XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trial
We conducted a phase Ib/II clinical trial to evaluate the safety, feasibility, and clinical activity of combining pembrolizumab (anti-PD-1) with XL888 (Hsp90 inhibitor) in patients with advanced colorectal cancer (CRC). We hypothesized that this regimen would modulate soluble and cellular immune med...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2025.2475620 |
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| author | Maggie J. Phillips Olatunji B. Alese Natalie K. Horvat Emily Greene Olumide B. Gbolahan Kathleen Coleman Deon B. Doxie Vaunita Parihar Zaid K. Mahdi Ashley McCook-Veal Jeffrey M. Switchenko Maria Diab Cameron J. Herting Chrystal M. Paulos Bassel F. El-Rayes Gregory B. Lesinski |
| author_facet | Maggie J. Phillips Olatunji B. Alese Natalie K. Horvat Emily Greene Olumide B. Gbolahan Kathleen Coleman Deon B. Doxie Vaunita Parihar Zaid K. Mahdi Ashley McCook-Veal Jeffrey M. Switchenko Maria Diab Cameron J. Herting Chrystal M. Paulos Bassel F. El-Rayes Gregory B. Lesinski |
| author_sort | Maggie J. Phillips |
| collection | DOAJ |
| description | We conducted a phase Ib/II clinical trial to evaluate the safety, feasibility, and clinical activity of combining pembrolizumab (anti-PD-1) with XL888 (Hsp90 inhibitor) in patients with advanced colorectal cancer (CRC). We hypothesized that this regimen would modulate soluble and cellular immune mediators and enhance clinical outcomes. The trial employed a 3 + 3 open-label design, with an expansion cohort at the recommended phase II dose (RP2D) in treatment-refractory, mismatch repair-proficient CRC patients. Comprehensive analyses of plasma cytokines, peripheral blood mononuclear cells (PBMCs), and spatial immune cell patterns in liver biopsies were performed to identify unique immune signatures resulting from the combined therapy. The combination of pembrolizumab and XL888 proved to be safe and feasible, with a subset of patients achieving stable disease, although no objective responses were observed in this heavily pre-treated population. Correlative studies revealed immunomodulatory effects in tumors and circulation, including a reduction in IL6+ cells and macrophages (CD68+) within metastatic liver tissue, alterations in blood CD3+ cells, and upregulation of numerous inflammatory plasma cytokines. These findings suggest local and systemic immune activation by the combination of pembrolizumab and XL888. While clinical activity was modest in treatment-refractory CRC patients, there were notable effects on the tumor immune environment and systemic immune modulation. |
| format | Article |
| id | doaj-art-b141e0b52a4c4524a49005d4e15fc8aa |
| institution | Kabale University |
| issn | 2162-402X |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-b141e0b52a4c4524a49005d4e15fc8aa2025-08-20T03:48:27ZengTaylor & Francis GroupOncoImmunology2162-402X2025-12-0114110.1080/2162402X.2025.2475620XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trialMaggie J. Phillips0Olatunji B. Alese1Natalie K. Horvat2Emily Greene3Olumide B. Gbolahan4Kathleen Coleman5Deon B. Doxie6Vaunita Parihar7Zaid K. Mahdi8Ashley McCook-Veal9Jeffrey M. Switchenko10Maria Diab11Cameron J. Herting12Chrystal M. Paulos13Bassel F. El-Rayes14Gregory B. Lesinski15Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USADepartment of Hematology and Medical Oncology, Emory University, Atlanta, GA, USADepartment of Hematology and Medical Oncology, Emory University, Atlanta, GA, USADepartment of Hematology and Medical Oncology, Emory University, Atlanta, GA, USADepartment of Hematology and Medical Oncology, Emory University, Atlanta, GA, USAWinship Cancer Institute of Emory University, Atlanta, GA, USAWinship Cancer Institute of Emory University, Atlanta, GA, USAWinship Cancer Institute of Emory University, Atlanta, GA, USADepartment of Pathology, Emory University, Atlanta, GA, USADepartment of Biostatistics & Bioinformatics, Emory University, Atlanta, GA, USADepartment of Biostatistics & Bioinformatics, Emory University, Atlanta, GA, USADepartment of Internal Medicine, Henry Ford Hospital, Detroit, MI, USADepartment of Hematology and Medical Oncology, Emory University, Atlanta, GA, USADepartment of Surgery, Emory University, Atlanta, GA, USADepartment of Medicine, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Hematology and Medical Oncology, Emory University, Atlanta, GA, USAWe conducted a phase Ib/II clinical trial to evaluate the safety, feasibility, and clinical activity of combining pembrolizumab (anti-PD-1) with XL888 (Hsp90 inhibitor) in patients with advanced colorectal cancer (CRC). We hypothesized that this regimen would modulate soluble and cellular immune mediators and enhance clinical outcomes. The trial employed a 3 + 3 open-label design, with an expansion cohort at the recommended phase II dose (RP2D) in treatment-refractory, mismatch repair-proficient CRC patients. Comprehensive analyses of plasma cytokines, peripheral blood mononuclear cells (PBMCs), and spatial immune cell patterns in liver biopsies were performed to identify unique immune signatures resulting from the combined therapy. The combination of pembrolizumab and XL888 proved to be safe and feasible, with a subset of patients achieving stable disease, although no objective responses were observed in this heavily pre-treated population. Correlative studies revealed immunomodulatory effects in tumors and circulation, including a reduction in IL6+ cells and macrophages (CD68+) within metastatic liver tissue, alterations in blood CD3+ cells, and upregulation of numerous inflammatory plasma cytokines. These findings suggest local and systemic immune activation by the combination of pembrolizumab and XL888. While clinical activity was modest in treatment-refractory CRC patients, there were notable effects on the tumor immune environment and systemic immune modulation.https://www.tandfonline.com/doi/10.1080/2162402X.2025.2475620Clinical trialcolorectal cancercytokinesheat shock proteinimmune checkpoint inhibitorsimmunotherapy |
| spellingShingle | Maggie J. Phillips Olatunji B. Alese Natalie K. Horvat Emily Greene Olumide B. Gbolahan Kathleen Coleman Deon B. Doxie Vaunita Parihar Zaid K. Mahdi Ashley McCook-Veal Jeffrey M. Switchenko Maria Diab Cameron J. Herting Chrystal M. Paulos Bassel F. El-Rayes Gregory B. Lesinski XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trial OncoImmunology Clinical trial colorectal cancer cytokines heat shock protein immune checkpoint inhibitors immunotherapy |
| title | XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trial |
| title_full | XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trial |
| title_fullStr | XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trial |
| title_full_unstemmed | XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trial |
| title_short | XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trial |
| title_sort | xl888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase ib ii clinical trial |
| topic | Clinical trial colorectal cancer cytokines heat shock protein immune checkpoint inhibitors immunotherapy |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2025.2475620 |
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