| 1. |
- Carlsson, Björn, et al.
(författare)
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Effector T cell analysis of melanoma tumor-infiltrating lymphocyte cultures using HLA-ABC semimatched melanoma cell lines
- 2008
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Ingår i: Journal of immunotherapy (1997). - 1524-9557 .- 1537-4513. ; 31:7, s. 633-43
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Tidskriftsartikel (refereegranskat)abstract
- The generation of T cells with specific reactivity against tumor-associated antigens is prerequisite for adoptive transfer therapy. Melanoma-specific lymphocyte cultures can be established from tumor-infiltrating lymphocytes (TILs) by in vitro culture with high levels of interleukin-2. In this report, we present TIL data originating from 728 attempted cultures from 33 consecutive melanoma biopsy specimens originating from 30 patients. Cultures were analyzed for the presence of interferon gamma (IFNgamma)-producing cells upon stimulation with a panel of HLA-ABC semimatched melanoma cell lines. We sought to find whether such cell lines could be used to analyze TIL reactivity. Cell lines were used as stimulators to circumvent the need for autologous primary tumor cells. Melanoma-reactive cultures were identified by flow cytometry in 25 of the 30 patients. Four hundred forty-four of 728 (60.9%) cultures contained TILs at the end of experiment. Ninety-one of 318 cultures (28.6%) contained IFNgamma-producing cells after stimulation. In HLA-A*0201 patients IFNgamma analysis was complemented with melanoma-specific tetramer staining. All but one HLA-A*0201 patient had MART-1/Melan-A27-35-directed TILs, with frequencies ranging from 0.1% to 90% of CD8 cells. In addition, tetramer analysis also identified TILs directed against gp100, Tyrosinase, and Her2Neu. Tumor material was collected via needle biopsy in 16 cases and surgery in 18 cases. Overall, surgical material generated more cultures positive for T cells. The described methods are efficient in characterizing clinically relevant melanoma-reactive TILs.
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| 2. |
- Dai, Min, et al.
(författare)
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Tumor Regression and Cure Depends on Sustained Th1 Responses
- 2018
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Ingår i: Journal of Immunotherapy. - 1524-9557. ; 41:8, s. 369-378
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Tidskriftsartikel (refereegranskat)abstract
- While immunomodulatory monoclonal antibodies (mAbs) have therapeutic efficacy against many tumors, few patients are cured. Attempting to improve their therapeutic efficacy we have applied the TC1 mouse lung carcinoma model and injected established subcutaneous tumors intratumorally with 3 weekly doses of various combinations of mAbs. Combinations of mAbs to CTLA4/PD1/CD137 (the 3 mAb combination) and to CTLA4/PD1/CD137/CD19 (the 4 mAb combination) were most efficacious to induce complete regression of both the injected tumor and an untreated tumor in the same mouse. Tumor cure was consistently associated with shifting a Th2 to a Th1 response in tumor-draining lymph nodes and spleen and it involved epitope specific and long-lived memory T cells as well as M1 macrophages. This shift and accompanying tumor rejection was harder to achieve as the treated tumors increased in size. Relapse of tumors which had initially regressed following treatment with immunomodulatory mAbs was associated with return of a Th2 microenvironment in tumors, tumor-draining lymph nodes and spleens rather than the emergence of immune-resistant tumor cells. While mAbs to CTLA4 plus PD-1 were therapeutically ineffective, combining the 2 of them with intraperitoneal cisplatin, 10 mg/kg, induced long-term complete tumor regression in most mice with small TC1 tumors and the therapeutic efficacy against larger tumors improved by administrating cisplatin together with the 3 or 4 mAb combination.
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| 3. |
- Hernberg, Micaela, et al.
(författare)
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The prognostic role of blood lymphocyte subset distribution in patients with resected high-risk primary or regionally metastatic melanoma.
- 2007
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Ingår i: Journal of immunotherapy (Hagerstown, Md. : 1997). - 1524-9557. ; 30:7, s. 773-9
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate whether the profile of peripheral blood lymphocyte subsets of patients with high-risk malignant melanoma is associated with prognosis. Blood samples were systematically obtained from 31 patients with high-risk melanoma eligible for the Nordic Melanoma Cooperative Group adjuvant interferon study. The frequencies of peripheral blood lymphocyte subsets were monitored by flow cytometry using CD3, CD4, CD8, CD56, and CD69 monoclonal antibodies. Patients with low proportions of CD3+CD4+CD69+ cells and of CD3+CD56+ cells before treatment had an improved disease-free survival compared to those with high proportions [77.7 vs. 16.8 mo, hazard ratio (HR) 0.25, confidence interval (CI) 0.09-0.71, P=0.005 and 77.2 vs. 16.0 mo, HR: 0.25, CI 0.086-0.73, P=0.001, respectively]. Low pretreatment levels of these cell populations also correlated with a better overall survival (79.2 vs. 22.6 mo, HR: 0.17, CI 0.05-0.52, P=0.0005 and 78.2 vs. 21.4 mo, HR: 0.2, CI 0.07-0.59, P=0.001, respectively). In the multivariate analysis both the pretreatment proportion of CD3+CD4+CD69+ cells (P=0.01, HR: 0.21, CI 0.07-0.67) and CD3+CD56+ cells (P=0.01, HR: 0.22, CI 0.062-0.65) were independent prognostic factors for overall survival. Our data show that both the proportions of CD3+CD4+CD69+ cells and of CD3+CD56+ cells seem to have a prognostic potential in the natural course of melanoma. These results need to be confirmed in larger studies.
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| 4. |
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| 5. |
- Janelidze, Shorena, et al.
(författare)
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Immunizations With IFN gamma Secreting Tumor Cells can Eliminate Fully Established and Invasive Rat Gliomas
- 2009
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Ingår i: Journal of Immunotherapy. - 1524-9557. ; 32:6, s. 593-601
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy of malignant primary brain tumors holds the potential to improve the dismal prognosis after current clinical therapy. Although immunotherapy of experimental gliomas has been demonstrated to have the capacity to cure intracerebral tumors no convincing effects of immunotherapy have been shown in clinical trials. One reason for this could be that some of the models used do not display full features of human glioblastomas. The N29 rat gliomas exhibited all the histologic features of human glioblastoma multiforme including nuclear atypia, mitotic figures, necrosis, and diffuse infiltration into the normal brain tissue. Surprisingly, immunotherapy with autologous interferon gamma producing tumor cells against preestablished intracerebral N29 turners yielded a higher cure rate than immunotherapy against less invasive tumors. Furthermore, when immunizations were postponed until day 5 after tumor establishment 50% of the animals survived. When immunizations were postponed until day 11 after tumor establishment no glioma-bearing animals were cured but survival was significantly prolonged. The superior effect of immunotherapy in the invasive N29 model compared with the less invasive tumors could depend oil combined effects of up-regulation of major histocompatibility complex I and induction of major histocompatibility complex II plus CD80 after transfection and irradiation of the tumor cells used for immunizations. This study demonstrates that immunotherapy against experimental brain tumors indeed is feasible even against highly invasive and established tumors. These results strengthen the translational potential of immunotherapy against malignant brain tumors.
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| 6. |
- Liljenfeldt, Lina, et al.
(författare)
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A Hexon and Fiber-modified Adenovirus Expressing CD40L Improves the Antigen Presentation Capacity of Dendritic Cells
- 2014
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Ingår i: Journal of immunotherapy (1997). - 1524-9557 .- 1537-4513. ; 37:3, s. 155-162
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Tidskriftsartikel (refereegranskat)abstract
- CD40 ligand (CD40L), a strong stimulator of Th1 immune responses, acts via dendritic cells to trigger T-cell activation. AdCD40L therapy introduces the CD40L gene into the tumor microenvironment with an adenoviral vector and has shown promising results in experimental tumor models, dogs, and patients (phase I-II trials). The transduction efficiency of AdCD40L is dependent on the expression of CAR (coxsackie/adenovirus adhesion receptor), which is commonly downregulated on tumor cells. To enhance transduction efficiency, and therefore the therapeutic efficacy, a double-modified adenovirus was developed. The double-modified Ad5PTDf35(mCD40L) had a protein transduction domain (PTD) inserted into the hexon protein and the virus fiber is switched from serotype 5 to serotype 35. These modifications enable transduction of a wider range of cell types. In comparison with Ad5(mCD40L), Ad5PTDf35(mCD40L) showed increased transduction capacity on a variety of murine cells. Furthermore, antigen presentation was improved after transduction with Ad5PTDf35(mCD40L). This was demonstrated in an antigen presentation assay, both in vitro and in vivo, in which transduced dendritic cells were loaded with suboptimal concentrations of the human gp100 peptide and allowed to interact with gp100-specific transgenic T cells (pmel). Finally, Ad5PTDf35(mCD40L) could delay tumor growth in a murine cancer model at a particle load, wherein therapeutic efficacy of the Ad5(mCD40L) vector was lost. Hence, the Ad5PTDf35(CD40L) vector holds great promise as a second-generation immune stimulatory therapy, as it not only targets tumor cells but also antigen-presenting cells that are, among other cells, present in the tumor microenvironment.
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| 7. |
- Lindqvist, Camilla, et al.
(författare)
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Local AdCD40L gene therapy is effective for disseminated murine experimental cancer by breaking T-cell tolerance and inducing tumor cell growth inhibition
- 2009
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Ingår i: Journal of immunotherapy (1997). - 1524-9557 .- 1537-4513. ; 32:8, s. 785-792
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Tidskriftsartikel (refereegranskat)abstract
- CD40 ligand (CD40L) is one of the most potent stimulators of Th1-type immunity through its maturation of dendritic cells that, in turn, stimulate effector cells such as T cells and NK cells. Lately, CD40-mediated cell growth inhibition and apoptosis have been in focus for the development of novel cancer treatment regiments, including recombinant soluble CD40L or CD40-stimulating antibodies. In this study, intravesical CD40L gene transfer through adenoviral vectors (AdCD40L) was used to treat an aggressive model of disseminated bladder cancer (MB49/C57BL/6). Three weekly AdCD40L vector instillations increased overall survival of tumor-bearing mice (mean 18.5 d, control mice 13 d). Furthermore, bladder tumors were eradicated (2 of 10) simultaneously as lung metastases (6 of 10) were cleared. FoxP3 levels were similar in the tumors of AdCD40L-treated mice and control mice but the tumor-infiltrating effector T cells in AdCD40L-treated mice were cytotoxic (CD107a+) in contrast to those in control-treated tumors. Furthermore, AdCD40L gene therapy could induce cell growth inhibition and cell death in the MB49 tumor cells in vitro and in vivo. However, this effect was not Potent enough to cure growing tumors in immunodeficient mice. In conclusion, AdCD40L gene therapy is potent for disseminated cancer both by activation of T cells and controlling tumor cell growth and viability.
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