Targeting tumor vasculature with TNF leads effector t cells to the tumor and enhances therapeutic efficacy of immune checkpoint blockers in combination with adoptive cell therapy

Research output: Contribution to journalArticle

Abstract

Purpose: Irregular blood flow and endothelial cell anergy, which characterize many solid tumors, hinder tumor infiltration by cytotoxic T lymphocytes (CTL). This confers resistance to cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes (i.e., immune checkpoint blockade, ICB). We investigated whether NGR-TNF, a TNF derivative capable of targeting the tumor vasculature, and improving intratumor infiltration by activated CTLs, could sensitize tumors to ICB with antibodies specific for the PD-1 and CTLA-4 receptors. Experimental Design: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with autochthonous prostate cancer and C57BL/6 mice with orthotopic B16 melanoma were treated with NGR-TNF, adoptive T-cell therapy (ACT), and ICB, and monitored for immune surveillance and disease progression. Results: The combination of ACT, NGR-TNF, and ICB was the most effective in delaying disease progression, and in improving overall survival of mice bearing ICB-resistant prostate cancer or melanoma. Mechanistically, the therapeutic effects were associated with potent tumor infiltration, especially by endogenous but also by adoptively transferred PD-1þ, granzyme Bþ, and interferon-gþCTLs. The therapeutic effects were also associated with favorable T-effector/regulatory T cell ratios. Conclusions: Targeting the tumor vasculature with low-dose TNF in association with ACT may represent a novel strategy for enhancing T-cell infiltration in tumors and overcoming resistance to immune checkpoint blockers. © 2018 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)2171-2181
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number9
DOIs
Publication statusPublished - 2018

Fingerprint

Cell- and Tissue-Based Therapy
Neoplasms
T-Lymphocytes
Therapeutic Uses
Therapeutics
Disease Progression
Prostatic Neoplasms
Granzymes
Experimental Melanomas
Immune System Diseases
Cytotoxic T-Lymphocytes
Regulatory T-Lymphocytes
Inbred C57BL Mouse
Immunotherapy
Interferons
Transgenic Mice
Prostate
Melanoma
Blood Cells
Adenocarcinoma

Cite this

@article{9177c5fd3fdb4c9cb48c315073a858a3,
title = "Targeting tumor vasculature with TNF leads effector t cells to the tumor and enhances therapeutic efficacy of immune checkpoint blockers in combination with adoptive cell therapy",
abstract = "Purpose: Irregular blood flow and endothelial cell anergy, which characterize many solid tumors, hinder tumor infiltration by cytotoxic T lymphocytes (CTL). This confers resistance to cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes (i.e., immune checkpoint blockade, ICB). We investigated whether NGR-TNF, a TNF derivative capable of targeting the tumor vasculature, and improving intratumor infiltration by activated CTLs, could sensitize tumors to ICB with antibodies specific for the PD-1 and CTLA-4 receptors. Experimental Design: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with autochthonous prostate cancer and C57BL/6 mice with orthotopic B16 melanoma were treated with NGR-TNF, adoptive T-cell therapy (ACT), and ICB, and monitored for immune surveillance and disease progression. Results: The combination of ACT, NGR-TNF, and ICB was the most effective in delaying disease progression, and in improving overall survival of mice bearing ICB-resistant prostate cancer or melanoma. Mechanistically, the therapeutic effects were associated with potent tumor infiltration, especially by endogenous but also by adoptively transferred PD-1{\th}, granzyme B{\th}, and interferon-g{\th}CTLs. The therapeutic effects were also associated with favorable T-effector/regulatory T cell ratios. Conclusions: Targeting the tumor vasculature with low-dose TNF in association with ACT may represent a novel strategy for enhancing T-cell infiltration in tumors and overcoming resistance to immune checkpoint blockers. {\circledC} 2018 American Association for Cancer Research.",
author = "AR Elia and M Grioni and V Basso and F Curnis and M Freschi and A Corti and A Mondino and M Bellone",
year = "2018",
doi = "10.1158/1078-0432.CCR-17-2210",
language = "English",
volume = "24",
pages = "2171--2181",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Targeting tumor vasculature with TNF leads effector t cells to the tumor and enhances therapeutic efficacy of immune checkpoint blockers in combination with adoptive cell therapy

AU - Elia, AR

AU - Grioni, M

AU - Basso, V

AU - Curnis, F

AU - Freschi, M

AU - Corti, A

AU - Mondino, A

AU - Bellone, M

PY - 2018

Y1 - 2018

N2 - Purpose: Irregular blood flow and endothelial cell anergy, which characterize many solid tumors, hinder tumor infiltration by cytotoxic T lymphocytes (CTL). This confers resistance to cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes (i.e., immune checkpoint blockade, ICB). We investigated whether NGR-TNF, a TNF derivative capable of targeting the tumor vasculature, and improving intratumor infiltration by activated CTLs, could sensitize tumors to ICB with antibodies specific for the PD-1 and CTLA-4 receptors. Experimental Design: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with autochthonous prostate cancer and C57BL/6 mice with orthotopic B16 melanoma were treated with NGR-TNF, adoptive T-cell therapy (ACT), and ICB, and monitored for immune surveillance and disease progression. Results: The combination of ACT, NGR-TNF, and ICB was the most effective in delaying disease progression, and in improving overall survival of mice bearing ICB-resistant prostate cancer or melanoma. Mechanistically, the therapeutic effects were associated with potent tumor infiltration, especially by endogenous but also by adoptively transferred PD-1þ, granzyme Bþ, and interferon-gþCTLs. The therapeutic effects were also associated with favorable T-effector/regulatory T cell ratios. Conclusions: Targeting the tumor vasculature with low-dose TNF in association with ACT may represent a novel strategy for enhancing T-cell infiltration in tumors and overcoming resistance to immune checkpoint blockers. © 2018 American Association for Cancer Research.

AB - Purpose: Irregular blood flow and endothelial cell anergy, which characterize many solid tumors, hinder tumor infiltration by cytotoxic T lymphocytes (CTL). This confers resistance to cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes (i.e., immune checkpoint blockade, ICB). We investigated whether NGR-TNF, a TNF derivative capable of targeting the tumor vasculature, and improving intratumor infiltration by activated CTLs, could sensitize tumors to ICB with antibodies specific for the PD-1 and CTLA-4 receptors. Experimental Design: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with autochthonous prostate cancer and C57BL/6 mice with orthotopic B16 melanoma were treated with NGR-TNF, adoptive T-cell therapy (ACT), and ICB, and monitored for immune surveillance and disease progression. Results: The combination of ACT, NGR-TNF, and ICB was the most effective in delaying disease progression, and in improving overall survival of mice bearing ICB-resistant prostate cancer or melanoma. Mechanistically, the therapeutic effects were associated with potent tumor infiltration, especially by endogenous but also by adoptively transferred PD-1þ, granzyme Bþ, and interferon-gþCTLs. The therapeutic effects were also associated with favorable T-effector/regulatory T cell ratios. Conclusions: Targeting the tumor vasculature with low-dose TNF in association with ACT may represent a novel strategy for enhancing T-cell infiltration in tumors and overcoming resistance to immune checkpoint blockers. © 2018 American Association for Cancer Research.

U2 - 10.1158/1078-0432.CCR-17-2210

DO - 10.1158/1078-0432.CCR-17-2210

M3 - Article

VL - 24

SP - 2171

EP - 2181

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 9

ER -