PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors

Kevin C. Soares, Agnieszka A. Rucki, Annie A. Wu, Kelly Olino, Qian Xiao, Yi Chai, Anthony Wamwea, Elaine Bigelow, Eric Lutz, Linda Liu, Sheng Yao, Robert A. Anders, Daniel Laheru, Christopher L. Wolfgang, Barish H. Edil, Richard D. Schulick, Elizabeth M. Jaffee, Lei Zheng

Research output: Contribution to journalArticle

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Abstract

Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a granulocyte macrophage colony-stimulating factor secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor-bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared with PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8+ T lymphocytes and tumor-specific interferon-γ production of CD8+ T cells in the tumor microenvironment. Immunosuppressive pathways, including regulatory T cells and CTLA-4 expression on T cells were overcome by the addition of vaccine and low-dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalJournal of Immunotherapy
Volume38
Issue number1
StatePublished - Jan 14 2015
Externally publishedYes

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Active Immunotherapy
Adenocarcinoma
T-Lymphocytes
CTLA-4 Antigen
Neoplasms
Tumor Microenvironment
Antibodies
Therapeutics
Vaccines
Regulatory T-Lymphocytes
Granulocyte-Macrophage Colony-Stimulating Factor
Immunosuppressive Agents
Immunotherapy
Cyclophosphamide
Interferons
Up-Regulation
Ligands
Survival

Keywords

  • Immune checkpoint
  • Immunotherapy
  • Pancreatic cancer
  • PD-1
  • PD-L1

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Cancer Research
  • Pharmacology

Cite this

Soares, K. C., Rucki, A. A., Wu, A. A., Olino, K., Xiao, Q., Chai, Y., ... Zheng, L. (2015). PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. Journal of Immunotherapy, 38(1), 1-11.

PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. / Soares, Kevin C.; Rucki, Agnieszka A.; Wu, Annie A.; Olino, Kelly; Xiao, Qian; Chai, Yi; Wamwea, Anthony; Bigelow, Elaine; Lutz, Eric; Liu, Linda; Yao, Sheng; Anders, Robert A.; Laheru, Daniel; Wolfgang, Christopher L.; Edil, Barish H.; Schulick, Richard D.; Jaffee, Elizabeth M.; Zheng, Lei.

In: Journal of Immunotherapy, Vol. 38, No. 1, 14.01.2015, p. 1-11.

Research output: Contribution to journalArticle

Soares, KC, Rucki, AA, Wu, AA, Olino, K, Xiao, Q, Chai, Y, Wamwea, A, Bigelow, E, Lutz, E, Liu, L, Yao, S, Anders, RA, Laheru, D, Wolfgang, CL, Edil, BH, Schulick, RD, Jaffee, EM & Zheng, L 2015, 'PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors', Journal of Immunotherapy, vol. 38, no. 1, pp. 1-11.
Soares, Kevin C. ; Rucki, Agnieszka A. ; Wu, Annie A. ; Olino, Kelly ; Xiao, Qian ; Chai, Yi ; Wamwea, Anthony ; Bigelow, Elaine ; Lutz, Eric ; Liu, Linda ; Yao, Sheng ; Anders, Robert A. ; Laheru, Daniel ; Wolfgang, Christopher L. ; Edil, Barish H. ; Schulick, Richard D. ; Jaffee, Elizabeth M. ; Zheng, Lei. / PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. In: Journal of Immunotherapy. 2015 ; Vol. 38, No. 1. pp. 1-11.
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abstract = "Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a granulocyte macrophage colony-stimulating factor secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor-bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared with PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8+ T lymphocytes and tumor-specific interferon-γ production of CD8+ T cells in the tumor microenvironment. Immunosuppressive pathways, including regulatory T cells and CTLA-4 expression on T cells were overcome by the addition of vaccine and low-dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment.",
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