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A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer
BACKGROUND: Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single‐agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole‐cell, granulocyte‐macrophage colony‐stimulating factor ‐secreting cellular immunotherapy that induces...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013064/ https://www.ncbi.nlm.nih.gov/pubmed/31876399 http://dx.doi.org/10.1002/cam4.2763 |
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author | Yarchoan, Mark Huang, Chiung‐Yu Zhu, Qingfeng Ferguson, Anna K. Durham, Jennifer N. Anders, Robert A. Thompson, Elizabeth D. Rozich, Noah S. Thomas, Dwayne L. Nauroth, Julie M. Rodriguez, Christina Osipov, Arsen De Jesus‐Acosta, Ana Le, Dung T. Murphy, Adrian G. Laheru, Daniel Donehower, Ross C. Jaffee, Elizabeth M. Zheng, Lei Azad, Nilofer S. |
author_facet | Yarchoan, Mark Huang, Chiung‐Yu Zhu, Qingfeng Ferguson, Anna K. Durham, Jennifer N. Anders, Robert A. Thompson, Elizabeth D. Rozich, Noah S. Thomas, Dwayne L. Nauroth, Julie M. Rodriguez, Christina Osipov, Arsen De Jesus‐Acosta, Ana Le, Dung T. Murphy, Adrian G. Laheru, Daniel Donehower, Ross C. Jaffee, Elizabeth M. Zheng, Lei Azad, Nilofer S. |
author_sort | Yarchoan, Mark |
collection | PubMed |
description | BACKGROUND: Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single‐agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole‐cell, granulocyte‐macrophage colony‐stimulating factor ‐secreting cellular immunotherapy that induces T‐cell immunity against tumor‐associated antigens and has previously been studied in combination with low‐dose cyclophosphamide (Cy) to inhibit regulatory T cells. METHODS: We conducted a single‐arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21‐day cycle. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary objectives included safety, overall survival, progression‐free survival, changes in carcinoembryonic antigen (CEA) levels, and immune‐related correlates. RESULTS: Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST 1.1. The median progression‐free survival was 82 days (95% confidence interval [CI], 48‐97 days) and the median overall survival was 213 days (95% CI 179‐441 days). Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Grade ≥ 3 treatment‐related adverse events were observed in two patients (hemolytic anemia and corneal transplant rejection). Paired pre‐ and on‐treatment biopsy specimens showed increases in programmed death‐ligand 1 expression and tumor necrosis in a subset of patients. CONCLUSIONS: GVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response. |
format | Online Article Text |
id | pubmed-7013064 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70130642020-03-24 A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer Yarchoan, Mark Huang, Chiung‐Yu Zhu, Qingfeng Ferguson, Anna K. Durham, Jennifer N. Anders, Robert A. Thompson, Elizabeth D. Rozich, Noah S. Thomas, Dwayne L. Nauroth, Julie M. Rodriguez, Christina Osipov, Arsen De Jesus‐Acosta, Ana Le, Dung T. Murphy, Adrian G. Laheru, Daniel Donehower, Ross C. Jaffee, Elizabeth M. Zheng, Lei Azad, Nilofer S. Cancer Med Cancer Biology BACKGROUND: Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single‐agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole‐cell, granulocyte‐macrophage colony‐stimulating factor ‐secreting cellular immunotherapy that induces T‐cell immunity against tumor‐associated antigens and has previously been studied in combination with low‐dose cyclophosphamide (Cy) to inhibit regulatory T cells. METHODS: We conducted a single‐arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21‐day cycle. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary objectives included safety, overall survival, progression‐free survival, changes in carcinoembryonic antigen (CEA) levels, and immune‐related correlates. RESULTS: Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST 1.1. The median progression‐free survival was 82 days (95% confidence interval [CI], 48‐97 days) and the median overall survival was 213 days (95% CI 179‐441 days). Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Grade ≥ 3 treatment‐related adverse events were observed in two patients (hemolytic anemia and corneal transplant rejection). Paired pre‐ and on‐treatment biopsy specimens showed increases in programmed death‐ligand 1 expression and tumor necrosis in a subset of patients. CONCLUSIONS: GVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response. John Wiley and Sons Inc. 2019-12-26 /pmc/articles/PMC7013064/ /pubmed/31876399 http://dx.doi.org/10.1002/cam4.2763 Text en © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Cancer Biology Yarchoan, Mark Huang, Chiung‐Yu Zhu, Qingfeng Ferguson, Anna K. Durham, Jennifer N. Anders, Robert A. Thompson, Elizabeth D. Rozich, Noah S. Thomas, Dwayne L. Nauroth, Julie M. Rodriguez, Christina Osipov, Arsen De Jesus‐Acosta, Ana Le, Dung T. Murphy, Adrian G. Laheru, Daniel Donehower, Ross C. Jaffee, Elizabeth M. Zheng, Lei Azad, Nilofer S. A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer |
title | A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer |
title_full | A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer |
title_fullStr | A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer |
title_full_unstemmed | A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer |
title_short | A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer |
title_sort | phase 2 study of gvax colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013064/ https://www.ncbi.nlm.nih.gov/pubmed/31876399 http://dx.doi.org/10.1002/cam4.2763 |
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