klinikum Rechts Der Isar, Technische Universitat München, Munich, Germany. 5. Institute for Diagnostic Radiology and Neuroradiology, Greifswald University Hospital, Ferdinand-Sauerbruch-Strasse, 17475, Greifswald, Germany. 6. Department of Biomedical Engineering, School of Engineering & Applied Science, 17 Hillhouse Avenue, New Haven, CT, 06510, USA. 7. Yale Cancer Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. 8. Visage Imaging, Inc., San Diego, CA, 92130, USA. 9. Division of Medical Oncology, Department of Medicine, Yale School of Medicine, New Haven, CT, 06510, USA. 10. Yale Liver Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. 11. Smilow Cancer Hospital Care Center - North Haven, 6 Devine Street, Fl 2, North Haven, CT, 06473, USA. 12. Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. j.chapiro@googlemail.com. 13. Yale Cancer Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. j.chapiro@googlemail.com.
Abstract
OBJECTIVES: The goal of this study was to investigate the effects of TACE using Lipiodol, Oncozene™ drug-eluting embolics (DEEs), or LUMI™-DEEs alone, or combined with bicarbonate on the metabolic and immunological tumor microenvironment in a rabbit VX2 tumor model. METHODS: VX2 liver tumor-bearing rabbits were assigned to five groups. MRI and extracellular pH (pHe) mapping using Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) were performed before and after intra-arterial therapy with conventional TACE (cTACE), DEE-TACE with Idarubicin-eluting Oncozene™-DEEs, or Doxorubicin-eluting LUMI™-DEEs, each with or without prior bicarbonate infusion, and in untreated rabbits or treated with intra-arterial bicarbonate only. Imaging results were validated with immunohistochemistry (IHC) staining of cell viability (PCNA, TUNEL) and immune response (HLA-DR, CD3). Statistical analysis was performed using Mann-Whitney U test. RESULTS: pHe mapping revealed that combining cTACE with prior bicarbonate infusion significantly increased tumor pHe compared to control (p = 0.0175) and cTACE alone (p = 0.0025). IHC staining revealed peritumoral accumulation of HLA-DR+ antigen-presenting cells and CD3 + T-lymphocytes in controls. cTACE-treated tumors showed reduced immune infiltration, which was restored through combination with bicarbonate. DEE-TACE with Oncozene™-DEEs induced moderate intratumoral and marked peritumoral infiltration, which was slightly reduced with bicarbonate. Addition of bicarbonate prior to LUMI™-beads enhanced peritumoral immune cell infiltration compared to LUMI™-beads alone and resulted in the strongest intratumoral immune cell infiltration across all treated groups. CONCLUSIONS: The choice of chemoembolic regimen for TACE strongly affects post-treatment TME pHe and the ability of immune cells to accumulate and infiltrate the tumor tissue. KEY POINTS: • Combining conventional transarterial chemotherapy with prior bicarbonate infusion increases the pHe towards a more physiological value (p = 0.0025). • Peritumoral infiltration and intratumoral accumulation patterns of antigen-presenting cells and T-lymphocytes after transarterial chemotherapy were dependent on the choice of the chemoembolic regimen. • Combination of intra-arterial treatment with Doxorubicin-eluting LUMI™-beads and bicarbonate infusion resulted in the strongest intratumoral presence of immune cells (positivity index of 0.47 for HLADR+-cells and 0.62 for CD3+-cells).
OBJECTIVES: The goal of this study was to investigate the effects of TACE using Lipiodol, Oncozene™ drug-eluting embolics (DEEs), or LUMI™-DEEs alone, or combined with bicarbonate on the metabolic and immunological tumor microenvironment in a rabbit VX2 tumor model. METHODS: VX2 liver tumor-bearing rabbits were assigned to five groups. MRI and extracellular pH (pHe) mapping using Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) were performed before and after intra-arterial therapy with conventional TACE (cTACE), DEE-TACE with Idarubicin-eluting Oncozene™-DEEs, or Doxorubicin-eluting LUMI™-DEEs, each with or without prior bicarbonate infusion, and in untreated rabbits or treated with intra-arterial bicarbonate only. Imaging results were validated with immunohistochemistry (IHC) staining of cell viability (PCNA, TUNEL) and immune response (HLA-DR, CD3). Statistical analysis was performed using Mann-Whitney U test. RESULTS: pHe mapping revealed that combining cTACE with prior bicarbonate infusion significantly increased tumor pHe compared to control (p = 0.0175) and cTACE alone (p = 0.0025). IHC staining revealed peritumoral accumulation of HLA-DR+ antigen-presenting cells and CD3 + T-lymphocytes in controls. cTACE-treated tumors showed reduced immune infiltration, which was restored through combination with bicarbonate. DEE-TACE with Oncozene™-DEEs induced moderate intratumoral and marked peritumoral infiltration, which was slightly reduced with bicarbonate. Addition of bicarbonate prior to LUMI™-beads enhanced peritumoral immune cell infiltration compared to LUMI™-beads alone and resulted in the strongest intratumoral immune cell infiltration across all treated groups. CONCLUSIONS: The choice of chemoembolic regimen for TACE strongly affects post-treatment TME pHe and the ability of immune cells to accumulate and infiltrate the tumor tissue. KEY POINTS: • Combining conventional transarterial chemotherapy with prior bicarbonate infusion increases the pHe towards a more physiological value (p = 0.0025). • Peritumoral infiltration and intratumoral accumulation patterns of antigen-presenting cells and T-lymphocytes after transarterial chemotherapy were dependent on the choice of the chemoembolic regimen. • Combination of intra-arterial treatment with Doxorubicin-eluting LUMI™-beads and bicarbonate infusion resulted in the strongest intratumoral presence of immune cells (positivity index of 0.47 for HLADR+-cells and 0.62 for CD3+-cells).
Authors: Laura Marelli; Rosa Stigliano; Christos Triantos; Marco Senzolo; Evangelos Cholongitas; Neil Davies; Jonathan Tibballs; Tim Meyer; David W Patch; Andrew K Burroughs Journal: Cardiovasc Intervent Radiol Date: 2007 Jan-Feb Impact factor: 2.740
Authors: Freddie Bray; Jacques Ferlay; Isabelle Soerjomataram; Rebecca L Siegel; Lindsey A Torre; Ahmedin Jemal Journal: CA Cancer J Clin Date: 2018-09-12 Impact factor: 508.702
Authors: Antonia M Berz; Jessica G Santana; Simon Iseke; Moritz Gross; Vasily Pekurovsky; Fabian Laage Gaupp; Lynn J Savic; Tabea Borde; Luzie A Gottwald; Anne Marie Boustani; Bernhard Gebauer; MingDe Lin; Xuchen Zhang; Todd Schlachter; David C Madoff; Julius Chapiro Journal: J Vasc Interv Radiol Date: 2022-03-26 Impact factor: 3.682
Authors: Yanqiao Ren; Yusheng Guo; Lei Chen; Tao Sun; Weihua Zhang; Bo Sun; Licheng Zhu; Fu Xiong; Chuansheng Zheng Journal: Cancer Control Date: 2022 Jan-Dec Impact factor: 3.302