A Non-interventional Clinical Trial Assessing Immune Responses After Radiofrequency Ablation of Liver Metastases From Colorectal Cancer
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A Non-interventional Clinical Trial Assessing Immune Responses After Radiofrequency Ablation of Liver Metastases From Colorectal Cancer. / Löffler, Markus W; Nussbaum, Bianca; Jäger, Günter; Jurmeister, Philipp S; Budczies, Jan; Pereira, Philippe L; Clasen, Stephan; Kowalewski, Daniel J; Mühlenbruch, Lena; Königsrainer, Ingmar; Beckert, Stefan; Ladurner, Ruth; Wagner, Silvia; Bullinger, Florian; Gross, Thorben H; Schroeder, Christopher; Sipos, Bence; Königsrainer, Alfred; Stevanović, Stefan; Denkert, Carsten; Rammensee, Hans-Georg; Gouttefangeas, Cécile; Haen, Sebastian P.
In: FRONT IMMUNOL, Vol. 10, 2019, p. 2526.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - A Non-interventional Clinical Trial Assessing Immune Responses After Radiofrequency Ablation of Liver Metastases From Colorectal Cancer
AU - Löffler, Markus W
AU - Nussbaum, Bianca
AU - Jäger, Günter
AU - Jurmeister, Philipp S
AU - Budczies, Jan
AU - Pereira, Philippe L
AU - Clasen, Stephan
AU - Kowalewski, Daniel J
AU - Mühlenbruch, Lena
AU - Königsrainer, Ingmar
AU - Beckert, Stefan
AU - Ladurner, Ruth
AU - Wagner, Silvia
AU - Bullinger, Florian
AU - Gross, Thorben H
AU - Schroeder, Christopher
AU - Sipos, Bence
AU - Königsrainer, Alfred
AU - Stevanović, Stefan
AU - Denkert, Carsten
AU - Rammensee, Hans-Georg
AU - Gouttefangeas, Cécile
AU - Haen, Sebastian P
N1 - Copyright © 2019 Löffler, Nussbaum, Jäger, Jurmeister, Budczies, Pereira, Clasen, Kowalewski, Mühlenbruch, Königsrainer, Beckert, Ladurner, Wagner, Bullinger, Gross, Schroeder, Sipos, Königsrainer, Stevanović, Denkert, Rammensee, Gouttefangeas and Haen.
PY - 2019
Y1 - 2019
N2 - Background: Radiofrequency ablation (RFA) is an established treatment option for malignancies located in the liver. RFA-induced irreversible coagulation necrosis leads to the release of danger signals and cellular content. Hence, RFA may constitute an endogenous in situ tumor vaccination, stimulating innate and adaptive immune responses, including tumor-antigen specific T cells. This may explain a phenomenon termed abscopal effect, namely tumor regression in untreated lesions evidenced after distant thermal ablation or irradiation. In this study, we therefore assessed systemic and local immune responses in individual patients treated with RFA. Methods: For this prospective clinical trial, patients with liver metastasis from colorectal carcinoma (mCRC) receiving RFA and undergoing metachronous liver surgery for another lesion were recruited (n = 9) during a 5-year period. Tumor and non-malignant liver tissue samples from six patients were investigated by whole transcriptome sequencing and tandem-mass spectrometry, characterizing naturally presented HLA ligands. Tumor antigen-derived HLA-restricted peptides were selected by different predefined approaches. Further, candidate HLA ligands were manually curated. Peripheral blood mononuclear cells were stimulated in vitro with epitope candidate peptides, and functional T cell responses were assessed by intracellular cytokine staining. Immunohistochemical markers were additionally investigated in surgically resected mCRC from patients treated with (n = 9) or without RFA (n = 7). Results: In all six investigated patients, either induced immune responses and/or pre-existing T cell immunity against the selected targets were observed. Multi-cytokine responses were inter alia directed against known tumor antigens such as cyclin D1 but also against a (predicted) mutation contained in ERBB3. Immunohistochemistry did not show a relevant influx of immune cells into distant malignant lesions after RFA treatment (n = 9) as compared to the surgery only mCRC group (n = 7). Conclusions: Using an individualized approach for target selection, RFA induced and/or boosted T cell responses specific for individual tumor antigens were more frequently detectable as compared to previously published observations with well-characterized tumor antigens. However, the witnessed modest RFA-induced immunological effects alone may not be sufficient for the rejection of established tumors. Therefore, these findings warrant further clinical investigation including the assessment of RFA combination therapies e.g., with immune stimulatory agents, cancer vaccination, and/or immune checkpoint inhibitors.
AB - Background: Radiofrequency ablation (RFA) is an established treatment option for malignancies located in the liver. RFA-induced irreversible coagulation necrosis leads to the release of danger signals and cellular content. Hence, RFA may constitute an endogenous in situ tumor vaccination, stimulating innate and adaptive immune responses, including tumor-antigen specific T cells. This may explain a phenomenon termed abscopal effect, namely tumor regression in untreated lesions evidenced after distant thermal ablation or irradiation. In this study, we therefore assessed systemic and local immune responses in individual patients treated with RFA. Methods: For this prospective clinical trial, patients with liver metastasis from colorectal carcinoma (mCRC) receiving RFA and undergoing metachronous liver surgery for another lesion were recruited (n = 9) during a 5-year period. Tumor and non-malignant liver tissue samples from six patients were investigated by whole transcriptome sequencing and tandem-mass spectrometry, characterizing naturally presented HLA ligands. Tumor antigen-derived HLA-restricted peptides were selected by different predefined approaches. Further, candidate HLA ligands were manually curated. Peripheral blood mononuclear cells were stimulated in vitro with epitope candidate peptides, and functional T cell responses were assessed by intracellular cytokine staining. Immunohistochemical markers were additionally investigated in surgically resected mCRC from patients treated with (n = 9) or without RFA (n = 7). Results: In all six investigated patients, either induced immune responses and/or pre-existing T cell immunity against the selected targets were observed. Multi-cytokine responses were inter alia directed against known tumor antigens such as cyclin D1 but also against a (predicted) mutation contained in ERBB3. Immunohistochemistry did not show a relevant influx of immune cells into distant malignant lesions after RFA treatment (n = 9) as compared to the surgery only mCRC group (n = 7). Conclusions: Using an individualized approach for target selection, RFA induced and/or boosted T cell responses specific for individual tumor antigens were more frequently detectable as compared to previously published observations with well-characterized tumor antigens. However, the witnessed modest RFA-induced immunological effects alone may not be sufficient for the rejection of established tumors. Therefore, these findings warrant further clinical investigation including the assessment of RFA combination therapies e.g., with immune stimulatory agents, cancer vaccination, and/or immune checkpoint inhibitors.
U2 - 10.3389/fimmu.2019.02526
DO - 10.3389/fimmu.2019.02526
M3 - SCORING: Journal article
C2 - 31803175
VL - 10
SP - 2526
JO - FRONT IMMUNOL
JF - FRONT IMMUNOL
SN - 1664-3224
ER -