Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy

Brett Schrand, Alexey Berezhnoy, Randall Brenneman, Anthony Williams, Agata Levay, Ling Yuan Kong, Ganesh Rao, Shouhao Zhou, Amy B. Heimberger, Eli Gilboa

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Despite the recent successes of using immune modulatory Abs in patients with cancer, autoimmune pathologies resulting from the activation of self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient, whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, VEGF. This approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma, the T cells will be costimulated before their engagement of the MHC-peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to noninternalizing cell surface products expressed on the tumor cells. Underscoring the potency of stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models, systemic administration of the VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, postsurgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared with nontargeted administration of an agonistic 4-1BB Ab or 4-1BB aptamer.

Original languageEnglish (US)
Pages (from-to)867-877
Number of pages11
JournalCancer immunology research
Volume2
Issue number9
DOIs
StatePublished - Sep 1 2014

Fingerprint

Immunotherapy
Neoplasms
Vascular Endothelial Growth Factor A
Therapeutics
Ligands
T-Lymphocytes
Fibrosarcoma
Oncogenes
Glioma
Oligonucleotides
Immunity
Pathology
Neoplasm Metastasis
Lung
Peptides

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy. / Schrand, Brett; Berezhnoy, Alexey; Brenneman, Randall; Williams, Anthony; Levay, Agata; Kong, Ling Yuan; Rao, Ganesh; Zhou, Shouhao; Heimberger, Amy B.; Gilboa, Eli.

In: Cancer immunology research, Vol. 2, No. 9, 01.09.2014, p. 867-877.

Research output: Contribution to journalArticle

Schrand, Brett ; Berezhnoy, Alexey ; Brenneman, Randall ; Williams, Anthony ; Levay, Agata ; Kong, Ling Yuan ; Rao, Ganesh ; Zhou, Shouhao ; Heimberger, Amy B. ; Gilboa, Eli. / Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy. In: Cancer immunology research. 2014 ; Vol. 2, No. 9. pp. 867-877.
@article{75c57aaaef7b447693e2c370fd51aca1,
title = "Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy",
abstract = "Despite the recent successes of using immune modulatory Abs in patients with cancer, autoimmune pathologies resulting from the activation of self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient, whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, VEGF. This approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma, the T cells will be costimulated before their engagement of the MHC-peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to noninternalizing cell surface products expressed on the tumor cells. Underscoring the potency of stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models, systemic administration of the VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, postsurgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared with nontargeted administration of an agonistic 4-1BB Ab or 4-1BB aptamer.",
author = "Brett Schrand and Alexey Berezhnoy and Randall Brenneman and Anthony Williams and Agata Levay and Kong, {Ling Yuan} and Ganesh Rao and Shouhao Zhou and Heimberger, {Amy B.} and Eli Gilboa",
year = "2014",
month = "9",
day = "1",
doi = "10.1158/2326-6066.CIR-14-0007",
language = "English (US)",
volume = "2",
pages = "867--877",
journal = "Cancer immunology research",
issn = "2326-6066",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy

AU - Schrand, Brett

AU - Berezhnoy, Alexey

AU - Brenneman, Randall

AU - Williams, Anthony

AU - Levay, Agata

AU - Kong, Ling Yuan

AU - Rao, Ganesh

AU - Zhou, Shouhao

AU - Heimberger, Amy B.

AU - Gilboa, Eli

PY - 2014/9/1

Y1 - 2014/9/1

N2 - Despite the recent successes of using immune modulatory Abs in patients with cancer, autoimmune pathologies resulting from the activation of self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient, whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, VEGF. This approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma, the T cells will be costimulated before their engagement of the MHC-peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to noninternalizing cell surface products expressed on the tumor cells. Underscoring the potency of stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models, systemic administration of the VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, postsurgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared with nontargeted administration of an agonistic 4-1BB Ab or 4-1BB aptamer.

AB - Despite the recent successes of using immune modulatory Abs in patients with cancer, autoimmune pathologies resulting from the activation of self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient, whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, VEGF. This approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma, the T cells will be costimulated before their engagement of the MHC-peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to noninternalizing cell surface products expressed on the tumor cells. Underscoring the potency of stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models, systemic administration of the VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, postsurgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared with nontargeted administration of an agonistic 4-1BB Ab or 4-1BB aptamer.

UR - http://www.scopus.com/inward/record.url?scp=84964314436&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964314436&partnerID=8YFLogxK

U2 - 10.1158/2326-6066.CIR-14-0007

DO - 10.1158/2326-6066.CIR-14-0007

M3 - Article

C2 - 24938283

AN - SCOPUS:84964314436

VL - 2

SP - 867

EP - 877

JO - Cancer immunology research

JF - Cancer immunology research

SN - 2326-6066

IS - 9

ER -