| 1. |
- Dias, J D, et al.
(författare)
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Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4
- 2012
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Ingår i: Gene Therapy. - : Springer Science and Business Media LLC. - 0969-7128 .- 1476-5462. ; 19:10, s. 988-998
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Tidskriftsartikel (refereegranskat)abstract
- Promising clinical results have been achieved with monoclonal antibodies (mAbs) such as ipilimumab and tremelimumab that block cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CD152). However, systemic administration of these agents also has the potential for severe immune-related adverse events. Thus, local production might allow higher concentrations at the target while reducing systemic side effects. We generated a transductionally and transcriptionally targeted oncolytic adenovirus Ad5/3-Δ24aCTLA4 expressing complete human mAb specific for CTLA-4 and tested it in vitro, in vivo and in peripheral blood mononuclear cells (PBMCs) of normal donors and patients with advanced solid tumors. mAb expression was confirmed by western blotting and immunohistochemistry. Biological functionality was determined in a T-cell line and in PBMCs from cancer patients. T cells of patients, but not those of healthy donors, were activated by an anti-CTLA4mAb produced by Ad5/3-Δ24aCTLA4. In addition to immunological effects, a direct anti-CTLA-4-mediated pro-apoptotic effect was observed in vitro and in vivo. Local production resulted in 43-fold higher (P<0.05) tumor versus plasma anti-CTLA4mAb concentration. Plasma levels in mice remained below what has been reported safe in humans. Replication-competent Ad5/3-Δ24aCTLA4 resulted in 81-fold higher (P<0.05) tumor mAb levels as compared with a replication-deficient control. This is the first report of an oncolytic adenovirus producing a full-length human mAb. High mAb concentrations were seen at tumors with lower systemic levels. Stimulation of T cells of cancer patients by Ad5/3-Δ24aCTLA4 suggests feasibility of testing the approach in clinical trials.
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| 2. |
- Burman, Joachim, et al.
(författare)
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T-cell responses after haematopoietic stem cell transplantation for aggressive relapsing-remitting multiple sclerosis
- 2013
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 140:2, s. 211-219
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Tidskriftsartikel (refereegranskat)abstract
- Autologous haematopoietic stem cell transplantation (HSCT) for relapsing-remitting multiple sclerosis is a potentially curative treatment, which can give rise to long-term disease remission. However, the mode of action is not yet fully understood. The aim of the study was to evaluate similarities and differences of the CD4(+) T-cell populations between HSCT-treated patients (n = 12) and healthy controls (n = 9). Phenotyping of memory T cells, regulatory T (Treg) cells and T helper type 1 (Th1) and type 17 (Th17) cells was performed. Further, T-cell reactivity to a tentative antigen, myelin oligodendrocyte glycoprotein, was investigated in these patient populations. Patients treated with natalizumab (n = 15) were included as a comparative group. White blood cells were analysed with flow cytometry and T-cell culture supernatants were analysed with magnetic bead panel immunoassays. HSCT-treated patients had similar levels of Treg cells and of Th1 and Th17 cells as healthy subjects, whereas natalizumab-treated patients had lower frequencies of Treg cells, and higher frequencies of Th1 and Th17 cells. Cells from HSCT-treated patients cultured with overlapping peptides from myelin oligodendrocyte glycoprotein produced more transforming growth factor-beta(1) than natalizumab-treated patients, which suggests a suppressive response. Conversely, T cells from natalizumab-treated patients cultured with those peptides produced more interleukin-17 (IL-17), IL-1 and IL-10, indicating a Th17 response. In conclusion, we demonstrate circumstantial evidence for the removal of autoreactive T-cell clones as well as development of tolerance after HSCT. These results parallel the long-term disease remission seen after HSCT.
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| 3. |
- Burman, Joachim, et al.
(författare)
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The cerebrospinal fluid cytokine signature of multiple sclerosis : A homogenous response that does not conform to the Th1/Th2/Th17 convention
- 2014
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 277:1-2, s. 153-159
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Tidskriftsartikel (refereegranskat)abstract
- In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS). To this end, cerebrospinal fluid from patients with MS was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Increased levels of CCL22, CXCL10 and sCD40L characterized relapsing-remitting MS patients with the presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of relapsing-remitting MS patients irrespectively of the presence of gadolinium-enhancing lesions. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses. (C) 2014 Elsevier B.V. All rights reserved.
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| 4. |
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| 5. |
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| 6. |
- Christiansson, Lisa, et al.
(författare)
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Increased Level of Myeloid-Derived Suppressor Cells, Programmed Death Receptor Ligand 1/Programmed Death Receptor 1, and Soluble CD25 in Sokal High Risk Chronic Myeloid Leukemia
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1, s. e55818-
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy (eg interferon α) in combination with tyrosine kinase inhibitors is currently in clinical trials for treatment of chronic myeloid leukemia (CML). Cancer patients commonly have problems with so called immune escape mechanisms that may hamper immunotherapy. Hence, to study the function of the immune system in CML is of interest. In the present paper we have identified immune escape mechanisms in CML with focus on those that directly hamper T cells since these cells are important to control tumor progression. CML patient samples were investigated for the presence of myeloid-derived suppressor cells (MDSCs), expression of programmed death receptor ligand 1/programmed death receptor 1 (PD-L1/PD-1), arginase 1 and soluble CD25. MDSC levels were increased in samples from Sokal high risk patients (p<0,05) and the cells were present on both CD34 negative and CD34 positive cell populations. Furthermore, expression of the MDSC-associated molecule arginase 1, known to inhibit T cells, was increased in the patients (p = 0,0079). Myeloid cells upregulated PD-L1 (p<0,05) and the receptor PD-1 was present on T cells. However, PD-L1 blockade did not increase T cell proliferation but upregulated IL-2 secretion. Finally, soluble CD25 was increased in high risk patients (p<0,0001). In conclusion T cells in CML patients may be under the control of different immune escape mechanisms that could hamper the use of immunotherapy in these patients. These escape mechanisms should be monitored in trials to understand their importance and how to overcome the immune suppression.
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| 7. |
- Christiansson, Lisa, 1983-
(författare)
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Myeloid-Derived Suppressor Cells and Other Immune Escape Mechanisms in Chronic Leukemia
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, a minute chromosome that leads to the creation of the fusion gene BCR/ABL and the transcription of the fusion protein BCR/ABL in transformed cells. The constitutively active tyrosine kinase BCR/ABL confers enhanced proliferation and survival on leukemic cells. CML has in only a few decades gone from being a disease with very bad prognosis to being a disease that can be effectively treated with oral tyrosine kinase inhibitors (TKIs). TKIs are drugs inhibiting BCR/ABL as well as other tyrosine kinases. In this thesis, the focus has been on the immune system of CML patients, on immune escape mechanisms present in untreated patients and on how these are affected by TKI therapy. We have found that newly diagnosed, untreated CML patients exert different kinds of immune escape mechanisms. Patients belonging to the Sokal high-risk group had higher levels of myeloid-derived suppressor cells (MDSCs) as well as high levels of the programmed death receptor 1 (PD-1)-expressing cytotoxic T cells compared to control subjects. Moreover, CML patients had higher levels of myeloid cells expressing the ligand for PD-1, PD-L1. CML patients as well as patients with B cell malignacies had high levels of soluble CD25 in blood plasma. In B cell malignacies, sCD25 was found to be released from T regulatory cells (Tregs). Treatment with the TKIs imatinib or dasatinib decreased the levels of MDSCs in peripheral blood. Tregs on the other hand increased during TKI therapy. The immunostimulatory molecule CD40 as well as NK cells increased during therapy, indicating an immunostimulatory effect of TKIs. When evaluating immune responses, multiplex techniques for quantification of proteins such as cytokines and chemokines are becoming increasingly popular. With these techniques a lot of information can be gained from a small sample volume and complex networks can be more easily studied than when using for example the singleplex ELISA. When comparing different multiplex platforms we found that the absolute protein concentration measured by one platform rarely correlated with the absolute concentration measured by another platform. However, relative quantification was better correlated.
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| 8. |
- Christiansson, Lisa, et al.
(författare)
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The use of multiplex platforms for absolute and relative protein quantification of clinical material
- 2014
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Ingår i: EuPA Open Proteomics. - : Elsevier BV. - 2212-9685. ; 3, s. 37-47
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Tidskriftsartikel (refereegranskat)abstract
- When introducing multiplex platforms to measure protein content in precious clinical material there is an increased risk of cross reactivity, loss of sensitivity as well as accuracy. In this paper, four multiplex platforms and one singleplex platform were compared by running pre- and post-treatment plasma samples from CML patients. We found a variation of absolute protein concentrations between platforms. For some of the analytes and platforms, relative differences between pre- and post-treatment samples correlated. We conclude that absolute concentrations measured by different platforms should be compared with caution and comparing relative differences could be more accurate.
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| 9. |
- Diaconu, Iulia, et al.
(författare)
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Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus
- 2012
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 72:9, s. 2327-2338
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Tidskriftsartikel (refereegranskat)abstract
- Oncolytic adenovirus is an attractive platform for immunotherapy because virus replication is highly immunogenic and not subject to tolerance. Although oncolysis releases tumor epitopes and provides costimulatory danger signals, arming the virus with immunostimulatory molecules can further improve efficacy. CD40 ligand (CD40L, CD154) induces apoptosis of tumor cells and triggers several immune mechanisms, including a T-helper type 1 (TH1) response, which leads to activation of cytotoxic T cells and reduction of immunosuppression. In this study, we constructed a novel oncolytic adenovirus, Ad5/3-hTERT-E1A-hCD40L, which features a chimeric Ad5/3 capsid for enhanced tumor transduction, a human telomerase reverse transcriptase (hTERT) promoter for tumor selectivity, and human CD40L for increased efficacy. Ad5/3-hTERT-E1A-hCD40L significantly inhibited tumor growth in vivo via oncolytic and apoptotic effects, and (Ad5/3-hTERT-E1A-hCD40L)–mediated oncolysis resulted in enhanced calreticulin exposure and HMGB1 and ATP release, which were suggestive of immunogenicity. In two syngeneic mouse models, murine CD40L induced recruitment and activation of antigen-presenting cells, leading to increased interleukin-12 production in splenocytes. This effect was associated with induction of the TH1 cytokines IFN-γ, RANTES, and TNF-α. Tumors treated with Ad5/3-CMV-mCD40L also displayed an enhanced presence of macrophages and cytotoxic CD8+ T cells but not B cells. Together, our findings show that adenoviruses coding for CD40L mediate multiple antitumor effects including oncolysis, apoptosis, induction of T-cell responses, and upregulation of TH1 cytokines.
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| 10. |
- Enblad, Gunilla, et al.
(författare)
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CAR T-Cell Therapy : The Role of Physical Barriers and Immunosuppression in Lymphoma
- 2015
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Ingår i: Human Gene Therapy. - : Mary Ann Liebert Inc. - 1043-0342 .- 1557-7422. ; 26:8, s. 498-505
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Forskningsöversikt (refereegranskat)abstract
- Chimeric antigen receptor (CAR) T-cells have shown remarkable results in patients with B-cell leukemia and lymphoma. However, while CAR T-cells have shown complete responses in a majority of patients with acute lymphoblastic leukemia (ALL), lymphomas are more difficult to treat. Different CAR designs and conditioning protocols seem to affect the persistence of patient responses. However, factors that determine if patients receiving the same CARs will respond or not remain obscure. In Sweden, a phase I/IIa trial using third-generation CAR T-cells is ongoing in which we intend to compare tumor biology and immunology, in each patient, to treatment response. CAR T-cell therapy is a powerful tool to add to the treatment options for this patient group but we need to perform the necessary basic research on the multifactorial mechanisms of action to give patients the best possible option of survival. Such studies are also crucial to expand the success of CAR T-cells beyond CD19+ B-cell malignancy. This review will focus on possible barriers of treating lymphoma to define factors that need to be investigated to develop the next generation of CAR T-cell therapy.
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