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Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers

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Abstract

Background

The primary objective was to study the antitumor activity of prolonged subcutaneous dosing of systemic 852A, a Toll-like receptor-7 agonist (TLR-7), in recurrent breast, ovarian and cervix cancer. Secondary objectives included assessment of safety and immune system activation.

Methods

Adults with recurrent breast, ovarian or cervix cancer failing multiple therapies received 0.6 mg/m2 of 852A subcutaneously twice weekly for 12 weeks. Doses increased by 0.2 mg/m2/week to a maximum of 1.2 mg/m2. Serum was collected to assess immune activation.

Results

Fifteen patients enrolled: 10 ovarian, 2 cervix and 3 breast. Three completed all 24 injections. There were two grade 2 (decreased ejection fractions), nine grade 3 (1 cardiovascular, 1 anorexia, 3 dehydration, 2 infections, 2 renal) and two grade 4 (hepatic and troponin elevation) unanticipated toxicities. Cardiac toxicities included three cardiomyopathies (2 asymptomatic) and one stress-related non-ST elevated myocardial infarction. Five patients discontinued therapy due to possibly associated side effects. One who had stable disease (SD) following 24 doses received 17 additional doses. A cervix patient with SD following 24 doses received chemotherapy after progressing 3 months later, and remains disease free at 18 months. Immune activation, as evidenced by increased IP-10 and IL-1ra, was observed.

Conclusions

In this first human experience of a TLR-7 agonist delivered subcutaneously using a prolonged dosing schedule, 852A demonstrated sustained tolerability in some patients. Clinical benefit was modest, but immune activation was seen suggesting further study of antitumor applications is warranted. Because of cardiac toxicity; 852A should be used cautiously in heavily pretreated patients.

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Acknowledgments

This study was initially supported by 3M. 3M oncology programs were acquired by Coley in June 2007 and Coley provided financial support for MUGA scans performed as part of the trial. Coley was acquired by Pfizer Inc in November 2007. Additional support was provided by the Minnesota Ovarian Cancer Alliance.

Conflict of interest

The authors declare that they have no conflict of interest

Author information

Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Women’s Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455, USA

    Melissa A. Geller, Peter A. Argenta, Levi S. Downs, Linda F. Carson, Patricia L. Judson & Rahel Ghebre

  2. Department of Medicine, University of Minnesota, MMC 806 420 Delaware St. SE., Minneapolis, MN, 55455, USA

    Sarah Cooley, Angela Panoskaltsis-Mortari & Jeffrey S. Miller

  3. Department of Pediatrics, University of Minnesota, MMC 391 420 Delaware St. SE., Minneapolis, MN, 55455, USA

    Brenda Weigel & Angela Panoskaltsis-Mortari

  4. Masonic Cancer Center, University of Minnesota, MMC 806 420 Delaware St. SE., Minneapolis, MN, 55455, USA

    Julie Curtsinger

  5. Division of Hematology, Oncology and Transplantation, University of Minnesota, MMC 806 420 Delaware St. SE., Minneapolis, MN, 55455, USA

    Jeffrey S. Miller

Authors
  1. Melissa A. Geller
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  2. Sarah Cooley
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  3. Peter A. Argenta
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  4. Levi S. Downs
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  5. Linda F. Carson
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  6. Patricia L. Judson
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  7. Rahel Ghebre
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  8. Brenda Weigel
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  9. Angela Panoskaltsis-Mortari
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  10. Julie Curtsinger
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  11. Jeffrey S. Miller
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Corresponding author

Correspondence to Jeffrey S. Miller.

Additional information

M. A. Geller and S. Cooley contributed equally to this work.

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Geller, M.A., Cooley, S., Argenta, P.A. et al. Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers. Cancer Immunol Immunother 59, 1877–1884 (2010). https://doi.org/10.1007/s00262-010-0914-1

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  • DOI: https://doi.org/10.1007/s00262-010-0914-1

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