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

Melissa A. Geller, Sarah Cooley, Peter A. Argenta, Levi S. Downs, Linda F. Carson, Patricia L. Judson, Rahel Ghebre, Brenda Weigel, Angela Panoskaltsis-Mortari, Julie Curtsinger, Jeffrey S. Miller

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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.

Original languageEnglish (US)
Pages (from-to)1877-1884
Number of pages8
JournalCancer Immunology, Immunotherapy
Volume59
Issue number12
DOIs
StatePublished - Dec 1 2010

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Toll-Like Receptor 7
Uterine Cervical Neoplasms
Ovarian Neoplasms
Appointments and Schedules
Breast Neoplasms
Cervix Uteri
Interleukin 1 Receptor Antagonist Protein
Troponin
Anorexia
Cardiomyopathies
Dehydration
Immune System
Breast
Kidney
Safety
Drug Therapy
Injections
Liver
Therapeutics
Infection

Keywords

  • 852A
  • Breast cancer
  • Cervix cancer
  • Ovarian cancer
  • TLR-7 agonist

Cite this

@article{b064efdffd6c443085750caf891b23bb,
title = "Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers",
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.",
keywords = "852A, Breast cancer, Cervix cancer, Ovarian cancer, TLR-7 agonist",
author = "Geller, {Melissa A.} and Sarah Cooley and Argenta, {Peter A.} and Downs, {Levi S.} and Carson, {Linda F.} and Judson, {Patricia L.} and Rahel Ghebre and Brenda Weigel and Angela Panoskaltsis-Mortari and Julie Curtsinger and Miller, {Jeffrey S.}",
year = "2010",
month = "12",
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doi = "10.1007/s00262-010-0914-1",
language = "English (US)",
volume = "59",
pages = "1877--1884",
journal = "Cancer Immunology and Immunotherapy",
issn = "0340-7004",
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number = "12",

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TY - JOUR

T1 - Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers

AU - Geller, Melissa A.

AU - Cooley, Sarah

AU - Argenta, Peter A.

AU - Downs, Levi S.

AU - Carson, Linda F.

AU - Judson, Patricia L.

AU - Ghebre, Rahel

AU - Weigel, Brenda

AU - Panoskaltsis-Mortari, Angela

AU - Curtsinger, Julie

AU - Miller, Jeffrey S.

PY - 2010/12/1

Y1 - 2010/12/1

N2 - 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.

AB - 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.

KW - 852A

KW - Breast cancer

KW - Cervix cancer

KW - Ovarian cancer

KW - TLR-7 agonist

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U2 - 10.1007/s00262-010-0914-1

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