| 1. |
- van Hooren, Luuk, et al.
(författare)
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Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer
- 2017
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 47:2, s. 385-393
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Tidskriftsartikel (refereegranskat)abstract
- Checkpoint blockade of CTLA-4 results in long-lasting survival benefits in metastatic cancer patients. However, patients treated with CTLA-4 blockade have suffered from immune-related adverse events, most likely due to the breadth of the induced T-cell activation. Here, we investigated the efficacy of a local low-dose anti-CTLA-4 administration for treatment of subcutaneous or orthotopic murine bladder 49 (MB49) bladder carcinoma in C57BL/6 mice. When MB49 tumors were grown s.c., peritumoral (p.t.) injection of anti-CTLA-4 treatment was equally effective as intravenous or s.c. (nontumor bearing flank) administration. Notably, p.t. injection was associated with lower circulating antibody levels and decreased IL-6 serum levels as compared to systemic treatment. Ultrasound-guided intratumoral anti-CTLA-4 antibody treatment of orthotopically growing MB49 tumors resulted in tumor regression, with more than tenfold reduction in systemic antibody levels as compared to i.v. or s.c. administration, in line with the compartmentally restrained nature of the bladder. Local anti-CTLA-4 therapy in combination with anti-PD-1 therapy resulted in complete responses, superior to each therapy alone. In addition, p.t. anti-CTLA-4 therapy was potentiated by depletion of regulatory T cells. Our results demonstrate that local anti-CTLA-4 antibody therapy is equally effective as systemic administration, but reduces systemic antibody levels and cytokine release, and enhances the response to anti-PD1 therapy.
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| 2. |
- Ellmark, Peter, et al.
(författare)
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Identification of protein expression signatures associated with Helicobacter pylori infection and gastric adenocarcinoma using recombinant antibody microarrays.
- 2006
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Ingår i: Molecular & cellular proteomics : MCP. - 1535-9476 .- 1535-9484. ; 5:9, s. 1638-46
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Tidskriftsartikel (refereegranskat)abstract
- Antibody microarray based technology is a powerful emerging tool in proteomics, target discovery, and differential analysis. Here, we report the first study where recombinant antibody fragments have been used to construct large scale antibody microarrays, composed of 127 different antibodies against mostly immunoregulatory antigens. The arrays were based on single framework recombinant antibody fragments (SinFabs) designed for high on-chip stability and functionality and were used for the analysis of malignant and normal stomach tissue samples from Helicobacter pylori-positive and -negative patients. Our results demonstrate that distinct tumor- as well as infection-associated protein expression signatures could be identified from these complex tissue proteomes, as well as biomarkers such as IL-9, IL-11, and MCP-4, previously not found in these diseases. In a longer perspective, this study may improve the understanding of H. pylori-induced stomach cancer and lead to development of improved diagnostics.
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| 3. |
- Ellmark, Peter
(författare)
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The CD40 Receptor - Target,Tool and Technology
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- CD40 is a cell surface receptor of pivotal importance that is expressed on several of the cells in the immune system. It is critical for many important events, such as T cell dependent B cell activation, isotype switching, somatic mutation and generation of B cell memory. The central role of CD40 in the immune system makes it an ideal target for antibody based immunotherapy. This led us to characterise a panel of monoclonal anti-CD40 antibodies. In PAPER I, we investigated their cellular activation potential and analysed to what extent this correlates with their affinity, epitope specificity and domain recognition profile. The antibody profiles we obtained in this first study may be valuable for understanding of the mechanisms that influence the therapeutic capacity of these antibodies. In fact, one of the antibodies that we investigated is currently in phase I/II trials. However, all of the antibodies that we characterised in PAPER I are of mouse origin, which probably limits their clinical efficiency, due to the human anti-mouse response that most patients develop against such antibodies. Therefore we selected a set of human anti-CD40 antibodies, which are described in PAPER II, from a recombinant antibody gene library. These antibodies display a wide variety of distinct properties, which may make them a valuable source when evaluating therapeutic candidates for in vivo trials. In PAPER III, we have used some of the anti-CD40 antibodies described in PAPER II to create an antibody library that was utilised to investigate antibody evolution in vitro. The results from this study showed that events, which resembles receptor revision, i.e. secondary rearrangements of antibody genes in the periphery, may provide an evolving antibody with competitive advantages during a selection process that is similar to the affinity maturation process in vivo. Our data reinforce the suggestion that receptor revision is an important complement to point mutations and insertions and deletions in the somatic hypermutation process that occur in germinal centres. It has been suggested that members of the TNFR family pre-associate in the membrane via one of the extracellular domains, the pre-ligand assembly domain (PLAD). Therefore, in PAPER IV, we investigated the functional role of the different domains of CD40, in a B cell model system. The results from this study showed that neither of the extracellular domains is essential for signal transduction and, furthermore, implies that conformational changes play no critical role for the CD40 signalling pathway. Based on the findings that all of the extracellular part of CD40 can be replaced with retained signalling capacity, we developed a novel selection method, named Selection of Protein Interactions by Receptor Engagement (SPIRE). In PAPER V, we demonstrated that this selection system can be used for clonal enrichment of cells that display a mock-CD40 receptor, used as prey, on the surface by interaction with a certain bait protein. Thus, SPIRE allows for clonal selection of interacting protein pairs in a mammalian environment. SPIRE may have several different applications such as identification of tumour antigens or for molecular evolution of complex proteins.
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| 4. |
- Ingvarsson, Johan, et al.
(författare)
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Detection of pancreatic cancer using antibody microarray-based serum protein profiling
- 2008
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Ingår i: Proteomics. - : Wiley. - 1615-9861 .- 1615-9853. ; 8:11, s. 2211-2219
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Tidskriftsartikel (refereegranskat)abstract
- The driving force behind oncoproteomics is to identify protein signatures that are associated with a particular malignancy. Here, we have used a recombinant scFv antibody microarray in an attempt to classify sera derived from pancreatic adenocarcinoma patients versus healthy subjects. Based on analysis of nonfractionated, directly labeled, whole human serum proteomes we have identified a protein signature based on 19 nonredundant analytes, that discriminates between cancer patients and healthy subjects. Furthermore, a potential protein signature, consisting of 21 protein analytes, could be defined that was shown to be associated with cancer patients having a life expectancy of <12 months. Taken together, the data suggest that antibody microarray analysis of complex proteomes will be a useful tool to define disease associated protein signatures.
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| 5. |
- Ellmark, Peter, et al.
(författare)
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Attovial-based antibody nanoarrays.
- 2009
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Ingår i: Proteomics. - : Wiley. - 1615-9861 .- 1615-9853. ; 9:24, s. 5406-5413
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Tidskriftsartikel (refereegranskat)abstract
- Antibody array-based technology is a powerful emerging tool in proteomics, but to enable global proteome analysis, antibody array layouts with even higher density has to be developed. To this end, we have further developed the first generation of a nanoarray platform, based on attoliter sized vials, attovials, which we have characterized and used for the detection of complement factor C1q in human serum samples. Finally, we demonstrated proof-of-concept for individual functionalisation of the attovials with a recombinant antibody.
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| 6. |
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| 7. |
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| 8. |
- Abolhalaj, Milad, et al.
(författare)
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Transcriptional profiling demonstrates altered characteristics of CD8 + cytotoxic T-cells and regulatory T-cells in TP53-mutated acute myeloid leukemia
- 2022
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 11:15, s. 3023-3032
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Tidskriftsartikel (refereegranskat)abstract
- Background: Acute myeloid leukemia (AML) patients have limited effect from T-cell-based therapies, such as PD-1 and CTLA-4 blockade. However, recent data indicate that AML patients with TP53 mutation have higher immune infiltration and other immunomodulatory therapies could thus potentially be effective. Here, we performed the transcriptional analysis of distinct T-cell subpopulations from TP53-mutated AML to identify gene expression signatures suggestive of altered functional properties.Methods: CD8+ cytotoxic T lymphocytes (CTLs), conventional helper T cells (Th), and regulatory T cells (Tregs) were sorted from peripheral blood of AML patients with TP53 mutation (n = 5) and healthy donors (n = 3), using FACS, and the different subpopulations were subsequently subjected to RNA-sequencing. Differentially expressed genes were identified and gene set enrichment analysis (GSEA) was performed to outline altered pathways and exhaustion status. Also, expression levels for a set of genes encoding established and emerging immuno-oncological targets were defined.Results: The results showed altered transcriptional profiles for each of the T-cell subpopulations from TP53-mutated AML as compared to control subjects. IFN-α and IFN-γ signaling were stronger in TP53-mutated AML for both CTLs and Tregs. Furthermore, in TP53-mutated AML as compared to healthy controls, Tregs showed gene expression signatures suggestive of metabolic adaptation to their environment, whereas CTLs exhibited features of exhaustion/dysfunction with a stronger expression of TIM3 as well as enrichment of a gene set related to exhaustion.Conclusions: The results provide insights on mechanisms underlying the inadequate immune response to leukemic cells in TP53-mutated AML and open up for further exploration toward novel treatment regimens for these patients.
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| 9. |
- Ellmark, Peter, et al.
(författare)
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Kick-starting the cancer-immunity cycle by targeting CD40
- 2015
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Ingår i: Oncoimmunology. - 2162-4011 .- 2162-402X. ; 4:7
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Stimulation of CD40 on dendritic cells to expand and activate tumor-specific T cells and generate anticancer immunity is an attractive therapeutic approach. Since CD40 agonists exert their effects upstream of checkpoint inhibitors, including PD-1 or PD-L1 antagonists, they are ideal candidates for combination regimens.
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| 10. |
- Ellmark, Peter, et al.
(författare)
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Tumor-directed immunotherapy can generate tumor-specific T cell responses through localized co-stimulation
- 2017
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Ingår i: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 66:1, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- The most important goals for the field of immuno-oncology are to improve the response rate and increase the number of tumor indications that respond to immunotherapy, without increasing adverse side effects. One approach to achieve these goals is to use tumor-directed immunotherapy, i.e., to focus the immune activation to the most relevant part of the immune system. This may improve anti-tumor efficacy as well as reduce immune-related adverse events. Tumor-directed immune activation can be achieved by local injections of immune modulators in the tumor area or by directing the immune modulator to the tumor using bispecific antibodies. In this review, we focus on therapies targeting checkpoint inhibitors and co-stimulatory receptors that can generate tumor-specific T cell responses through localized immune activation.
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