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Clinical Trials: Immunotherapy

Immune Activation in Patients with Locally Advanced Cervical Cancer Treated with Ipilimumab Following Definitive Chemoradiation (GOG-9929)

Diane M. Da Silva, Danielle M. Enserro, Jyoti S. Mayadev, Joseph G. Skeate, Koji Matsuo, Huyen Q. Pham, Heather A. Lankes, Katherine M. Moxley, Sharad A. Ghamande, Yvonne G. Lin, Russell J. Schilder, Michael J. Birrer and W. Martin Kast
Diane M. Da Silva
1Department of Obstetrics & Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California.
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  • ORCID record for Diane M. Da Silva
  • For correspondence: Diane.DaSilva@med.usc.edu
Danielle M. Enserro
2Clinical Trial Development Division, NRG Oncology, Philadelphia, Pennsylvania.
3Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Jyoti S. Mayadev
4Department of Radiation Medicine and Applied Sciences, UC San Diego Medical Center, La Jolla, California.
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Joseph G. Skeate
5Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California.
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Koji Matsuo
1Department of Obstetrics & Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California.
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Huyen Q. Pham
1Department of Obstetrics & Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California.
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Heather A. Lankes
6Operations Center-Philadelphia East, NRG Oncology, Philadelphia, Pennsylvania.
7Department of Obstetrics & Gynecology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
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Katherine M. Moxley
8Department of Obstetrics & Gynecology, Oklahoma University Health Science Center, Oklahoma City, Oklahoma.
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  • ORCID record for Katherine M. Moxley
Sharad A. Ghamande
9Department of Gynecology/Oncology, Augusta University Medical Center, Augusta, Georgia.
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Yvonne G. Lin
1Department of Obstetrics & Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California.
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Russell J. Schilder
10Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
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Michael J. Birrer
11Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
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W. Martin Kast
1Department of Obstetrics & Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California.
5Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California.
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DOI: 10.1158/1078-0432.CCR-20-0776 Published November 2020
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Abstract

Purpose: A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti–CTL antigen-4 (anti–CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment.

Patients and Methods: Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot.

Results: Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival.

Conclusions: Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.

This article is featured in Highlights of This Issue, p. 5541

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • ClinicalTrials.gov registration ID: NCT01711515

  • Clin Cancer Res 2020;26:5621–30

  • Received February 26, 2020.
  • Revision received July 7, 2020.
  • Accepted August 14, 2020.
  • Published first August 18, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 26 (21)
November 2020
Volume 26, Issue 21
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Immune Activation in Patients with Locally Advanced Cervical Cancer Treated with Ipilimumab Following Definitive Chemoradiation (GOG-9929)
Diane M. Da Silva, Danielle M. Enserro, Jyoti S. Mayadev, Joseph G. Skeate, Koji Matsuo, Huyen Q. Pham, Heather A. Lankes, Katherine M. Moxley, Sharad A. Ghamande, Yvonne G. Lin, Russell J. Schilder, Michael J. Birrer and W. Martin Kast
Clin Cancer Res November 1 2020 (26) (21) 5621-5630; DOI: 10.1158/1078-0432.CCR-20-0776

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Immune Activation in Patients with Locally Advanced Cervical Cancer Treated with Ipilimumab Following Definitive Chemoradiation (GOG-9929)
Diane M. Da Silva, Danielle M. Enserro, Jyoti S. Mayadev, Joseph G. Skeate, Koji Matsuo, Huyen Q. Pham, Heather A. Lankes, Katherine M. Moxley, Sharad A. Ghamande, Yvonne G. Lin, Russell J. Schilder, Michael J. Birrer and W. Martin Kast
Clin Cancer Res November 1 2020 (26) (21) 5621-5630; DOI: 10.1158/1078-0432.CCR-20-0776
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