Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells

Scott K. Pruitt, David Boczkowski, Nicole de Rosa, N. Rebecca Haley, Michael A. Morse, Douglas Tyler, Jens Dannull, Smita Nair

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Cancer vaccines have now demonstrated clinical efficacy, but immune modulatory mechanisms that prevent autoimmunity limit their effectiveness. Systemic administration of mAbs targeting the immune modulatory receptors CTLA-4 and glucocorticoid-induced TNFR-related protein (GITR) on Treg and effector T cells augments anti-tumor immunity both experimentally and clinically, but can induce life-threatening autoimmunity. We hypothesized that local delivery of anti-CTLA-4 and anti-GITR mAbs to the sites where T cells and tumor antigen-loaded DC vaccines interact would enhance the induction of anti-tumor immunity while avoiding autoimmunity. To achieve this goal, DCs transfected with mRNA encoding the H and L chains of anti-mouse CTLA-4 and GITR mAbs were co-administered with tumor antigen mRNA-transfected DCs. We observed enhanced induction of anti-tumor immunity and significantly improved survival in melanoma-bearing mice, without signs of autoimmunity. Using in vitro assays with human DCs, we demonstrated that DCs transfected with mRNA encoding a humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens. Based on these results, this approach of using local delivery of immune modulators to enhance vaccine-induced immunity is currently being evaluated in a phase I clinical cancer immunotherapy trial.

Original languageEnglish (US)
Pages (from-to)3553-3563
Number of pages11
JournalEuropean Journal of Immunology
Volume41
Issue number12
DOIs
StatePublished - Dec 2011
Externally publishedYes

Fingerprint

Glucocorticoid-Induced TNFR-Related Protein
Dendritic Cells
Immunity
Autoimmunity
Messenger RNA
Neoplasm Antigens
Neoplasms
Melanoma
Vaccines
T-Lymphocytes
Cancer Vaccines
Viral Tumor Antigens
Immunotherapy
Breast Neoplasms
Antigens
Survival

Keywords

  • Cancer
  • DC
  • Immunotherapy
  • Tumor immunology

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. / Pruitt, Scott K.; Boczkowski, David; de Rosa, Nicole; Haley, N. Rebecca; Morse, Michael A.; Tyler, Douglas; Dannull, Jens; Nair, Smita.

In: European Journal of Immunology, Vol. 41, No. 12, 12.2011, p. 3553-3563.

Research output: Contribution to journalArticle

Pruitt, SK, Boczkowski, D, de Rosa, N, Haley, NR, Morse, MA, Tyler, D, Dannull, J & Nair, S 2011, 'Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells', European Journal of Immunology, vol. 41, no. 12, pp. 3553-3563. https://doi.org/10.1002/eji.201141383
Pruitt, Scott K. ; Boczkowski, David ; de Rosa, Nicole ; Haley, N. Rebecca ; Morse, Michael A. ; Tyler, Douglas ; Dannull, Jens ; Nair, Smita. / Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. In: European Journal of Immunology. 2011 ; Vol. 41, No. 12. pp. 3553-3563.
@article{14d8697ab8ee453c86db6657bfee0270,
title = "Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells",
abstract = "Cancer vaccines have now demonstrated clinical efficacy, but immune modulatory mechanisms that prevent autoimmunity limit their effectiveness. Systemic administration of mAbs targeting the immune modulatory receptors CTLA-4 and glucocorticoid-induced TNFR-related protein (GITR) on Treg and effector T cells augments anti-tumor immunity both experimentally and clinically, but can induce life-threatening autoimmunity. We hypothesized that local delivery of anti-CTLA-4 and anti-GITR mAbs to the sites where T cells and tumor antigen-loaded DC vaccines interact would enhance the induction of anti-tumor immunity while avoiding autoimmunity. To achieve this goal, DCs transfected with mRNA encoding the H and L chains of anti-mouse CTLA-4 and GITR mAbs were co-administered with tumor antigen mRNA-transfected DCs. We observed enhanced induction of anti-tumor immunity and significantly improved survival in melanoma-bearing mice, without signs of autoimmunity. Using in vitro assays with human DCs, we demonstrated that DCs transfected with mRNA encoding a humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens. Based on these results, this approach of using local delivery of immune modulators to enhance vaccine-induced immunity is currently being evaluated in a phase I clinical cancer immunotherapy trial.",
keywords = "Cancer, DC, Immunotherapy, Tumor immunology",
author = "Pruitt, {Scott K.} and David Boczkowski and {de Rosa}, Nicole and Haley, {N. Rebecca} and Morse, {Michael A.} and Douglas Tyler and Jens Dannull and Smita Nair",
year = "2011",
month = "12",
doi = "10.1002/eji.201141383",
language = "English (US)",
volume = "41",
pages = "3553--3563",
journal = "European Journal of Immunology",
issn = "0014-2980",
publisher = "Wiley-VCH Verlag",
number = "12",

}

TY - JOUR

T1 - Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells

AU - Pruitt, Scott K.

AU - Boczkowski, David

AU - de Rosa, Nicole

AU - Haley, N. Rebecca

AU - Morse, Michael A.

AU - Tyler, Douglas

AU - Dannull, Jens

AU - Nair, Smita

PY - 2011/12

Y1 - 2011/12

N2 - Cancer vaccines have now demonstrated clinical efficacy, but immune modulatory mechanisms that prevent autoimmunity limit their effectiveness. Systemic administration of mAbs targeting the immune modulatory receptors CTLA-4 and glucocorticoid-induced TNFR-related protein (GITR) on Treg and effector T cells augments anti-tumor immunity both experimentally and clinically, but can induce life-threatening autoimmunity. We hypothesized that local delivery of anti-CTLA-4 and anti-GITR mAbs to the sites where T cells and tumor antigen-loaded DC vaccines interact would enhance the induction of anti-tumor immunity while avoiding autoimmunity. To achieve this goal, DCs transfected with mRNA encoding the H and L chains of anti-mouse CTLA-4 and GITR mAbs were co-administered with tumor antigen mRNA-transfected DCs. We observed enhanced induction of anti-tumor immunity and significantly improved survival in melanoma-bearing mice, without signs of autoimmunity. Using in vitro assays with human DCs, we demonstrated that DCs transfected with mRNA encoding a humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens. Based on these results, this approach of using local delivery of immune modulators to enhance vaccine-induced immunity is currently being evaluated in a phase I clinical cancer immunotherapy trial.

AB - Cancer vaccines have now demonstrated clinical efficacy, but immune modulatory mechanisms that prevent autoimmunity limit their effectiveness. Systemic administration of mAbs targeting the immune modulatory receptors CTLA-4 and glucocorticoid-induced TNFR-related protein (GITR) on Treg and effector T cells augments anti-tumor immunity both experimentally and clinically, but can induce life-threatening autoimmunity. We hypothesized that local delivery of anti-CTLA-4 and anti-GITR mAbs to the sites where T cells and tumor antigen-loaded DC vaccines interact would enhance the induction of anti-tumor immunity while avoiding autoimmunity. To achieve this goal, DCs transfected with mRNA encoding the H and L chains of anti-mouse CTLA-4 and GITR mAbs were co-administered with tumor antigen mRNA-transfected DCs. We observed enhanced induction of anti-tumor immunity and significantly improved survival in melanoma-bearing mice, without signs of autoimmunity. Using in vitro assays with human DCs, we demonstrated that DCs transfected with mRNA encoding a humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens. Based on these results, this approach of using local delivery of immune modulators to enhance vaccine-induced immunity is currently being evaluated in a phase I clinical cancer immunotherapy trial.

KW - Cancer

KW - DC

KW - Immunotherapy

KW - Tumor immunology

UR - http://www.scopus.com/inward/record.url?scp=82255181369&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=82255181369&partnerID=8YFLogxK

U2 - 10.1002/eji.201141383

DO - 10.1002/eji.201141383

M3 - Article

C2 - 22028176

AN - SCOPUS:82255181369

VL - 41

SP - 3553

EP - 3563

JO - European Journal of Immunology

JF - European Journal of Immunology

SN - 0014-2980

IS - 12

ER -