Therapy-induced antitumor vaccination by targeting tumor necrosis factor-α to tumor vessels in combination with melphalan

Lorenzo Mortara, Enrica Balza, Francesca Sassi, Patrizia Castellani, Barbara Carnemolla, Andrea De Lerma Barbaro, Sara Fossati, Giovanna Tosi, Roberto S. Accolla, Laura Borsi

Research output: Contribution to journalArticle

Abstract

Treatment of tumor-bearing mice with mouse (m)TNF-α, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4 + T cells and consequent activation and maturation of CD8 + CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4 + and CD8 + T cells 6 days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-α and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4 +CD25 + regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and long-lasting antitumor adaptive immune response.

Original languageEnglish
Pages (from-to)3381-3392
Number of pages12
JournalEuropean Journal of Immunology
Volume37
Issue number12
DOIs
Publication statusPublished - Dec 2007

Fingerprint

Melphalan
Vaccination
Tumor Necrosis Factor-alpha
Neoplasms
Therapeutics
T-Lymphocytes
Single-Chain Antibodies
Adoptive Transfer
Adaptive Immunity
Regulatory T-Lymphocytes
Fibronectins
Immunity
Lymph Nodes
Pharmacology

Keywords

  • Antitumor immunity
  • CD4 priming
  • Melphalan
  • Th1/Th2 cells
  • TNF-α

ASJC Scopus subject areas

  • Immunology

Cite this

Therapy-induced antitumor vaccination by targeting tumor necrosis factor-α to tumor vessels in combination with melphalan. / Mortara, Lorenzo; Balza, Enrica; Sassi, Francesca; Castellani, Patrizia; Carnemolla, Barbara; De Lerma Barbaro, Andrea; Fossati, Sara; Tosi, Giovanna; Accolla, Roberto S.; Borsi, Laura.

In: European Journal of Immunology, Vol. 37, No. 12, 12.2007, p. 3381-3392.

Research output: Contribution to journalArticle

Mortara, L, Balza, E, Sassi, F, Castellani, P, Carnemolla, B, De Lerma Barbaro, A, Fossati, S, Tosi, G, Accolla, RS & Borsi, L 2007, 'Therapy-induced antitumor vaccination by targeting tumor necrosis factor-α to tumor vessels in combination with melphalan', European Journal of Immunology, vol. 37, no. 12, pp. 3381-3392. https://doi.org/10.1002/eji.200737450
Mortara, Lorenzo ; Balza, Enrica ; Sassi, Francesca ; Castellani, Patrizia ; Carnemolla, Barbara ; De Lerma Barbaro, Andrea ; Fossati, Sara ; Tosi, Giovanna ; Accolla, Roberto S. ; Borsi, Laura. / Therapy-induced antitumor vaccination by targeting tumor necrosis factor-α to tumor vessels in combination with melphalan. In: European Journal of Immunology. 2007 ; Vol. 37, No. 12. pp. 3381-3392.
@article{9387e3e9c4644de28c40f08eb29af8c2,
title = "Therapy-induced antitumor vaccination by targeting tumor necrosis factor-α to tumor vessels in combination with melphalan",
abstract = "Treatment of tumor-bearing mice with mouse (m)TNF-α, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4 + T cells and consequent activation and maturation of CD8 + CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4 + and CD8 + T cells 6 days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-α and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4 +CD25 + regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and long-lasting antitumor adaptive immune response.",
keywords = "Antitumor immunity, CD4 priming, Melphalan, Th1/Th2 cells, TNF-α",
author = "Lorenzo Mortara and Enrica Balza and Francesca Sassi and Patrizia Castellani and Barbara Carnemolla and {De Lerma Barbaro}, Andrea and Sara Fossati and Giovanna Tosi and Accolla, {Roberto S.} and Laura Borsi",
year = "2007",
month = "12",
doi = "10.1002/eji.200737450",
language = "English",
volume = "37",
pages = "3381--3392",
journal = "European Journal of Immunology",
issn = "0014-2980",
publisher = "wiley",
number = "12",

}

TY - JOUR

T1 - Therapy-induced antitumor vaccination by targeting tumor necrosis factor-α to tumor vessels in combination with melphalan

AU - Mortara, Lorenzo

AU - Balza, Enrica

AU - Sassi, Francesca

AU - Castellani, Patrizia

AU - Carnemolla, Barbara

AU - De Lerma Barbaro, Andrea

AU - Fossati, Sara

AU - Tosi, Giovanna

AU - Accolla, Roberto S.

AU - Borsi, Laura

PY - 2007/12

Y1 - 2007/12

N2 - Treatment of tumor-bearing mice with mouse (m)TNF-α, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4 + T cells and consequent activation and maturation of CD8 + CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4 + and CD8 + T cells 6 days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-α and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4 +CD25 + regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and long-lasting antitumor adaptive immune response.

AB - Treatment of tumor-bearing mice with mouse (m)TNF-α, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4 + T cells and consequent activation and maturation of CD8 + CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4 + and CD8 + T cells 6 days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-α and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4 +CD25 + regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and long-lasting antitumor adaptive immune response.

KW - Antitumor immunity

KW - CD4 priming

KW - Melphalan

KW - Th1/Th2 cells

KW - TNF-α

UR - http://www.scopus.com/inward/record.url?scp=37549021446&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37549021446&partnerID=8YFLogxK

U2 - 10.1002/eji.200737450

DO - 10.1002/eji.200737450

M3 - Article

C2 - 18022863

AN - SCOPUS:37549021446

VL - 37

SP - 3381

EP - 3392

JO - European Journal of Immunology

JF - European Journal of Immunology

SN - 0014-2980

IS - 12

ER -