Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies
Abstract Background Immune 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 th...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0601-5 |
| _version_ | 1811202375018348544 |
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| author | Victoria M. Kim Alex B. Blair Peter Lauer Kelly Foley Xu Che Kevin Soares Tao Xia Stephen T. Muth Jennifer Kleponis Todd D. Armstrong Christopher L. Wolfgang Elizabeth M. Jaffee Dirk Brockstedt Lei Zheng |
| author_facet | Victoria M. Kim Alex B. Blair Peter Lauer Kelly Foley Xu Che Kevin Soares Tao Xia Stephen T. Muth Jennifer Kleponis Todd D. Armstrong Christopher L. Wolfgang Elizabeth M. Jaffee Dirk Brockstedt Lei Zheng |
| author_sort | Victoria M. Kim |
| collection | DOAJ |
| description | Abstract Background Immune 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. Methods We developed a Listeria-based, ANXA2-targeting cancer immunotherapy (Lm-ANXA2) and investigated its effectiveness within two murine models of PDAC. Results We 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. Conclusions For 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. |
| first_indexed | 2024-04-12T02:38:38Z |
| format | Article |
| id | doaj.art-54280b372b12429ab75fc9c756155e36 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-12T02:38:38Z |
| publishDate | 2019-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-54280b372b12429ab75fc9c756155e362022-12-22T03:51:25ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-05-017111310.1186/s40425-019-0601-5Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodiesVictoria M. Kim0Alex B. Blair1Peter Lauer2Kelly Foley3Xu Che4Kevin Soares5Tao Xia6Stephen T. Muth7Jennifer Kleponis8Todd D. Armstrong9Christopher L. Wolfgang10Elizabeth M. Jaffee11Dirk Brockstedt12Lei Zheng13The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineAduro Biotech, Inc.The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineAduro Biotech, Inc.The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineAbstract Background Immune 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. Methods We developed a Listeria-based, ANXA2-targeting cancer immunotherapy (Lm-ANXA2) and investigated its effectiveness within two murine models of PDAC. Results We 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. Conclusions For 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.http://link.springer.com/article/10.1186/s40425-019-0601-5Pancreatic cancerImmunotherapyAnnexin A2Anti-PD-1 antibody, interferon-gamma, CD8 T cells |
| spellingShingle | Victoria M. Kim Alex B. Blair Peter Lauer Kelly Foley Xu Che Kevin Soares Tao Xia Stephen T. Muth Jennifer Kleponis Todd D. Armstrong Christopher L. Wolfgang Elizabeth M. Jaffee Dirk Brockstedt Lei Zheng Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies Journal for ImmunoTherapy of Cancer Pancreatic cancer Immunotherapy Annexin A2 Anti-PD-1 antibody, interferon-gamma, CD8 T cells |
| title | Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies |
| title_full | Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies |
| title_fullStr | Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies |
| title_full_unstemmed | Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies |
| title_short | Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies |
| title_sort | anti pancreatic tumor efficacy of a listeria based annexin a2 targeting immunotherapy in combination with anti pd 1 antibodies |
| topic | Pancreatic cancer Immunotherapy Annexin A2 Anti-PD-1 antibody, interferon-gamma, CD8 T cells |
| url | http://link.springer.com/article/10.1186/s40425-019-0601-5 |
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