Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies

Journal for ImmunoTherapy of Cancer

Todd D. Armstrong¹  Jennifer Kleponis¹  Kelly Foley¹  Kevin Soares²  Victoria M. Kim²  Lei Zheng³  Christopher L. Wolfgang³  Alex B. Blair³  Stephen T. Muth⁴  Xu Che⁴  Elizabeth M. Jaffee⁴  Tao Xia⁴  Dirk Brockstedt⁵  Peter Lauer⁵ 

[1] 0000 0001 2171 9311, grid.21107.35, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 21287, Baltimore, MD, USA;0000 0001 2171 9311, grid.21107.35, Department of Oncology, The Johns Hopkins University School of Medicine, 21287, Baltimore, MD, USA;0000 0001 2171 9311, grid.21107.35, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 21287, Baltimore, MD, USA;0000 0001 2171 9311, grid.21107.35, Department of Oncology, The Johns Hopkins University School of Medicine, 21287, Baltimore, MD, USA;0000 0001 2171 9311, grid.21107.35, Department of Surgery, The Johns Hopkins University School of Medicine, 21287, Baltimore, MD, USA;0000 0001 2171 9311, grid.21107.35, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 21287, Baltimore, MD, USA;0000 0001 2171 9311, grid.21107.35, Department of Oncology, The Johns Hopkins University School of Medicine, 21287, Baltimore, MD, USA;0000 0001 2171 9311, grid.21107.35, Department of Surgery, The Johns Hopkins University School of Medicine, 21287, Baltimore, MD, USA;0000 0001 2171 9311, grid.21107.35, The Pancreatic Cancer Precision Medicine Program of Excellence, The Johns Hopkins University School of Medicine, 21287, Baltimore, MD, USA;0000 0001 2171 9311, grid.21107.35, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 21287, Baltimore, MD, USA;0000 0001 2171 9311, grid.21107.35, Department of Oncology, The Johns Hopkins University School of Medicine, 21287, Baltimore, MD, USA;0000 0001 2171 9311, grid.21107.35, The Pancreatic Cancer Precision Medicine Program of Excellence, The Johns Hopkins University School of Medicine, 21287, Baltimore, MD, USA;grid.417411.6, Aduro Biotech, Inc., Berkeley, California, USA;

关键词: Pancreatic cancer;    Immunotherapy;    Annexin A2;    Anti-PD-1 antibody, interferon-gamma, CD8 T cells;   

DOI  :  10.1186/s40425-019-0601-5

来源: publisher

【 摘 要 】

BackgroundImmune checkpoint inhibitors are not effective for pancreatic ductal adenocarcinoma (PDAC) as single agents. Vaccine therapy may sensitize PDACs to checkpoint inhibitor treatments. Annexin A2 (ANXA2) is a pro-metastasis protein, previously identified as a relevant PDAC antigen that is expressed by a GM-CSF-secreting allogenic whole pancreatic tumor cell vaccine (GVAX) to induce an anti-ANXA2 antibody response in patients with PDAC. We hypothesized that an ANXA2-targeting vaccine approach not only provokes an immune response but also mounts anti-tumor effects.MethodsWe developed a Listeria-based, ANXA2-targeting cancer immunotherapy (Lm-ANXA2) and investigated its effectiveness within two murine models of PDAC.ResultsWe show that Lm-ANXA2 prolonged the survival in a transplant model of mouse PDACs. More importantly, priming with the Lm-ANXA2 treatment prior to administration of anti-PD-1 antibodies increased cure rates in the implanted PDAC model and resulted in objective tumor responses and prolonged survival in the genetically engineered spontaneous PDAC model. In tumors treated with Lm-ANXA2 followed by anti-PD-1 antibody, the T cells specific to ANXA2 had significantly increased INFγ expression.ConclusionsFor the first time, a listeria vaccine-based immunotherapy was shown to be able to induce a tumor antigen-specific T cell response within the tumor microenvironment of a “cold” tumor such as PDAC and sensitize the tumor to checkpoint inhibitor therapy. Moreover, this combination immunotherapy led to objective tumor responses and survival benefit in the mice with spontaneously developed PDAC tumors. Therefore, our study supports developing Lm-ANXA2 as a therapeutic agent in combination with anti-PD-1 antibody for PDAC treatment.

【 授权许可】

CC BY