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Ramachandran, MohanrajORCID iD iconorcid.org/0000-0003-2685-0575
Publications (10 of 18) Show all publications
Lugano, R., Ramachandran, M. & Dimberg, A. (2019). Tumor angiogenesis: causes, consequences, challenges and opportunities. Cellular and Molecular Life Sciences (CMLS)
Open this publication in new window or tab >>Tumor angiogenesis: causes, consequences, challenges and opportunities
2019 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071Article in journal (Refereed) Epub ahead of print
Abstract [en]

Tumor vascularization occurs through several distinct biological processes, which not only vary between tumor type and anatomic location, but also occur simultaneously within the same cancer tissue. These processes are orchestrated by a range of secreted factors and signaling pathways and can involve participation of non-endothelial cells, such as progenitors or cancer stem cells. Anti-angiogenic therapies using either antibodies or tyrosine kinase inhibitors have been approved to treat several types of cancer. However, the benefit of treatment has so far been modest, some patients not responding at all and others acquiring resistance. It is becoming increasingly clear that blocking tumors from accessing the circulation is not an easy task to accomplish. Tumor vessel functionality and gene expression often differ vastly when comparing different cancer subtypes, and vessel phenotype can be markedly heterogeneous within a single tumor. Here, we summarize the current understanding of cellular and molecular mechanisms involved in tumor angiogenesis and discuss challenges and opportunities associated with vascular targeting.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Angiogenesis, Cancer, Endothelial, Vascular targeting, VEGF, Anti-angiogenic therapy
National Category
Cell Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-397923 (URN)10.1007/s00018-019-03351-7 (DOI)000494382600001 ()31690961 (PubMedID)
Funder
Swedish Cancer Society, CAN 2017/502Swedish Research Council, 2016-02495Swedish Cancer SocietySwedish Childhood Cancer Foundation, PR2018-0148
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-06Bibliographically approved
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
Ma, J., Ramachandran, M., Jin, C., Essand, M. & Yu, D. (2017). Adenovirus, Semliki Forest virus and vaccinia virus-induced immunogenic cell death augments oncolytic virus immunotherapy. Paper presented at 44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN. Scandinavian Journal of Immunology, 86(4), 341-341
Open this publication in new window or tab >>Adenovirus, Semliki Forest virus and vaccinia virus-induced immunogenic cell death augments oncolytic virus immunotherapy
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2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 341-341Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-346971 (URN)000411865200218 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-03-27Bibliographically approved
Essand, M., Ma, J., Jin, C., Ramachandran, M. & Yu, D. (2017). CAR T-Cells with Induced Secretion of Helicobacter Pylori Neutrophil-Activating Protein (HP-NAP) Yields Improved Anti-Tumor Activity and Reduced Immunosuppression. Paper presented at 20th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 10-13, 2017, Washington, DC. Molecular Therapy, 25(5 S1), 288-288
Open this publication in new window or tab >>CAR T-Cells with Induced Secretion of Helicobacter Pylori Neutrophil-Activating Protein (HP-NAP) Yields Improved Anti-Tumor Activity and Reduced Immunosuppression
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2017 (English)In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 25, no 5 S1, p. 288-288Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-331372 (URN)000401083600621 ()
Conference
20th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 10-13, 2017, Washington, DC
Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2017-10-18Bibliographically approved
Sarén, T., Ramachandran, M., Martikainen, M. & Yu, D. (2017). Insertion of the Type-I IFN Decoy Receptor B18R in a miRNA-Tagged Semliki Forest Virus Improves Oncolytic Capacity but Results in Neurotoxicity. Paper presented at 10th International Conference on Replicating Oncolytic Virus Therapeutics, OCT 01-04, 2016, Vancouver, CANADA. MOLECULAR THERAPY-ONCOLYTICS, 7, 67-75
Open this publication in new window or tab >>Insertion of the Type-I IFN Decoy Receptor B18R in a miRNA-Tagged Semliki Forest Virus Improves Oncolytic Capacity but Results in Neurotoxicity
2017 (English)In: MOLECULAR THERAPY-ONCOLYTICS, ISSN 2372-7705, Vol. 7, p. 67-75Article in journal (Refereed) Published
Abstract [en]

Oncolytic Semliki Forest virus (SFV) has been suggested as a potential candidate for the treatment of glioblastoma and neuroblastoma. However, the oncolytic capacity of SFV is restricted by the anti-viral type-I interferon (IFN) response. The aim of this study was to increase the oncolytic capacity of a microRNA target tagged SFV against glioblastoma by arming it with the Vaccinia-virus-encoded type-I IFN decoy receptor B18R (SFV4B18RmiRT) to neutralize type-I IFN response. Expression of B18R by SFV4B18RmiRT aided neutralization of IFN-b, which was shown by reduced STAT-1 phosphorylation and improved virus spread in plaque assays. B18R expression by SFV4 increased its oncolytic capacity in vitro against murine glioblastoma (CT-2A), regardless of the presence of exogenous IFN-b. Both SFV4B18RmiRT and SFV4miRT treatments controlled tumor growth in mice with syngeneic orthotopic gliomablastoma (CT-2A). However, treatment with SFV4B18RmiRT induced severe neurological symptoms in some mice because of virus replication in the healthy brain. Neither neurotoxicity nor virus replication in the brain was observed when SFV4miRT was administered. In summary, our results indicate that the oncolytic capacity of SFV4 was improved in vitro and in vivo by incorporation of B18R, but neurotoxicity of the virus was increased, possibly due to loss of microRNA targets.

Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-341813 (URN)10.1016/j.omto.2017.10.001 (DOI)000419677400008 ()29159280 (PubMedID)
Conference
10th International Conference on Replicating Oncolytic Virus Therapeutics, OCT 01-04, 2016, Vancouver, CANADA
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-20Bibliographically approved
Ramachandran, M., Yu, D., Dyczynski, M., Baskaran, S., Zhang, L., Lulla, A., . . . Essand, M. (2017). Safe and effective treatment of experimental neuroblastoma and glioblastoma using systemically administered triple microRNA-detargeted oncolytic Semliki Forest virus. Clinical Cancer Research, 23(6), 1519-1530
Open this publication in new window or tab >>Safe and effective treatment of experimental neuroblastoma and glioblastoma using systemically administered triple microRNA-detargeted oncolytic Semliki Forest virus
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2017 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 6, p. 1519-1530Article in journal (Refereed) Published
Abstract [en]

PURPOSE:

Glioblastoma multiforme (GBM) and high-risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic strategy for these malignancies. Here we evaluate the oncolytic potential of the neurovirulent and partly interferon (IFN)-β-resistant Semliki Forest virus (SFV)-4 in GBMs and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal CNS cells through insertion of microRNA target sequences for miR124, miR125, miR134 Experimental Design:Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and GBM cell lines and in patient-derived human glioblastoma cell cultures (HGCC). In vivo neurovirulence and therapeutic efficacy was evaluated in two syngeneic orthotopic glioma models (CT-2A, GL261) and syngeneic subcutaneous neuroblastoma model (NXS2). The role of IFN-β in inhibiting therapeutic efficacy was investigated.

RESULTS:

The introduction of microRNA target sequences reduced neurovirulence of SFV4 in terms of attenuated replication in mouse CNS cells and ability to cause encephalitis when administered intravenously. A single intravenous injection of SFV4miRT prolonged survival and cured 4 of 8 mice (50%) with NXS2 and 3 of 11 mice (27%) with CT-2A, but not for GL261 tumor bearing mice. In vivo therapeutic efficacy in different tumor models inversely correlated to secretion of IFN-β by respective cells upon SFV4 infection in vitro Similarly, killing efficacy of HGCC lines inversely correlated to IFN-β response and interferon-α⁄β receptor (IFNAR)-1 expression.

CONCLUSIONS:

SFV4miRT has reduced neurovirulence, while retaining its oncolytic potential. SFV4miRT is an excellent candidate for treatment of GBMs and neuroblastomas with low IFN-β secretion.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2017
Keywords
Semliki Forest virus, Glioblastoma, Neuroblastoma, Oncolytic virus immunotherapy, Type-I antiviral response
National Category
Other Basic Medicine
Research subject
Oncology; Biology with specialization in Molecular Biotechnology
Identifiers
urn:nbn:se:uu:diva-303633 (URN)10.1158/1078-0432.CCR-16-0925 (DOI)000397344800018 ()27637889 (PubMedID)
Funder
Swedish Research Council, K2013-22191-01-3Swedish Cancer Society, CAN2013/373Swedish Childhood Cancer Foundation, PROJ12/082
Available from: 2016-09-21 Created: 2016-09-21 Last updated: 2018-01-10Bibliographically approved
Ramachandran, M., Dimberg, A. & Essand, M. (2017). The cancer-immunity cycle as rational design for synthetic cancer drugs: Novel DC vaccines and CAR T-cells. Seminars in Cancer Biology, 45, 23-35
Open this publication in new window or tab >>The cancer-immunity cycle as rational design for synthetic cancer drugs: Novel DC vaccines and CAR T-cells
2017 (English)In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 45, p. 23-35Article, review/survey (Refereed) Published
Abstract [en]

Cell therapy is an advanced form of cancer immunotherapy that has had remarkable clinical progress in the past decade in the search for cure of cancer. Most success has been achieved for chimeric antigen receptor (CAR) T-cells where CAR T-cells targeting CD19 show very high complete response rates for patients with refractory acute B-cell acute lymphoblastic leukemia (ALL) and are close to approval for this indication. CD19 CAR T-cells are also effective against B-cell chronic lymphoblastic leukemia (CLL) and B-cell lymphomas. Although encouraging, CAR T-cells have not yet proven clinically effective for solid tumors. This is mainly due to the lack of specific and homogenously expressed targets to direct the T-cells against and a hostile immunosuppressive tumor microenvironment in solid tumors. Cancer vaccines based on dendritic cells (DC) are also making progress although clinical efficacy is still lacking. The likelihood of success is however increasing now when individual tumors can be sequences and patient-specific neoepitopes identified. Neoepitopes and/or neoantigens can then be included in patient based DC vaccines. This review discusses recent advancements of DC vaccines and CAR T-cells with emphasis on the cancer-immunity cycle, and current efforts to design novel cell therapies.

Keywords
Dendritic cell vaccines, CAR T-cells, Cancer-immunity cycle, Gene therapy, Cancer immunotherapy
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-345892 (URN)10.1016/j.semcancer.2017.02.010 (DOI)000408782400004 ()28257957 (PubMedID)
Funder
Swedish Childhood Cancer Foundation, PROJ12/082Swedish Cancer Society, CAN2013/373Swedish Research Council, K2013-22191-01-3
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13Bibliographically 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
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2685-0575

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