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Fotaki, Grammatiki
Publications (10 of 11) Show all publications
Fotaki, G. (2019). Allogeneic dendritic cells as adjuvants in cancer immunotherapy. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
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)
Opponent
Supervisors
Available from: 2019-03-22 Created: 2019-02-21 Last updated: 2019-05-07
Fotaki, G., Jin, C., Kerzeli, I. K., Ramachandran, M., Martikainen, M.-M., Karlsson-Parra, A., . . . Essand, M. (2018). 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. Oncoimmunology, 7(3), Article ID e1397250.
Open this publication in new window or tab >>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
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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.

Keywords
adjuvants, Allogeneic dendritic cells, cell-based immunotherapy, tumor microenvironment, tumor-associated antigen
National Category
Cancer and Oncology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-346362 (URN)10.1080/2162402X.2017.1397250 (DOI)000423567000013 ()29399398 (PubMedID)
Funder
Swedish Cancer Society, CAN 2013/373; CAN 2016/318Swedish Childhood Cancer Foundation, PR2015-0049Swedish Research Council, 2015-03688
Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2019-02-21Bibliographically approved
Fotaki, G., Jin, C., Ramachandran, M., Kerzeli, I. K., Karlsson-Parra, A., Yu, D. & Essand, M. (2018). Pro-inflammatory allogeneic DCs promote activation of bystander immune cells and thereby license antigen-specific T-cell responses. Oncoimmunology, 7(3), Article ID e1395126.
Open this publication in new window or tab >>Pro-inflammatory allogeneic DCs promote activation of bystander immune cells and thereby license antigen-specific T-cell responses
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2018 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 7, no 3, article id e1395126Article in journal (Refereed) Published
Abstract [en]

Accumulating evidence support an important role for endogenous bystander dendritic cells (DCs) in the efficiency of autologous patient-derived DC-vaccines, as bystander DCs take up material from vaccine-DCs, migrate to draining lymph node and initiate antitumor T-cell responses. We examined the possibility of using allogeneic DCs as vaccine-DCs to activate bystander immune cells and promote antigen-specific T-cell responses. We demonstrate that human DCs matured with polyI:C, R848 and IFN-γ (denoted COMBIG) in combination with an infection-enhanced adenovirus vector (denoted Ad5M) exhibit a pro-inflammatory state. COMBIG/Ad5M-matured allogeneic DCs (alloDCs) efficiently activated T-cells and NK-cells in allogeneic co-culture experiments. The secretion of immunostimulatory factors during the co-culture promoted the maturation of bystander-DCs, which efficiently cross-presented a model-antigen to activate antigen-specific CD8+ T-cells in vitro. We propose that alloDCs, in combination with Ad5M as loading vehicle, may be a cost-effective and logistically simplified DC vaccination strategy to induce anti-tumor immune responses in cancer patients.

Keywords
Allogeneic dendritic cells, cell-based immunotherapy, innate immune cells, cell activation
National Category
Immunology in the medical area Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-346363 (URN)10.1080/2162402X.2017.1395126 (DOI)000423567000006 ()
Funder
Swedish Cancer Society, CAN 2013/373; CAN 2016/318Swedish Childhood Cancer Foundation, PR2015-0049Swedish Research Council, 2015-03688
Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2019-02-21Bibliographically approved
Fotaki, G., Jin, C., Karlsson-Parra, A., Yu, D. & Essand, M. (2016). Allogeneic dendritic cells (AlloDCs) transduced with an infection enhanced adenovirus as adjuvant for cancer immunotherapy. CANCER IMMUNOLOGY RESEARCH, 4(1)
Open this publication in new window or tab >>Allogeneic dendritic cells (AlloDCs) transduced with an infection enhanced adenovirus as adjuvant for cancer immunotherapy
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2016 (English)In: CANCER IMMUNOLOGY RESEARCH, ISSN 2326-6066, Vol. 4, no 1Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-299396 (URN)10.1158/2326-6074.CRICIMTEATIAACR15-A172 (DOI)000375484400309 ()
Available from: 2016-07-18 Created: 2016-07-18 Last updated: 2018-01-10Bibliographically approved
Jin, C., Ramachandran, M., Fotaki, G., Nilsson, B., Essand, M. & Yu, D. (2016). Long-term episomal gene transfer for safe engineering of T cells for adoptive cell therapy of cancer. CANCER IMMUNOLOGY RESEARCH, 4(1)
Open this publication in new window or tab >>Long-term episomal gene transfer for safe engineering of T cells for adoptive cell therapy of cancer
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2016 (English)In: CANCER IMMUNOLOGY RESEARCH, ISSN 2326-6066, Vol. 4, no 1Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-299397 (URN)10.1158/2326-6074.CRICIMTEATIAACR15-A171 (DOI)000375484400296 ()
Available from: 2016-07-18 Created: 2016-07-18 Last updated: 2018-01-10Bibliographically approved
Jin, C., Fotaki, G., Ramachandran, M., Nilsson, B., Essand, M. & Yu, D. (2016). Safe engineering of CAR T cells for adoptive cell therapy of cancer using long-term episomal gene transfer. EMBO Molecular Medicine, 8(7), 702-711
Open this publication in new window or tab >>Safe engineering of CAR T cells for adoptive cell therapy of cancer using long-term episomal gene transfer
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2016 (English)In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 8, no 7, p. 702-711Article in journal (Refereed) Published
Abstract [en]

Chimeric antigen receptor (CAR) T-cell therapy is a new successful treatment for refractory B-cell leukemia. Successful therapeutic outcome depends on long-term expression of CAR transgene in T cells, which is achieved by delivering transgene using integrating gamma retrovirus (RV) or lentivirus (LV). However, uncontrolled RV/LV integration in host cell genomes has the potential risk of causing insertional mutagenesis. Herein, we describe a novel episomal long-term cell engineering method using non-integrating lentiviral (NILV) vector containing a scaffold/matrix attachment region (S/MAR) element, for either expression of transgenes or silencing of target genes. The insertional events of this vector into the genome of host cells are below detection level. CD19 CAR T cells engineered with a NILV-S/MAR vector have similar levels of CAR expression as T cells engineered with an integrating LV vector, even after numerous rounds of cell division. NILV-S/MAR-engineered CD19 CAR T cells exhibited similar cytotoxic capacity upon CD19(+) target cell recognition as LV-engineered T cells and are as effective in controlling tumor growth in vivo We propose that NILV-S/MAR vectors are superior to current options as they enable long-term transgene expression without the risk of insertional mutagenesis and genotoxicity.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-300197 (URN)10.15252/emmm.201505869 (DOI)000383632300003 ()27189167 (PubMedID)
Funder
Swedish Childhood Cancer FoundationSwedish Cancer SocietySwedish Research CouncilGunnar Nilsson Cancer Foundation
Note

GT och MR delar på andraförfattarskapet.

Available from: 2016-08-05 Created: 2016-08-05 Last updated: 2018-01-10Bibliographically approved
Jin, C., Ramachandran, M., Fotaki, G., Nilsson, B., Essand, M. & Yu, D. (2014). Long-term episomal gene transfer for safe engineering of T-cells for adoptive cell therapy of cancer. Paper presented at ESGCT and NVGCT Collaborative Congress, OCT 23-26, 2014, The Hague, NETHERLANDS. Human Gene Therapy, 25(11), A50-A50
Open this publication in new window or tab >>Long-term episomal gene transfer for safe engineering of T-cells for adoptive cell therapy of cancer
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2014 (English)In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 25, no 11, p. A50-A50Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-240874 (URN)000344774700152 ()
Conference
ESGCT and NVGCT Collaborative Congress, OCT 23-26, 2014, The Hague, NETHERLANDS
Note

Meeting Abstract: OR077

Available from: 2015-01-08 Created: 2015-01-08 Last updated: 2018-01-11Bibliographically approved
Savov, V., Fotaki, G., Remke, M., Dubuc, A. M., Ramaswamy, V., Cancer, M., . . . Swartling, F. J. (2014). Metastasis and tumor recurrence from rare SOX9-positive cells in Group 4 medulloblastoma. Paper presented at 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR), APR 05-09, 2014, San Diego, CA. Cancer Research, 74(19)
Open this publication in new window or tab >>Metastasis and tumor recurrence from rare SOX9-positive cells in Group 4 medulloblastoma
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2014 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-257319 (URN)10.1158/1538-7445.AM2014-996 (DOI)000349906900222 ()
Conference
105th Annual Meeting of the American-Association-for-Cancer-Research (AACR), APR 05-09, 2014, San Diego, CA
Note

Abstract nr 996

Available from: 2015-07-01 Created: 2015-07-01 Last updated: 2017-12-04Bibliographically approved
Swartling, F. J., Savov, V., Cancer, M., Bolin, S., Fotaki, G., Dubuc, A., . . . Taylor, M. D. (2014). Metastasis and Tumor Recurrence from Rare SOX9-Positive Cells in MYCN-Driven Medulloblastoma. Paper presented at 20th International Conference on Brain Tumor Research and Therapy, JUL 20-22, 2014, CA. Neuro-Oncology, 16
Open this publication in new window or tab >>Metastasis and Tumor Recurrence from Rare SOX9-Positive Cells in MYCN-Driven Medulloblastoma
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2014 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology Neurology
Identifiers
urn:nbn:se:uu:diva-240675 (URN)10.1093/neuonc/nou208.20 (DOI)000344236400101 ()
Conference
20th International Conference on Brain Tumor Research and Therapy, JUL 20-22, 2014, CA
Available from: 2015-01-13 Created: 2015-01-08 Last updated: 2017-12-05Bibliographically approved
Fotaki, G., Yu, D., Essand, M. & Karlsson-Parra, A.Concomitant targeting of PD-1 or CD137 enhances the effect of adjuvant pro-inflammatory allogeneic dendritic cells..
Open this publication in new window or tab >>Concomitant targeting of PD-1 or CD137 enhances the effect of adjuvant pro-inflammatory allogeneic dendritic cells.
(English)Manuscript (preprint) (Other academic)
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-377270 (URN)
Available from: 2019-02-16 Created: 2019-02-16 Last updated: 2019-02-21
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