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Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer
PURPOSE: Zolbetuximab (IMAB362) is engineered to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity. We evaluated ADCC activity and the impact of the immune-modulating drugs zoledronic acid (ZA) and interleukin-2 (IL-2) as co-treatment with zolbetuximab...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Springer Berlin Heidelberg
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10356865/ https://www.ncbi.nlm.nih.gov/pubmed/36607429 http://dx.doi.org/10.1007/s00432-022-04459-3 |
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author | Lordick, Florian Thuss-Patience, Peter Bitzer, Michael Maurus, Daniel Sahin, Ugur Türeci, Özlem |
author_facet | Lordick, Florian Thuss-Patience, Peter Bitzer, Michael Maurus, Daniel Sahin, Ugur Türeci, Özlem |
author_sort | Lordick, Florian |
collection | PubMed |
description | PURPOSE: Zolbetuximab (IMAB362) is engineered to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity. We evaluated ADCC activity and the impact of the immune-modulating drugs zoledronic acid (ZA) and interleukin-2 (IL-2) as co-treatment with zolbetuximab on relevant immune cell populations and ADCC lysis activity. METHODS: This phase 1, multicenter, open-label study investigated the immunological effects and activity, safety, tolerability, and antitumor activity of multiple doses of zolbetuximab alone (n = 5) or in combination with ZA (n = 7) or with ZA plus two different dose levels of IL-2 (low dose: 1 million international units [mIU] [n = 9]; intermediate dose: 3 mIU [n = 7]) in pretreated patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. RESULTS: Twenty-eight patients with previously treated advanced G/GEJ adenocarcinoma that was CLDN18.2-expressing were enrolled into four treatment arms. Treatment with zolbetuximab + ZA + IL-2 induced short-lived expansion and activation of ADCC-mediating cell populations, namely γ9δ2 T cells and natural killer cells, within 2 days after administration; this effect was more pronounced with intermediate-dose IL-2. Expansion and activation of regulatory T cells treated with either IL2 dose was moderate and short-lived. Strong ADCC activity was observed with zolbetuximab alone. Short-lived ADCC activity was observed in several patients treated with ZA + intermediate-dose IL-2, but not lower-dose IL-2. In the clinical efficacy population, the best confirmed response was stable disease (n = 11/19; 58%). CONCLUSIONS: Zolbetuximab mediates proficient ADCC in patients with pretreated advanced G/GEJ cancers. Co-treatment with ZA + IL-2 did not further improve this effect. Trial registration: NCT01671774 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00432-022-04459-3. |
format | Online Article Text |
id | pubmed-10356865 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-103568652023-07-21 Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer Lordick, Florian Thuss-Patience, Peter Bitzer, Michael Maurus, Daniel Sahin, Ugur Türeci, Özlem J Cancer Res Clin Oncol Research PURPOSE: Zolbetuximab (IMAB362) is engineered to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity. We evaluated ADCC activity and the impact of the immune-modulating drugs zoledronic acid (ZA) and interleukin-2 (IL-2) as co-treatment with zolbetuximab on relevant immune cell populations and ADCC lysis activity. METHODS: This phase 1, multicenter, open-label study investigated the immunological effects and activity, safety, tolerability, and antitumor activity of multiple doses of zolbetuximab alone (n = 5) or in combination with ZA (n = 7) or with ZA plus two different dose levels of IL-2 (low dose: 1 million international units [mIU] [n = 9]; intermediate dose: 3 mIU [n = 7]) in pretreated patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. RESULTS: Twenty-eight patients with previously treated advanced G/GEJ adenocarcinoma that was CLDN18.2-expressing were enrolled into four treatment arms. Treatment with zolbetuximab + ZA + IL-2 induced short-lived expansion and activation of ADCC-mediating cell populations, namely γ9δ2 T cells and natural killer cells, within 2 days after administration; this effect was more pronounced with intermediate-dose IL-2. Expansion and activation of regulatory T cells treated with either IL2 dose was moderate and short-lived. Strong ADCC activity was observed with zolbetuximab alone. Short-lived ADCC activity was observed in several patients treated with ZA + intermediate-dose IL-2, but not lower-dose IL-2. In the clinical efficacy population, the best confirmed response was stable disease (n = 11/19; 58%). CONCLUSIONS: Zolbetuximab mediates proficient ADCC in patients with pretreated advanced G/GEJ cancers. Co-treatment with ZA + IL-2 did not further improve this effect. Trial registration: NCT01671774 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00432-022-04459-3. Springer Berlin Heidelberg 2023-01-06 2023 /pmc/articles/PMC10356865/ /pubmed/36607429 http://dx.doi.org/10.1007/s00432-022-04459-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Lordick, Florian Thuss-Patience, Peter Bitzer, Michael Maurus, Daniel Sahin, Ugur Türeci, Özlem Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer |
title | Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer |
title_full | Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer |
title_fullStr | Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer |
title_full_unstemmed | Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer |
title_short | Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer |
title_sort | immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10356865/ https://www.ncbi.nlm.nih.gov/pubmed/36607429 http://dx.doi.org/10.1007/s00432-022-04459-3 |
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