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Cancer vaccine based on a combination of an infection-enhanced adenoviral vector and pro-inflammatory allogeneic DCs leads to sustained antigen-specific immune responses in three melanoma models
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2018 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 7, no 3, article id e1397250Article in journal (Refereed) Published
Abstract [en]

Autologous patient-derived dendritic cells (DCs) modified ex vivo to present tumor-associated antigens (TAAs) are frequently used as cancer vaccines. However, apart from the stringent logistics in producing DCs on a patient basis, accumulating evidence indicate that ex vivo engineered DCs are poor in migration and in fact do not directly present TAA epitopes to naïve T cells in vivo. Instead, it is proposed that bystander host DCs take up material from vaccine-DCs, migrate and subsequently initiate antitumor T-cell responses. We used mouse models to examine the possibility of using pro-inflammatory allogeneic DCs (alloDCs) to activate host DCs and enable them to promote antigen-specific T-cell immunity. We found that alloDCs were able to initiate host DC activation and migration to draining lymph node leading to T-cell activation. The pro-inflammatory milieu created by alloDCs also led to recruitment of NK cells and neutrophils at the site of injection. Vaccination with alloDCs combined with Ad5M(gp100), an infection-enhanced adenovirus encoding the human melanoma-associated antigen gp100 resulted in generation of CD8+ T cells with a T-cell receptor (TCR) specific for the gp10025-33 epitope (gp100-TCR+). Ad5M(gp100)-alloDC vaccination in combination with transfer of gp100-specific pmel-1 T cells resulted in prolonged survival of B16-F10 melanoma-bearing mice and altered the composition of the tumor microenvironment (TME). We hereby propose that alloDCs together with TAA- or neoepitope-encoding Ad5M can become an “off-the-shelf” cancer vaccine, which can reverse the TME-induced immunosuppression and induce host cellular anti-tumor immune responses in patients without the need of a time-consuming preparation step of autologous DCs.

Place, publisher, year, edition, pages
2018. Vol. 7, no 3, article id e1397250
Keywords [en]
adjuvants, Allogeneic dendritic cells, cell-based immunotherapy, tumor microenvironment, tumor-associated antigen
National Category
Cancer and Oncology Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-346362DOI: 10.1080/2162402X.2017.1397250ISI: 000423567000013PubMedID: 29399398OAI: oai:DiVA.org:uu-346362DiVA, id: diva2:1191184
Funder
Swedish Cancer Society, CAN 2013/373; CAN 2016/318Swedish Childhood Cancer Foundation, PR2015-0049Swedish Research Council, 2015-03688Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2019-02-21Bibliographically approved
In thesis
1. Allogeneic dendritic cells as adjuvants in cancer immunotherapy
Open this publication in new window or tab >>Allogeneic dendritic cells as adjuvants in cancer immunotherapy
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In recent years, immunotherapeutic approaches have achieved remarkable successes through checkpoint blockade antibodies, advances in the use of chimeric antigen receptor (CAR) T cells and new insights into the immunosuppressive role of the tumor microenvironment (TME). Through the advances, the role of cancer vaccines based on ex vivo manipulated autologous dendritic cells (DC) has been challenged. The main aim of DC-based vaccination is the induction of tumor-specific T-cell responses through presentation of tumor-associated antigens. However, this process has been found to be highly dependent on the ability of the injected vaccine-DCs to activate endogenous bystander DCs.

In this work, we examined the feasibility of having an allogeneic source of vaccine-DCs (alloDCs), not for direct antigen-presentation to T cells but as an immune primer aiming to activate bystander DCs. In paper I, we treated alloDCs with a T helper cell type 1 (Th1)-promoting maturation cocktail alone or combined with a replication-deficient, infection-enhanced adenoviral vector (Ad5M) as a potential gene delivery vehicle. We found that mature pro-inflammatory alloDCs, either non-transduced or transduced, created a cytokine- and chemokine-enriched milieu in vitro, and promoted the activation of co-cultured immune cells, including cytolytic NK cells, from unrelated donors. The emerged milieu induced the maturation of bystander DCs, which cross-presented antigens from their environment to autologous antigen-specific T cells. In paper II, we found that alloDCs promoted the migration of murine immune cells both to the site of injection and to the draining lymph node. When Ad5M was used for the delivery of the melanoma-associated antigen gp100, we found that gp100-expressing alloDCs were able to control tumor growth through gp100-specific T-cell responses and alteration of the TME. In paper III, we found that co-administration of alloDCs with an adenoviral vector encoding for HPV-antigens is effective in controlling the growth of HPV-related tumors and this may depend on a cross-talk between alloDCs and NK cells which leads to further recruitment of immune cells into the TME. In paper IV, we observed that concomitant targeting of immune checkpoint receptors or co-stimulatory molecules results in synergistic therapeutic effects in a murine colorectal model.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 50
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1542
Keywords
Allogeneic dendritic cells, immune primer, adjuvant, adenoviral vector, cancer immunotherapy, tumor microenvironment
National Category
Immunology in the medical area
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-377269 (URN)978-91-513-0579-0 (ISBN)
Public defence
2019-04-12, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Supervisors
Available from: 2019-03-22 Created: 2019-02-21 Last updated: 2019-05-07

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Fotaki, GrammatikiJin, ChuanKerzeli, Iliana KyriakiRamachandran, MohanrajMartikainen, Minttu-MariaKarlsson-Parra, AlexYu, DiEssand, Magnus

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Fotaki, GrammatikiJin, ChuanKerzeli, Iliana KyriakiRamachandran, MohanrajMartikainen, Minttu-MariaKarlsson-Parra, AlexYu, DiEssand, Magnus
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