Modulation of lymphocyte regulation for cancer therapy: A phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma

Christy Ralph, Eyad Elkord, Deborah J. Burt, Jackie F. O'Dwyer, Eric B. Austin, Peter L. Stern, Robert E. Hawkins, Fiona C. Thistlethwaite

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

Purpose: Cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of T-cell activation, is targeted by the antibody tremelimumab to release potentially useful antitumor activity. Experimental Design: This phase II trial investigated tremelimumab as a second-line treatment for patients with metastatic gastric and esophageal adenocarcinomas. Tremelimumab was given every 3 months until symptomatic disease progression. Safety, clinical efficacy, and immunologic activity were evaluated. Results: Eighteen patients received tremelimumab. Most drug-related toxicity was mild; however, there was a single death due to bowel perforation that complicated colitis. Four patients had stable disease with clinical benefit; one patient achieved a partial response after eight cycles (25.4 months) and remains well on study at 32.7 months. Markers of regulatory phenotype, forkhead box protein 3 and CTLA4, doubled transiently in CD4+CD25high lymphocytes in the first month after tremelimumab before returning to baseline. In contrast, CTLA4 increased in CD4+CD25low/negative lymphocytes throughout the cycle of treatment. De novo proliferative responses to tumor-associated antigens 5T4 (8 of 18 patients) and carcinoembryonic antigen (5 of 13) were detected. Patients with a posttreatment carcinoembryonic antigen proliferative response had median survival of 17.1 months compared with 4.7 months for nonresponders (P = 0.004). Baseline interleukin-2 release after T-cell activation was higher in patients with clinical benefit and toxicity. Conclusion: Despite the disappointing response rate of tremelimumab, one patient had a remarkably durable benefit for this poor-prognosis disease. In vitro evidence of enhanced proliferative responses to relevant tumor-associated antigens suggests that combining CTLA4 blockade with antigen-targeted therapy may warrant further investigation.

Original languageEnglish
Pages (from-to)1662-1672
Number of pages11
JournalClinical Cancer Research
Volume16
Issue number5
DOIs
Publication statusPublished - 1 Mar 2010
Externally publishedYes

Fingerprint

Stomach
Adenocarcinoma
CTLA-4 Antigen
Lymphocytes
Neoplasms
Carcinoembryonic Antigen
Neoplasm Antigens
Therapeutics
Forkhead Transcription Factors
T-Lymphocytes
tremelimumab
Colitis
Drug-Related Side Effects and Adverse Reactions
Interleukin-2
Disease Progression
Research Design
Phenotype
Safety
Antigens
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Modulation of lymphocyte regulation for cancer therapy : A phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. / Ralph, Christy; Elkord, Eyad; Burt, Deborah J.; O'Dwyer, Jackie F.; Austin, Eric B.; Stern, Peter L.; Hawkins, Robert E.; Thistlethwaite, Fiona C.

In: Clinical Cancer Research, Vol. 16, No. 5, 01.03.2010, p. 1662-1672.

Research output: Contribution to journalArticle

Ralph, Christy ; Elkord, Eyad ; Burt, Deborah J. ; O'Dwyer, Jackie F. ; Austin, Eric B. ; Stern, Peter L. ; Hawkins, Robert E. ; Thistlethwaite, Fiona C. / Modulation of lymphocyte regulation for cancer therapy : A phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 5. pp. 1662-1672.
@article{2d1d2ca97ff44117be13d2b84525c640,
title = "Modulation of lymphocyte regulation for cancer therapy: A phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma",
abstract = "Purpose: Cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of T-cell activation, is targeted by the antibody tremelimumab to release potentially useful antitumor activity. Experimental Design: This phase II trial investigated tremelimumab as a second-line treatment for patients with metastatic gastric and esophageal adenocarcinomas. Tremelimumab was given every 3 months until symptomatic disease progression. Safety, clinical efficacy, and immunologic activity were evaluated. Results: Eighteen patients received tremelimumab. Most drug-related toxicity was mild; however, there was a single death due to bowel perforation that complicated colitis. Four patients had stable disease with clinical benefit; one patient achieved a partial response after eight cycles (25.4 months) and remains well on study at 32.7 months. Markers of regulatory phenotype, forkhead box protein 3 and CTLA4, doubled transiently in CD4+CD25high lymphocytes in the first month after tremelimumab before returning to baseline. In contrast, CTLA4 increased in CD4+CD25low/negative lymphocytes throughout the cycle of treatment. De novo proliferative responses to tumor-associated antigens 5T4 (8 of 18 patients) and carcinoembryonic antigen (5 of 13) were detected. Patients with a posttreatment carcinoembryonic antigen proliferative response had median survival of 17.1 months compared with 4.7 months for nonresponders (P = 0.004). Baseline interleukin-2 release after T-cell activation was higher in patients with clinical benefit and toxicity. Conclusion: Despite the disappointing response rate of tremelimumab, one patient had a remarkably durable benefit for this poor-prognosis disease. In vitro evidence of enhanced proliferative responses to relevant tumor-associated antigens suggests that combining CTLA4 blockade with antigen-targeted therapy may warrant further investigation.",
author = "Christy Ralph and Eyad Elkord and Burt, {Deborah J.} and O'Dwyer, {Jackie F.} and Austin, {Eric B.} and Stern, {Peter L.} and Hawkins, {Robert E.} and Thistlethwaite, {Fiona C.}",
year = "2010",
month = "3",
day = "1",
doi = "10.1158/1078-0432.CCR-09-2870",
language = "English",
volume = "16",
pages = "1662--1672",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

TY - JOUR

T1 - Modulation of lymphocyte regulation for cancer therapy

T2 - A phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma

AU - Ralph, Christy

AU - Elkord, Eyad

AU - Burt, Deborah J.

AU - O'Dwyer, Jackie F.

AU - Austin, Eric B.

AU - Stern, Peter L.

AU - Hawkins, Robert E.

AU - Thistlethwaite, Fiona C.

PY - 2010/3/1

Y1 - 2010/3/1

N2 - Purpose: Cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of T-cell activation, is targeted by the antibody tremelimumab to release potentially useful antitumor activity. Experimental Design: This phase II trial investigated tremelimumab as a second-line treatment for patients with metastatic gastric and esophageal adenocarcinomas. Tremelimumab was given every 3 months until symptomatic disease progression. Safety, clinical efficacy, and immunologic activity were evaluated. Results: Eighteen patients received tremelimumab. Most drug-related toxicity was mild; however, there was a single death due to bowel perforation that complicated colitis. Four patients had stable disease with clinical benefit; one patient achieved a partial response after eight cycles (25.4 months) and remains well on study at 32.7 months. Markers of regulatory phenotype, forkhead box protein 3 and CTLA4, doubled transiently in CD4+CD25high lymphocytes in the first month after tremelimumab before returning to baseline. In contrast, CTLA4 increased in CD4+CD25low/negative lymphocytes throughout the cycle of treatment. De novo proliferative responses to tumor-associated antigens 5T4 (8 of 18 patients) and carcinoembryonic antigen (5 of 13) were detected. Patients with a posttreatment carcinoembryonic antigen proliferative response had median survival of 17.1 months compared with 4.7 months for nonresponders (P = 0.004). Baseline interleukin-2 release after T-cell activation was higher in patients with clinical benefit and toxicity. Conclusion: Despite the disappointing response rate of tremelimumab, one patient had a remarkably durable benefit for this poor-prognosis disease. In vitro evidence of enhanced proliferative responses to relevant tumor-associated antigens suggests that combining CTLA4 blockade with antigen-targeted therapy may warrant further investigation.

AB - Purpose: Cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of T-cell activation, is targeted by the antibody tremelimumab to release potentially useful antitumor activity. Experimental Design: This phase II trial investigated tremelimumab as a second-line treatment for patients with metastatic gastric and esophageal adenocarcinomas. Tremelimumab was given every 3 months until symptomatic disease progression. Safety, clinical efficacy, and immunologic activity were evaluated. Results: Eighteen patients received tremelimumab. Most drug-related toxicity was mild; however, there was a single death due to bowel perforation that complicated colitis. Four patients had stable disease with clinical benefit; one patient achieved a partial response after eight cycles (25.4 months) and remains well on study at 32.7 months. Markers of regulatory phenotype, forkhead box protein 3 and CTLA4, doubled transiently in CD4+CD25high lymphocytes in the first month after tremelimumab before returning to baseline. In contrast, CTLA4 increased in CD4+CD25low/negative lymphocytes throughout the cycle of treatment. De novo proliferative responses to tumor-associated antigens 5T4 (8 of 18 patients) and carcinoembryonic antigen (5 of 13) were detected. Patients with a posttreatment carcinoembryonic antigen proliferative response had median survival of 17.1 months compared with 4.7 months for nonresponders (P = 0.004). Baseline interleukin-2 release after T-cell activation was higher in patients with clinical benefit and toxicity. Conclusion: Despite the disappointing response rate of tremelimumab, one patient had a remarkably durable benefit for this poor-prognosis disease. In vitro evidence of enhanced proliferative responses to relevant tumor-associated antigens suggests that combining CTLA4 blockade with antigen-targeted therapy may warrant further investigation.

UR - http://www.scopus.com/inward/record.url?scp=77649136167&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77649136167&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-09-2870

DO - 10.1158/1078-0432.CCR-09-2870

M3 - Article

C2 - 20179239

AN - SCOPUS:77649136167

VL - 16

SP - 1662

EP - 1672

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 5

ER -