Evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer
Purpose Triple negative breast cancer (TNBC) is characterized by the presence of immune cells in the tumor microenvironment, however, the response to single-agent immune checkpoint inhibitor (ICI) therapy is modest. Preclinical models have demonstrated that intratumoral regulatory T cells (Tregs) da...
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BMJ Publishing Group
2022-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/2/e003427.full |
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| author | Karen McKinnon Kristen Cowens Dante Bortone Lisa Carey Trevor Jolly Hyman Muss Katherine Reeder-Hayes Rebecca Kaltman Rachel Jankowitz Vinay Gudena Oludamilola Olajide Charles Perou Carey K Anders Mark G Woodcock Amanda E D Van Swearingen Dominic T Moore Maria J Sambade Sonia Laurie Alexander Robeson Oleg Kolupaev Luz A Cuaboy Amy L Garrett Benjamin C Calhoun Alec D Wilkinson E Claire Dees Benjamin G Vincent Jonathan S Serody |
| author_facet | Karen McKinnon Kristen Cowens Dante Bortone Lisa Carey Trevor Jolly Hyman Muss Katherine Reeder-Hayes Rebecca Kaltman Rachel Jankowitz Vinay Gudena Oludamilola Olajide Charles Perou Carey K Anders Mark G Woodcock Amanda E D Van Swearingen Dominic T Moore Maria J Sambade Sonia Laurie Alexander Robeson Oleg Kolupaev Luz A Cuaboy Amy L Garrett Benjamin C Calhoun Alec D Wilkinson E Claire Dees Benjamin G Vincent Jonathan S Serody |
| author_sort | Karen McKinnon |
| collection | DOAJ |
| description | Purpose Triple negative breast cancer (TNBC) is characterized by the presence of immune cells in the tumor microenvironment, however, the response to single-agent immune checkpoint inhibitor (ICI) therapy is modest. Preclinical models have demonstrated that intratumoral regulatory T cells (Tregs) dampen the antitumor response to ICI. We performed a single-arm phase II trial to evaluate the efficacy of a single low dose of cyclophosphamide (Cy) to deplete Tregs administered before initiating pembrolizumab.Patients and methods 40 patients with pretreated metastatic TNBC were enrolled. The primary endpoints were progression-free survival (PFS) and change in peripheral blood Tregs after Cy. Secondary endpoints included overall response rate (ORR), duration of response, overall survival, treatment-related adverse events (AEs), and correlative evaluations.Results Median PFS was 1.8 months, and the ORR was 21%. Tregs were not significantly decreased after Cy prior to ICI (−3.3%, p=0.19), and increased significantly after the first cycle of therapy (+21% between cycles 1 and 2, p=0.005). Immune-related AEs were similar to historical pembrolizumab monotherapy, and were associated with response to therapy (p=0.02). Patients with pretreatment tumors harboring increased expression of B cell metagene signatures and increased circulating B cell receptor repertoire diversity were associated with clinical response and immune-related toxicity (IRT).Conclusions Among patients with heavily pretreated TNBC, Cy prior to pembrolizumab did not significantly deplete Tregs, and in those with decreased numbers there was rapid recovery following therapy. Increased B cell gene expression in baseline samples was associated with clinical response and IRT. |
| format | Article |
| id | doaj-art-4b4477f689454bc2b5fe6bd317c412e0 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-4b4477f689454bc2b5fe6bd317c412e02025-08-20T02:13:03ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-02-0110210.1136/jitc-2021-003427Evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancerKaren McKinnon0Kristen Cowens1Dante Bortone2Lisa Carey3Trevor Jolly4Hyman Muss5Katherine Reeder-Hayes6Rebecca Kaltman7Rachel Jankowitz8Vinay Gudena9Oludamilola Olajide10Charles Perou11Carey K Anders12Mark G Woodcock13Amanda E D Van Swearingen14Dominic T Moore15Maria J Sambade16Sonia Laurie17Alexander Robeson18Oleg Kolupaev19Luz A Cuaboy20Amy L Garrett21Benjamin C Calhoun22Alec D Wilkinson23E Claire Dees24Benjamin G Vincent25Jonathan S Serody26Division of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USALineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USALineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USADivision of Medical Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USADivision of Medical Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USADivision of Medical Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USADivision of Medical Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USADepartment of Hematology and Oncology, George Washington Cancer Center, Washington, District of Columbia, USAAbramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USADivision of Hematology/Oncology, Cone Health Cancer Center, Greensboro, North Carolina, USARex Hematology Oncology Associates, Rex Cancer Care, Raleigh, North Carolina, USALineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USADuke Cancer Institute, Durham, North Carolina, USALineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USADuke Cancer Institute, Durham, North Carolina, USALineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USALineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USALineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USALineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USALineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USALineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USALineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USADepartment of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USALineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USADivision of Medical Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USADivision of Hematology, Department of Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USALineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAPurpose Triple negative breast cancer (TNBC) is characterized by the presence of immune cells in the tumor microenvironment, however, the response to single-agent immune checkpoint inhibitor (ICI) therapy is modest. Preclinical models have demonstrated that intratumoral regulatory T cells (Tregs) dampen the antitumor response to ICI. We performed a single-arm phase II trial to evaluate the efficacy of a single low dose of cyclophosphamide (Cy) to deplete Tregs administered before initiating pembrolizumab.Patients and methods 40 patients with pretreated metastatic TNBC were enrolled. The primary endpoints were progression-free survival (PFS) and change in peripheral blood Tregs after Cy. Secondary endpoints included overall response rate (ORR), duration of response, overall survival, treatment-related adverse events (AEs), and correlative evaluations.Results Median PFS was 1.8 months, and the ORR was 21%. Tregs were not significantly decreased after Cy prior to ICI (−3.3%, p=0.19), and increased significantly after the first cycle of therapy (+21% between cycles 1 and 2, p=0.005). Immune-related AEs were similar to historical pembrolizumab monotherapy, and were associated with response to therapy (p=0.02). Patients with pretreatment tumors harboring increased expression of B cell metagene signatures and increased circulating B cell receptor repertoire diversity were associated with clinical response and immune-related toxicity (IRT).Conclusions Among patients with heavily pretreated TNBC, Cy prior to pembrolizumab did not significantly deplete Tregs, and in those with decreased numbers there was rapid recovery following therapy. Increased B cell gene expression in baseline samples was associated with clinical response and IRT.https://jitc.bmj.com/content/10/2/e003427.full |
| spellingShingle | Karen McKinnon Kristen Cowens Dante Bortone Lisa Carey Trevor Jolly Hyman Muss Katherine Reeder-Hayes Rebecca Kaltman Rachel Jankowitz Vinay Gudena Oludamilola Olajide Charles Perou Carey K Anders Mark G Woodcock Amanda E D Van Swearingen Dominic T Moore Maria J Sambade Sonia Laurie Alexander Robeson Oleg Kolupaev Luz A Cuaboy Amy L Garrett Benjamin C Calhoun Alec D Wilkinson E Claire Dees Benjamin G Vincent Jonathan S Serody Evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer Journal for ImmunoTherapy of Cancer |
| title | Evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer |
| title_full | Evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer |
| title_fullStr | Evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer |
| title_full_unstemmed | Evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer |
| title_short | Evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer |
| title_sort | evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer |
| url | https://jitc.bmj.com/content/10/2/e003427.full |
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