Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
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
_version_ 1783496335425536000
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
work_keys_str_mv AT yarchoanmark aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT huangchiungyu aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT zhuqingfeng aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT fergusonannak aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT durhamjennifern aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT andersroberta aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT thompsonelizabethd aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT rozichnoahs aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT thomasdwaynel aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT naurothjuliem aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT rodriguezchristina aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT osipovarsen aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT dejesusacostaana aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT ledungt aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT murphyadriang aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT laherudaniel aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT donehowerrossc aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT jaffeeelizabethm aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT zhenglei aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT azadnilofers aphase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT yarchoanmark phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT huangchiungyu phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT zhuqingfeng phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT fergusonannak phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT durhamjennifern phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT andersroberta phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT thompsonelizabethd phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT rozichnoahs phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT thomasdwaynel phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT naurothjuliem phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT rodriguezchristina phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT osipovarsen phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT dejesusacostaana phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT ledungt phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT murphyadriang phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT laherudaniel phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT donehowerrossc phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT jaffeeelizabethm phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT zhenglei phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer
AT azadnilofers phase2studyofgvaxcolonvaccinewithcyclophosphamideandpembrolizumabinpatientswithmismatchrepairproficientadvancedcolorectalcancer