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1.
Cells ; 10(11)2021 11 19.
Article in English | MEDLINE | ID: mdl-34831455

ABSTRACT

DCP-001 is a cell-based cancer vaccine generated by differentiation and maturation of cells from the human DCOne myeloid leukemic cell line. This results in a vaccine comprising a broad array of endogenous tumor antigens combined with a mature dendritic cell (mDC) costimulatory profile, functioning as a local inflammatory adjuvant when injected into an allogeneic recipient. Intradermal DCP-001 vaccination has been shown to be safe and feasible as a post-remission therapy in acute myeloid leukemia. In the current study, the mode of action of DCP-001 was further characterized by static and dynamic analysis of the interaction between labelled DCP-001 and host antigen-presenting cells (APCs). Direct cell-cell interactions and uptake of DCP-001 cellular content by APCs were shown to depend on DCP-001 cell surface expression of calreticulin and phosphatidylserine, while blockade of CD47 enhanced the process. Injection of DCP-001 in an ex vivo human skin model led to its uptake by activated skin-emigrating DCs. These data suggest that, following intradermal DCP-001 vaccination, local and recruited host APCs capture tumor-associated antigens from the vaccine, become activated and migrate to the draining lymph nodes to subsequently (re)activate tumor-reactive T-cells. The improved uptake of DCP-001 by blocking CD47 rationalizes the possible combination of DCP-001 vaccination with CD47 blocking therapies.


Subject(s)
Allogeneic Cells/immunology , CD47 Antigen/antagonists & inhibitors , Cancer Vaccines/immunology , Dendritic Cells/immunology , Phosphatidylserines/metabolism , Antigen-Presenting Cells/immunology , CD47 Antigen/metabolism , Cell Differentiation , Cell Membrane/metabolism , Chemokines/metabolism , Humans , Inflammation/pathology , Models, Biological , Phagocytosis , Phenotype , Pinocytosis , Signal Transduction
2.
Cancer Immunol Immunother ; 67(10): 1505-1518, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30039426

ABSTRACT

In elderly acute myeloid leukemia (AML) patients post-remission treatment options are associated with high comorbidity rates and poor survival. Dendritic cell (DC)-based immunotherapy is a promising alternative treatment strategy. A novel allogeneic DC vaccine, DCP-001, was developed from an AML-derived cell line that uniquely combines the positive features of allogeneic DC vaccines and expression of multi-leukemia-associated antigens. Here, we present data from a phase I study conducted with DCP-001 in 12 advanced-stage elderly AML patients. Patients enrolled were in complete remission (CR1/CR2) (n = 5) or had smoldering disease (n = 7). All patients were at high risk of relapse and ineligible for post-remission intensification therapies. A standard 3 + 3 dose escalation design with extension to six patients in the highest dose was performed. Patients received four biweekly intradermal DCP-001 injections at different dose levels (10, 25, and 50 million cells DCP-001) and were monitored for clinical and immunological responses. Primary objectives of the study (feasibility and safety) were achieved with 10/12 patients completing the vaccination program. Treatment was well tolerated. A clear-cut distinction between patients with and without detectable circulating leukemic blasts during the vaccination period was noted. Patients with no circulating blasts showed an unusually prolonged survival [median overall survival 36 months (range 7-63) from the start of vaccination] whereas patients with circulating blasts, died within 6 months. Long-term survival was correlated with maintained T cell levels and induction of multi-functional immune responses. It is concluded that DCP-001 in elderly AML patients is safe, feasible and generates both cellular and humoral immune responses.


Subject(s)
Cancer Vaccines/immunology , Dendritic Cells/immunology , Immunotherapy , Leukemia, Myeloid, Acute/prevention & control , T-Lymphocytes/immunology , Aged , Cancer Vaccines/administration & dosage , Female , Humans , Leukemia, Myeloid, Acute/immunology , Male , Middle Aged , Remission Induction , Treatment Outcome
3.
Vaccine ; 25(8): 1426-36, 2007 Feb 09.
Article in English | MEDLINE | ID: mdl-17161889

ABSTRACT

Previous studies have shown that the immunogenicity of rodent malaria parasite-derived circumsporozoite protein (CS) can be improved by deleting the glycosyl-phosphatidyl-inositol (GPI) signal sequence. To study whether GPI signal sequence deletion would also improve immunogenicity of CS derived from the major plasmodium species causing mortality in humans (P. falciparum), we tested different variants of the P. falciparum CS protein in the context of a live vector-based vaccine carrier (rAd35). We demonstrate that deletion of the GPI signal sequence from CS did not result in altered expression or secretion. In contrast, cellular localization was clearly altered, which perhaps helps to explain the significant improvement of anti-CS antibody and T-cell responses observed in mice using deletion variants in the context of the rAd35 carrier. Our results show that rational design of antigens is warranted for further development of malaria vaccines.


Subject(s)
Glycosylphosphatidylinositols/immunology , Malaria Vaccines/immunology , Plasmodium falciparum/immunology , Protein Sorting Signals/physiology , Protozoan Proteins/immunology , Adenoviridae/genetics , Amino Acid Sequence , Animals , B-Lymphocytes/immunology , Cell Line, Tumor , Female , Gene Deletion , Glycosylphosphatidylinositols/genetics , Glycosylphosphatidylinositols/metabolism , Humans , Malaria Vaccines/genetics , Mice , Mice, Inbred CBA , Molecular Sequence Data , Plasmodium falciparum/genetics , Plasmodium falciparum/metabolism , Protein Sorting Signals/genetics , Protozoan Proteins/biosynthesis , Protozoan Proteins/genetics , T-Lymphocytes/immunology
4.
J Clin Microbiol ; 44(10): 3781-3, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17021110

ABSTRACT

We assessed neutralizing antibody titers to adenovirus serotype 5 (Ad5) and six rare adenovirus serotypes, serotypes 11, 35, 50, 26, 48, and 49, in pediatric populations in sub-Saharan Africa. We observed a clear age dependence of Ad5-specific neutralizing antibody titers. These data will help to guide the development of Ad vector-based vaccines for human immunodeficiency virus type 1 and other pathogens.


Subject(s)
Adenovirus Infections, Human/immunology , Adenoviruses, Human/immunology , Aging , Antibodies, Viral/blood , Adenovirus Infections, Human/blood , Adenovirus Infections, Human/epidemiology , Adolescent , Africa South of the Sahara/epidemiology , Child , Child, Preschool , Humans , Infant , Infectious Disease Transmission, Vertical , Seroepidemiologic Studies
5.
J Virol ; 78(23): 13207-15, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15542673

ABSTRACT

A novel plasmid-based adenovirus vector system that enables manufacturing of replication-incompetent (DeltaE1) adenovirus type 11 (Ad11)-based vectors is described. Ad11 vectors are produced on PER.C6/55K cells yielding high-titer vector batches after purification. Ad11 seroprevalence proves to be significantly lower than that of Ad5, and neutralizing antibody titers against Ad11 are low. Ad11 seroprevalence among human immunodeficiency virus-positive (HIV(+)) individuals is as low as that among HIV(-) individuals, independent of the level of immune suppression. The low level of coinciding seroprevalence between Ad11 and Ad35 in addition to a lack of correlation between high neutralizing antibody titers towards either adenovirus strongly suggest that the limited humoral cross-reactive immunity between these two highly related B viruses appears not to preclude the use of both vectors in the same individual. Ad11 transduces primary cells including smooth muscle cells, synoviocytes, and dendritic cells and cardiovascular tissues with higher efficiency than Ad5. Ad11 and Ad35 appear to have a similar tropism as judged by green fluorescent protein expression levels determined by using a panel of cancer cell lines. In addition, Ad5 preimmunization did not significantly affect Ad11-mediated transduction in C57BL/6 mice. We therefore conclude that the Ad11-based vector represents a novel and useful candidate gene transfer vehicle for vaccination and gene therapy.


Subject(s)
Adenoviruses, Human/genetics , Genetic Therapy , Genetic Vectors/genetics , Virus Replication , Adenoviruses, Human/immunology , Adult , Aged , Animals , Antibodies, Viral/blood , Antigens, CD/analysis , Cross Reactions , Genetic Vectors/immunology , Humans , Membrane Cofactor Protein , Membrane Glycoproteins/analysis , Mice , Mice, Inbred BALB C , Middle Aged , Seroepidemiologic Studies , Tropism , Vaccination
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