A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer

Mark Yarchoan; Chiung Yu Huang; Qingfeng Zhu; Anna K. Ferguson; Jennifer N. Durham; Robert A. Anders; Elizabeth D. Thompson; Noah S. Rozich; Dwayne L. Thomas; Julie M. Nauroth; Christina Rodriguez; Arsen Osipov; Ana De Jesus-Acosta; Dung T. Le; Adrian G. Murphy; Daniel Laheru; Ross C. Donehower; Elizabeth M. Jaffee; Lei Zheng; Nilofer S. Azad

doi:10.1002/cam4.2763

A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer

Mark Yarchoan, Chiung Yu Huang, Qingfeng Zhu, Anna K. Ferguson, Jennifer N. Durham, Robert A. Anders, Elizabeth D. Thompson, Noah S. Rozich, Dwayne L. Thomas, Julie M. Nauroth, Christina Rodriguez, Arsen Osipov, Ana De Jesus-Acosta, Dung T. Le, Adrian G. Murphy, Daniel Laheru, Ross C. Donehower, Elizabeth M. Jaffee, Lei Zheng, Nilofer S. Azad

School of Medicine

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1485-1494
Number of pages	10
Journal	Cancer medicine
Volume	9
Issue number	4
DOIs	https://doi.org/10.1002/cam4.2763
State	Published - Feb 1 2020

Keywords

PD-1
checkpoint inhibitor
colorectal cancer
immunotherapy
vaccine

ASJC Scopus subject areas

Oncology
Radiology Nuclear Medicine and imaging
Cancer Research

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10.1002/cam4.2763

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Yarchoan, M., Huang, C. Y., Zhu, Q., Ferguson, A. K., Durham, J. N., Anders, R. A., Thompson, E. D., Rozich, N. S., Thomas, D. L., Nauroth, J. M., Rodriguez, C., Osipov, A., De Jesus-Acosta, A., Le, D. T., Murphy, A. G., Laheru, D., Donehower, R. C., Jaffee, E. M., Zheng, L., & Azad, N. S. (2020). A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer. Cancer medicine, 9(4), 1485-1494. https://doi.org/10.1002/cam4.2763

Yarchoan, M, Huang, CY, Zhu, Q, Ferguson, AK, Durham, JN , Anders, RA , Thompson, ED, Rozich, NS, Thomas, DL, Nauroth, JM, Rodriguez, C, Osipov, A, De Jesus-Acosta, A , Le, DT, Murphy, AG, Laheru, D , Donehower, RC , Jaffee, EM , Zheng, L & Azad, NS 2020, 'A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer', Cancer medicine, vol. 9, no. 4, pp. 1485-1494. https://doi.org/10.1002/cam4.2763

@article{8a5d817913d54308a0a5ccfdf4584fa4,

title = "A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer",

abstract = "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.",

keywords = "PD-1, checkpoint inhibitor, colorectal cancer, immunotherapy, vaccine",

author = "Mark Yarchoan and Huang, {Chiung Yu} and Qingfeng Zhu and Ferguson, {Anna K.} and Durham, {Jennifer N.} and Anders, {Robert A.} and Thompson, {Elizabeth D.} and Rozich, {Noah S.} and Thomas, {Dwayne L.} and Nauroth, {Julie M.} and Christina Rodriguez and Arsen Osipov and {De Jesus-Acosta}, Ana and Le, {Dung T.} and Murphy, {Adrian G.} and Daniel Laheru and Donehower, {Ross C.} and Jaffee, {Elizabeth M.} and Lei Zheng and Azad, {Nilofer S.}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.",

year = "2020",

month = feb,

day = "1",

doi = "10.1002/cam4.2763",

language = "English (US)",

volume = "9",

pages = "1485--1494",

journal = "Cancer medicine",

issn = "2045-7634",

publisher = "John Wiley and Sons Ltd",

number = "4",

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TY - JOUR

T1 - A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer

AU - Yarchoan, Mark

AU - Huang, Chiung Yu

AU - Zhu, Qingfeng

AU - Ferguson, Anna K.

AU - Durham, Jennifer N.

AU - Anders, Robert A.

AU - Thompson, Elizabeth D.

AU - Rozich, Noah S.

AU - Thomas, Dwayne L.

AU - Nauroth, Julie M.

AU - Rodriguez, Christina

AU - Osipov, Arsen

AU - De Jesus-Acosta, Ana

AU - Le, Dung T.

AU - Murphy, Adrian G.

AU - Laheru, Daniel

AU - Donehower, Ross C.

AU - Jaffee, Elizabeth M.

AU - Zheng, Lei

AU - Azad, Nilofer S.

PY - 2020/2/1

Y1 - 2020/2/1

N2 - 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.

AB - 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.

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KW - checkpoint inhibitor

KW - colorectal cancer

KW - immunotherapy

KW - vaccine

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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

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