Impact of a New Fusion Receptor on PD-1-Mediated Immunosuppression in Adoptive T Cell Therapy.

Abstract

BACKGROUND:

Adoptive T cell transfer (ACT) is currently under investigation for the treatment of metastatic cancer. Recent evidence suggests that the coinhibitory PD-1-PD-L1 axis plays a major role in ACT failure. We hypothesized that a new fusion receptor reverting PD-1-mediated inhibition into CD28 costimulation may break peripheral tolerance.

METHODS:

Different PD-1-CD28 fusion receptor constructs were created and retrovirally transduced into primary T cell receptor transgenic murine CD8(+) T cells specific for ovalbumin (OT-1). Cytokine release, proliferation, cytotoxicity, and tumor recognition were analyzed in vitro. Antitumor efficacy and mode of action were investigated in mice bearing subcutaneous tumors induced with the pancreatic carcinoma cell line Panc02 expressing the model antigen ovalbumin (Panc-OVA). For antitumoral efficacy, six to eight mice per group were used. All statistical tests are two-sided.

RESULTS:

Transduction of the PD-1-CD28 receptor constructs mediated enhanced cytokine release, T cell proliferation, and T cell-induced lysis of target tumor cells. The PD-1-CD28 receptor function was dependent on two of the CD28-signaling motifs and IFN-γ release. Treatment of mice with established Panc-OVA tumors with fusion receptor-transduced OT-1 T cells mediated complete tumor regression. Mice rejecting the tumor were protected upon subsequent rechallenge with either ovalbumin-positive or -negative tumors, indicative of a memory response and epitope spreading in nine of 11 mice vs none of the six naïve mice (P < .001). Treatment efficacy was associated with accumulation of IFN-γ-producing T cells and an increased ratio of CD8(+) T cells to immunosuppressive myeloid-derived suppressor cells in the tumors.

CONCLUSIONS:

Transduction of T cells with this new PD-1-CD28 receptor has the potential of breaking the PD-1-PD-L1-immunosuppressive axis in ACT.

• Authors: Sebastian Kobold, Simon Grassmann, Michael Chaloupka, Christopher Lampert, Susanne Wenk, Fabian Kraus, Moritz Rapp, Peter Düwell, Yi Zeng, Jan C Schmollinger, Max Schnurr, Stefan Endres, Simon Rothenfußer
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 107 Issue 8 (Aug 2015) ISSN: 1460-2105 [Electronic] United States
• PMID: 26105028 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• B7-H1 Antigen
• CD28 Antigens
• Cd274 protein, mouse
• Epitopes
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Interferon-gamma
• Ovalbumin

Topics

• Adoptive Transfer (methods)
• Animals
• B7-H1 Antigen (immunology)
• CD28 Antigens (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Epitopes
• Immunosuppression Therapy
• Interferon-gamma (metabolism)
• Lymphocyte Count
• Mice
• Mice, Transgenic
• Ovalbumin (immunology)
• Pancreatic Neoplasms (immunology, therapy)
• Programmed Cell Death 1 Receptor (immunology)
• Signal Transduction (immunology)
• Transduction, Genetic
• Treatment Outcome