Kris Thielemans - Academia.edu (original) (raw)

Papers by Kris Thielemans

Oncotarget, Jan 30, 2014

It is generally accepted that the success of immunotherapy depends on the presence of tumor-speci... more It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8⁺ cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral delivery of mRNA encoding a fusion protein consisting of interferon-β and the ectodomain of the transforming growth factor-β receptor II, referred to as Fβ², showed therapeutic potential. The treatment efficacy was dependent on CD8⁺ T cells and could be improved through blockade of PD-1/PD-L1 interactions. In vitro studies revealed that administration of Fβ² to tumor cells resulted in a reduced proliferation and increased expression of MHC I but also PD-L1. Importantly, Fβ² enhanced the antigen presenting capacity of dendritic cells, whilst reducing the suppressive activity of myeloid-derived suppressor cells. In conclusion, these data suggest th...

Oncoimmunology, 2015

Melanoma patients are at a high risk of developing brain metastases, which are strongly vasculari... more Melanoma patients are at a high risk of developing brain metastases, which are strongly vascularized and therefore have a significant risk of spontaneous bleeding. VEGF not only plays a role in neo-angiogenesis but also in the antitumor immune response. VEGFR-targeted therapy might not only have an impact on the tumor vascularization but also on tumor-infiltrating immune cells. In this study, we investigated the effect of axitinib, a small molecule TKI of VEGFR-1, -2, and -3, on tumor growth and on the composition of tumor-infiltrating immune cells in subcutaneous and intracranial mouse melanoma models. In vivo treatment with axitinib induced a strong inhibition of tumor growth and significantly improved survival in both tumor models. Characterization of the immune cells within the spleen and tumor of tumor-bearing mice respectively showed a significant increase in the number of CD3(+)CD8(+) T cells and CD11b(+) cells of axitinib-treated mice. More specifically, we observed a signif...

Oncoimmunology, 2015

The immunosuppressive tumor microenvironment (TME) is a major obstacle in cancer immunotherapy. T... more The immunosuppressive tumor microenvironment (TME) is a major obstacle in cancer immunotherapy. Therefore, it has gained attention as a target site. mRNA emerged as a versatile drug class for cancer therapy. We reported that intratumoral administration of mRNA encoding the fusokine Fβ(2) supports tumor-specific T-cell immunity. This study provides proof of concept of the use of mRNA to modulate the TME.

Molecular Therapy, 2005

We previously described mRNA electroporation as an efficient gene delivery method to introduce tu... more We previously described mRNA electroporation as an efficient gene delivery method to introduce tumor-antigens (Ag) into murine immature dendritic cells (DC). Here, we further optimize the protocol and evaluate the capacity of mRNA-electroporated DC as a vaccine for immunotherapy. First, the early DC maturation kinetics and the effect of different lipopolysaccharide incubation periods on the phenotypic maturation profile of DC are determined. Next, we show that either immature or mature DC are equally well electroporated and express and present the transgene at a comparable level after electroporation. We point out that the mRNA electroporation results in a negative effect on the interleukin (IL)-12p70, IL-6, and tumor necrosis factor-A secretion after maturation. Nevertheless, mRNA-electroporated DC induce an effective cytotoxic T lymphocyte (CTL) response in vivo. Mature electroporated DC are significantly more potent in eliciting an Agspecific CD8 + CTL response compared to their immature electroporated counterparts. In addition, a significant improvement in CTL response is obtained both in the primary and in the memory effector phases when CD4 + CD25 + regulatory T cells (Treg) are depleted in vivo prior to immunization. These findings are further substantiated in tumor protection experiments and hold convincing evidence for the merit of Treg cell depletion prior to immunization with mRNA-electroporated DC.

British Journal of Haematology, 1997

Mobilized CD34+ blood cells were immunomagnetically enriched from leukapheresis products in five ... more Mobilized CD34+ blood cells were immunomagnetically enriched from leukapheresis products in five multiple myeloma (MM) patients. Thawed samples of selected CD34+ cells were cultured for up to 21 d in a liquid and stroma-free culture system with different combinations of recombinant cytokines. The most successful cell expansion was obtained when a combination of rh-IL-1beta, rh-IL-3, rh-IL-6, rh-SCF, rh-G-CSF and rh-GM-CSF was used. After 14 d this mixture gave a 120-187-fold overall increase of total nuclear cells and a 4-8-fold overall increase of early CFU-GM numbers. In four patients a very sensitive patient-specific PCR analysis showed the presence of monoclonal cells in the initial leukapheresis products. After immunomagnetic separation a tumour cell depletion of 2-4 logs was observed, although all samples still contained malignant cells. Cell suspensions that were cultured with the most potent cytokine combination showed tumour contamination in two-thirds of evaluable cases at the moment of maximal CFU-GM output. Serial cDNA dilution experiments indicated that the positive PCR results at day 14 reflected the persistence of pre-culture tumour cells rather than in vitro expansion of tumour cells in two cases. This study demonstrates that ex vivo expansion of myeloid precursor cells from mobilized CD34+ cells in MM patients does not always result in an effective purging of residual tumour cells. On the other hand, our culture conditions do not seem to favour in vitro expansion of malignant cells, despite the use of a cytokine cocktail that includes potential myeloma growth factors.

Oncoimmunology, 2014

An increasing number of studies is focusing on the role of myeloid-derived suppressor cells (MDSC... more An increasing number of studies is focusing on the role of myeloid-derived suppressor cells (MDSCs) in the suppression of antitumor immune responses. Although the main site of action for MDSCs is most likely the tumor microenvironment, the study of these cells has been largely restricted to MDSCs derived from peripheral lymphoid organs. Only in a minority of studies MDSCs isolated from the tumor microenvironment have been characterized. This review will give an overview of the data available on the phenotypical and functional differences between tumor-derived MDSCs and MDSCs isolated from the spleen of tumor-bearing mice or from the peripheral blood of cancer patients.

Journal of Nuclear Medicine, 2015

Respiratory motion during PET acquisition may lead to blurring in resulting images and underestim... more Respiratory motion during PET acquisition may lead to blurring in resulting images and underestimation of uptake parameters. The advent of integrated PET/MR scanners allows us to exploit the integration of modalities, using high spatial resolution and high-contrast MR images to monitor and correct PET images degraded by motion. We proposed a practical, anatomy-independent MR-based correction strategy for PET data affected by respiratory motion and showed that it can improve image quality both for PET acquired simultaneously to the motion-capturing MR and for PET acquired up to 1 h earlier during a clinical scan. To estimate the respiratory motion, our method needs only an extra 1-min dynamic MR scan, acquired at the end of the clinical PET/MR protocol. A respiratory signal was extracted directly from the PET list-mode data. This signal was used to gate the PET data and to construct a motion model built from the dynamic MR data. The estimated motion was then incorporated into the PET image reconstruction to obtain a single motion-corrected PET image. We evaluated our method in 2 steps. The PET-derived respiratory signal was compared with an MR measure of diaphragmatic displacement via a pencil-beam navigator. The motion-corrected images were compared with uncorrected images with visual inspection, line profiles, and standardized uptake value (SUV) in focally avid lesions. We showed a strong correlation between the PET-derived and MR-derived respiratory signals for 9 patients, with a mean correlation of 0.89. We then showed 4 clinical case study examples ((18)F-FDG and (68)Ga-DOTATATE) using the motion-correction technique, demonstrating improvements in image sharpness and reduction of respiratory artifacts in scans containing pancreatic, liver, and lung lesions as well as cardiac scans. The mean increase in peak SUV (SUVpeak) and maximum SUV (SUVmax) in a patient with 4 pancreatic lesions was 23.1% and 34.5% in PET acquired simultaneously with motion-capturing MR, and 17.6% and 24.7% in PET acquired 50 min before as part of the clinical scan. We showed that a respiratory signal can be obtained from raw PET data and that the clinical PET image quality can be improved using only a short additional PET/MR acquisition. Our method does not need external respiratory hardware or modification of the normal clinical MR sequences.

2001 IEEE Nuclear Science Symposium Conference Record (Cat. No.01CH37310), 2002

Likelihood Expectation Maximization (MLEM) algorithm depending on the activity distribution in th... more Likelihood Expectation Maximization (MLEM) algorithm depending on the activity distribution in the field of view is extended to MLEM/Ordered Subsets EM (OSEM) where different types of regularization are applied. It will be shown that although different parts of the image converge at different rates, pure and post filtered MLEM/OSEM achieves reasonably uniform resolution. By contrast, inter iteration filtering (IF OSEM) with smoothing filters, such as Gaussian, renders images with varying spatial resolution that is dependent on the surrounding activity. Furthermore, a similar effect is noticed on images reconstructed with MAP using a Gaussian root prior. We conclude that resolution non-uniformity is entirely due to the filtering.

2002 IEEE Nuclear Science Symposium Conference Record, 2003

In this work the level of positive bias in images generated by various iterative reconstructions ... more In this work the level of positive bias in images generated by various iterative reconstructions of low activity PET data was investigated. A 3D acquisition of a low activity cylinder was performed upon an EXACT3D PET scanner followed by a multi-trial single plane simulation based upon this scan, taking into account randoms, scatter and attenuation. These were reconstructed using different implementations of maximum likelihood expectation maximisation, including the simple case of fully precorrected data and also using a separate randoms estimate with the shifted Poisson and prompts approaches. The effect of estimating the mean of randoms from the noisy delayed randoms with a maximum likelihood technique was also investigated.

Oncotarget, Jan 23, 2015

Myeloid-derived suppressor cells (MDSC) are contributing to an immunosuppressive environment by t... more Myeloid-derived suppressor cells (MDSC) are contributing to an immunosuppressive environment by their ability to inhibit T cell activity and thereby promoting cancer progression. An important feature of the incurable plasma cell malignancy Multiple Myeloma (MM) is immune dysfunction. MDSC were previously identified to be present and active in MM patients, however little is known about the MDSC-inducing and -activating capacity of MM cells. In this study we investigated the effects of the tumor microenvironment on MDSC survival. During MM progression in the 5TMM mouse model, accumulation of MDSC in the bone marrow was observed in early stages of disease development, while circulating myeloid cells were increased at later stages of disease. Interestingly, in vivo MDSC targeting by anti-GR1 antibodies and 5-Fluorouracil resulted in a significant reduced tumor load in 5TMM-diseased mice. In vitro generation of MDSC was demonstrated by increased T cell immunosuppressive capacity and MDSC...

Oncotarget, Jan 30, 2014

AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 p... more AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 phosphorylation and tumor growth. Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model. When MO4 tumor-bearing mice were treated with AZD1480 we observed a strong inhibition of tumor growth as well as a prolonged survival. Moreover, a significant decrease in the percentage of myeloid-derived suppressor cells (MDSCs) was observed after treatment with AZD1480. However, AZD1480 enhanced the suppressive capacity of murine MDSCs while at the same time impairing the proliferative as well as the IFN-γ secretion capacity of murine T cells. The addition of AZD1480 to co-cultures of human MDSCs and T cells does not affect the suppressive activity of MDSCs but it does reduce the IFN-γ secretion and the proliferative capacity of T cells. We showed that although AZD1480 has the ability to delay the tumor growth of MO4 tumor-bearing mice, ...

Cancer research, 2003

For the induction of an optimal immune response against cancer or infections not only CD8(+) CTLs... more For the induction of an optimal immune response against cancer or infections not only CD8(+) CTLs but also CD4(+) T helper cells must be induced, in particular IFN-gamma-secreting type 1 T helper cells. Several strategies have been explored to target tumor-associated antigens to the HLA class II processing compartments. We engineered a genetic construct encoding an invariant chain (Ii) protein where the CLIP region has been replaced by sequences encoding HLA class II-restricted MAGE-A3 epitopes. Monocyte-derived dendritic cells (DCs) were electroporated with in vitro transcribed mRNA encoding a modified Ii protein containing the HLA-DP4-restricted MAGE-A3 epitope. The capacity of these electroporated DCs to stimulate a MAGE-A3-specific T-cell clone was compared at different stages of DC maturation with the T-cell stimulatory capacity of DCs pulsed with the synthetic peptide. After electroporation, the T-cell stimulatory capacity was shown to be high and long lasting, whereas the sti...

EJNMMI Physics, 2014

Respiratory motion during PET acquisitions can cause image artefacts, with sharpness and tracer q... more Respiratory motion during PET acquisitions can cause image artefacts, with sharpness and tracer quantification adversely affected due to count 'smearing'. Motion correction by registration of PET gates becomes increasingly difficult with shorter scan times and less counts. The advent of simultaneous PET/MRI scanners allows the use of high spatial resolution MRI to capture motion states during respiration . In this work, we use a respiratory signal derived from the PET list-mode data , with no requirement for an external device or MR sequence modifications.

Recently, it has become more and more obvious that not only CD8 + cytotoxic T lymphocytes, but al... more Recently, it has become more and more obvious that not only CD8 + cytotoxic T lymphocytes, but also CD4 + T helper cells are required for the induction of an optimal, long-lasting anti-tumor immune response. CD4 + T helper cells, and in particular IFN-γ -secreting type 1 T helper cells, have been shown to fulfill a critical function in the mounting of a cancer-specific response. Consequently, targeting antigens into MHC class II molecules would greatly enhance the efficacy of an anti-cancer vaccine. The dissection of the MHC class II presentation pathway has paved the way for rational approaches to achieve this goal: novel systems have been developed to genetically manipulate the MHC class II presentation pathway. First, different genetic approaches have been used for the delivery of known epitopes into the MHC class II processing pathway or directly onto the peptide-binding groove of the MHC molecules. Second, several strategies exist for the targeting of whole tumor antigens, containing both MHC class I and class II restricted epitopes, to the MHC class II processing pathway. We review these data and describe how this knowledge is currently applied in vaccine development.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2006

Head movement presents a continuing problem in PET studies. Head restraint minimizes movement but... more Head movement presents a continuing problem in PET studies. Head restraint minimizes movement but is unreliable, resulting in the need to develop alternative strategies. These include frame-by-frame (FBF) realignment or use of motion tracking (MT) during the scan to realign PET acquisition data. Here we present a comparative analysis of these 2 methods of motion correction. Eight volunteers were examined at rest using (11)C-raclopride PET with the radioligand administered as a bolus followed by constant infusion to achieve steady state. Binding potential (BP) was estimated using the ratio method during 2 periods of the scan at steady state. Head movement was compensated by using coregistration between frames (FBF) and 3 methods using MT measurements of head position acquired with a commercially available optical tracking system. All methods of realignment improved test-retest reliability and noise characteristics of the raw data, with important consequences for the power to detect s...

It is generally accepted that the success of immunotherapy depends on the presence of tumor-spec... more It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8 + cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral delivery of mRNA encoding a fusion protein consisting of interferon-β and the ectodomain of the transforming growth factor-β receptor II, referred to as Fβ 2 , showed therapeutic potential. The treatment efficacy was dependent on CD8 + T cells and could be improved through blockade of PD-1/PD-L1 interactions. In vitro studies revealed that administration of Fβ 2 to tumor cells resulted in a reduced proliferation and increased expression of MHC I but also PD-L1. Importantly, Fβ 2 enhanced the antigen presenting capacity of dendritic cells, whilst reducing the suppressive activity of myeloid-derived suppressor cells. In conclusion, these data suggest that intratumoral delivery of mRNA encoding soluble proteins, such as Fβ 2 , can modulate the tumor microenvironment, leading to effective antitumor T cell responses, which can be further potentiated through combination therapy.

Genes of the MAGE, BAGE, GAGE, and LAGE-1/NY-ESO-1 families encode antigenic peptides that are pr... more Genes of the MAGE, BAGE, GAGE, and LAGE-1/NY-ESO-1 families encode antigenic peptides that are presented by HLA class I molecules and that are recognized on human tumors by autologous cytolytic T lymphocytes. These genes are expressed in many solid tumor types but not in normal tissues, except male germline cells. Because the latter cells are devoid of HLA molecules, the derived antigens are strictly tumor-specific and should constitute safe immunogens for cancer immunotherapy. We detected a significant expression of these genes in a high proportion of bone marrow samples from patients with advanced multiple myeloma. This observation provides a basis for clinical trials aimed at inducing a cellular immune response directed at malignant plasma cells in advanced myeloma patients.

Oncotarget, Jan 30, 2014

It is generally accepted that the success of immunotherapy depends on the presence of tumor-speci... more It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8⁺ cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral delivery of mRNA encoding a fusion protein consisting of interferon-β and the ectodomain of the transforming growth factor-β receptor II, referred to as Fβ², showed therapeutic potential. The treatment efficacy was dependent on CD8⁺ T cells and could be improved through blockade of PD-1/PD-L1 interactions. In vitro studies revealed that administration of Fβ² to tumor cells resulted in a reduced proliferation and increased expression of MHC I but also PD-L1. Importantly, Fβ² enhanced the antigen presenting capacity of dendritic cells, whilst reducing the suppressive activity of myeloid-derived suppressor cells. In conclusion, these data suggest th...

Oncoimmunology, 2015

Melanoma patients are at a high risk of developing brain metastases, which are strongly vasculari... more Melanoma patients are at a high risk of developing brain metastases, which are strongly vascularized and therefore have a significant risk of spontaneous bleeding. VEGF not only plays a role in neo-angiogenesis but also in the antitumor immune response. VEGFR-targeted therapy might not only have an impact on the tumor vascularization but also on tumor-infiltrating immune cells. In this study, we investigated the effect of axitinib, a small molecule TKI of VEGFR-1, -2, and -3, on tumor growth and on the composition of tumor-infiltrating immune cells in subcutaneous and intracranial mouse melanoma models. In vivo treatment with axitinib induced a strong inhibition of tumor growth and significantly improved survival in both tumor models. Characterization of the immune cells within the spleen and tumor of tumor-bearing mice respectively showed a significant increase in the number of CD3(+)CD8(+) T cells and CD11b(+) cells of axitinib-treated mice. More specifically, we observed a signif...

Oncoimmunology, 2015

The immunosuppressive tumor microenvironment (TME) is a major obstacle in cancer immunotherapy. T... more The immunosuppressive tumor microenvironment (TME) is a major obstacle in cancer immunotherapy. Therefore, it has gained attention as a target site. mRNA emerged as a versatile drug class for cancer therapy. We reported that intratumoral administration of mRNA encoding the fusokine Fβ(2) supports tumor-specific T-cell immunity. This study provides proof of concept of the use of mRNA to modulate the TME.

Molecular Therapy, 2005

We previously described mRNA electroporation as an efficient gene delivery method to introduce tu... more We previously described mRNA electroporation as an efficient gene delivery method to introduce tumor-antigens (Ag) into murine immature dendritic cells (DC). Here, we further optimize the protocol and evaluate the capacity of mRNA-electroporated DC as a vaccine for immunotherapy. First, the early DC maturation kinetics and the effect of different lipopolysaccharide incubation periods on the phenotypic maturation profile of DC are determined. Next, we show that either immature or mature DC are equally well electroporated and express and present the transgene at a comparable level after electroporation. We point out that the mRNA electroporation results in a negative effect on the interleukin (IL)-12p70, IL-6, and tumor necrosis factor-A secretion after maturation. Nevertheless, mRNA-electroporated DC induce an effective cytotoxic T lymphocyte (CTL) response in vivo. Mature electroporated DC are significantly more potent in eliciting an Agspecific CD8 + CTL response compared to their immature electroporated counterparts. In addition, a significant improvement in CTL response is obtained both in the primary and in the memory effector phases when CD4 + CD25 + regulatory T cells (Treg) are depleted in vivo prior to immunization. These findings are further substantiated in tumor protection experiments and hold convincing evidence for the merit of Treg cell depletion prior to immunization with mRNA-electroporated DC.

British Journal of Haematology, 1997

Mobilized CD34+ blood cells were immunomagnetically enriched from leukapheresis products in five ... more Mobilized CD34+ blood cells were immunomagnetically enriched from leukapheresis products in five multiple myeloma (MM) patients. Thawed samples of selected CD34+ cells were cultured for up to 21 d in a liquid and stroma-free culture system with different combinations of recombinant cytokines. The most successful cell expansion was obtained when a combination of rh-IL-1beta, rh-IL-3, rh-IL-6, rh-SCF, rh-G-CSF and rh-GM-CSF was used. After 14 d this mixture gave a 120-187-fold overall increase of total nuclear cells and a 4-8-fold overall increase of early CFU-GM numbers. In four patients a very sensitive patient-specific PCR analysis showed the presence of monoclonal cells in the initial leukapheresis products. After immunomagnetic separation a tumour cell depletion of 2-4 logs was observed, although all samples still contained malignant cells. Cell suspensions that were cultured with the most potent cytokine combination showed tumour contamination in two-thirds of evaluable cases at the moment of maximal CFU-GM output. Serial cDNA dilution experiments indicated that the positive PCR results at day 14 reflected the persistence of pre-culture tumour cells rather than in vitro expansion of tumour cells in two cases. This study demonstrates that ex vivo expansion of myeloid precursor cells from mobilized CD34+ cells in MM patients does not always result in an effective purging of residual tumour cells. On the other hand, our culture conditions do not seem to favour in vitro expansion of malignant cells, despite the use of a cytokine cocktail that includes potential myeloma growth factors.

Oncoimmunology, 2014

An increasing number of studies is focusing on the role of myeloid-derived suppressor cells (MDSC... more An increasing number of studies is focusing on the role of myeloid-derived suppressor cells (MDSCs) in the suppression of antitumor immune responses. Although the main site of action for MDSCs is most likely the tumor microenvironment, the study of these cells has been largely restricted to MDSCs derived from peripheral lymphoid organs. Only in a minority of studies MDSCs isolated from the tumor microenvironment have been characterized. This review will give an overview of the data available on the phenotypical and functional differences between tumor-derived MDSCs and MDSCs isolated from the spleen of tumor-bearing mice or from the peripheral blood of cancer patients.

Journal of Nuclear Medicine, 2015

Respiratory motion during PET acquisition may lead to blurring in resulting images and underestim... more Respiratory motion during PET acquisition may lead to blurring in resulting images and underestimation of uptake parameters. The advent of integrated PET/MR scanners allows us to exploit the integration of modalities, using high spatial resolution and high-contrast MR images to monitor and correct PET images degraded by motion. We proposed a practical, anatomy-independent MR-based correction strategy for PET data affected by respiratory motion and showed that it can improve image quality both for PET acquired simultaneously to the motion-capturing MR and for PET acquired up to 1 h earlier during a clinical scan. To estimate the respiratory motion, our method needs only an extra 1-min dynamic MR scan, acquired at the end of the clinical PET/MR protocol. A respiratory signal was extracted directly from the PET list-mode data. This signal was used to gate the PET data and to construct a motion model built from the dynamic MR data. The estimated motion was then incorporated into the PET image reconstruction to obtain a single motion-corrected PET image. We evaluated our method in 2 steps. The PET-derived respiratory signal was compared with an MR measure of diaphragmatic displacement via a pencil-beam navigator. The motion-corrected images were compared with uncorrected images with visual inspection, line profiles, and standardized uptake value (SUV) in focally avid lesions. We showed a strong correlation between the PET-derived and MR-derived respiratory signals for 9 patients, with a mean correlation of 0.89. We then showed 4 clinical case study examples ((18)F-FDG and (68)Ga-DOTATATE) using the motion-correction technique, demonstrating improvements in image sharpness and reduction of respiratory artifacts in scans containing pancreatic, liver, and lung lesions as well as cardiac scans. The mean increase in peak SUV (SUVpeak) and maximum SUV (SUVmax) in a patient with 4 pancreatic lesions was 23.1% and 34.5% in PET acquired simultaneously with motion-capturing MR, and 17.6% and 24.7% in PET acquired 50 min before as part of the clinical scan. We showed that a respiratory signal can be obtained from raw PET data and that the clinical PET image quality can be improved using only a short additional PET/MR acquisition. Our method does not need external respiratory hardware or modification of the normal clinical MR sequences.

2001 IEEE Nuclear Science Symposium Conference Record (Cat. No.01CH37310), 2002

Likelihood Expectation Maximization (MLEM) algorithm depending on the activity distribution in th... more Likelihood Expectation Maximization (MLEM) algorithm depending on the activity distribution in the field of view is extended to MLEM/Ordered Subsets EM (OSEM) where different types of regularization are applied. It will be shown that although different parts of the image converge at different rates, pure and post filtered MLEM/OSEM achieves reasonably uniform resolution. By contrast, inter iteration filtering (IF OSEM) with smoothing filters, such as Gaussian, renders images with varying spatial resolution that is dependent on the surrounding activity. Furthermore, a similar effect is noticed on images reconstructed with MAP using a Gaussian root prior. We conclude that resolution non-uniformity is entirely due to the filtering.

2002 IEEE Nuclear Science Symposium Conference Record, 2003

In this work the level of positive bias in images generated by various iterative reconstructions ... more In this work the level of positive bias in images generated by various iterative reconstructions of low activity PET data was investigated. A 3D acquisition of a low activity cylinder was performed upon an EXACT3D PET scanner followed by a multi-trial single plane simulation based upon this scan, taking into account randoms, scatter and attenuation. These were reconstructed using different implementations of maximum likelihood expectation maximisation, including the simple case of fully precorrected data and also using a separate randoms estimate with the shifted Poisson and prompts approaches. The effect of estimating the mean of randoms from the noisy delayed randoms with a maximum likelihood technique was also investigated.

Oncotarget, Jan 23, 2015

Myeloid-derived suppressor cells (MDSC) are contributing to an immunosuppressive environment by t... more Myeloid-derived suppressor cells (MDSC) are contributing to an immunosuppressive environment by their ability to inhibit T cell activity and thereby promoting cancer progression. An important feature of the incurable plasma cell malignancy Multiple Myeloma (MM) is immune dysfunction. MDSC were previously identified to be present and active in MM patients, however little is known about the MDSC-inducing and -activating capacity of MM cells. In this study we investigated the effects of the tumor microenvironment on MDSC survival. During MM progression in the 5TMM mouse model, accumulation of MDSC in the bone marrow was observed in early stages of disease development, while circulating myeloid cells were increased at later stages of disease. Interestingly, in vivo MDSC targeting by anti-GR1 antibodies and 5-Fluorouracil resulted in a significant reduced tumor load in 5TMM-diseased mice. In vitro generation of MDSC was demonstrated by increased T cell immunosuppressive capacity and MDSC...

Oncotarget, Jan 30, 2014

AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 p... more AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 phosphorylation and tumor growth. Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model. When MO4 tumor-bearing mice were treated with AZD1480 we observed a strong inhibition of tumor growth as well as a prolonged survival. Moreover, a significant decrease in the percentage of myeloid-derived suppressor cells (MDSCs) was observed after treatment with AZD1480. However, AZD1480 enhanced the suppressive capacity of murine MDSCs while at the same time impairing the proliferative as well as the IFN-γ secretion capacity of murine T cells. The addition of AZD1480 to co-cultures of human MDSCs and T cells does not affect the suppressive activity of MDSCs but it does reduce the IFN-γ secretion and the proliferative capacity of T cells. We showed that although AZD1480 has the ability to delay the tumor growth of MO4 tumor-bearing mice, ...

Cancer research, 2003

For the induction of an optimal immune response against cancer or infections not only CD8(+) CTLs... more For the induction of an optimal immune response against cancer or infections not only CD8(+) CTLs but also CD4(+) T helper cells must be induced, in particular IFN-gamma-secreting type 1 T helper cells. Several strategies have been explored to target tumor-associated antigens to the HLA class II processing compartments. We engineered a genetic construct encoding an invariant chain (Ii) protein where the CLIP region has been replaced by sequences encoding HLA class II-restricted MAGE-A3 epitopes. Monocyte-derived dendritic cells (DCs) were electroporated with in vitro transcribed mRNA encoding a modified Ii protein containing the HLA-DP4-restricted MAGE-A3 epitope. The capacity of these electroporated DCs to stimulate a MAGE-A3-specific T-cell clone was compared at different stages of DC maturation with the T-cell stimulatory capacity of DCs pulsed with the synthetic peptide. After electroporation, the T-cell stimulatory capacity was shown to be high and long lasting, whereas the sti...

EJNMMI Physics, 2014

Respiratory motion during PET acquisitions can cause image artefacts, with sharpness and tracer q... more Respiratory motion during PET acquisitions can cause image artefacts, with sharpness and tracer quantification adversely affected due to count 'smearing'. Motion correction by registration of PET gates becomes increasingly difficult with shorter scan times and less counts. The advent of simultaneous PET/MRI scanners allows the use of high spatial resolution MRI to capture motion states during respiration . In this work, we use a respiratory signal derived from the PET list-mode data , with no requirement for an external device or MR sequence modifications.

Recently, it has become more and more obvious that not only CD8 + cytotoxic T lymphocytes, but al... more Recently, it has become more and more obvious that not only CD8 + cytotoxic T lymphocytes, but also CD4 + T helper cells are required for the induction of an optimal, long-lasting anti-tumor immune response. CD4 + T helper cells, and in particular IFN-γ -secreting type 1 T helper cells, have been shown to fulfill a critical function in the mounting of a cancer-specific response. Consequently, targeting antigens into MHC class II molecules would greatly enhance the efficacy of an anti-cancer vaccine. The dissection of the MHC class II presentation pathway has paved the way for rational approaches to achieve this goal: novel systems have been developed to genetically manipulate the MHC class II presentation pathway. First, different genetic approaches have been used for the delivery of known epitopes into the MHC class II processing pathway or directly onto the peptide-binding groove of the MHC molecules. Second, several strategies exist for the targeting of whole tumor antigens, containing both MHC class I and class II restricted epitopes, to the MHC class II processing pathway. We review these data and describe how this knowledge is currently applied in vaccine development.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2006

Head movement presents a continuing problem in PET studies. Head restraint minimizes movement but... more Head movement presents a continuing problem in PET studies. Head restraint minimizes movement but is unreliable, resulting in the need to develop alternative strategies. These include frame-by-frame (FBF) realignment or use of motion tracking (MT) during the scan to realign PET acquisition data. Here we present a comparative analysis of these 2 methods of motion correction. Eight volunteers were examined at rest using (11)C-raclopride PET with the radioligand administered as a bolus followed by constant infusion to achieve steady state. Binding potential (BP) was estimated using the ratio method during 2 periods of the scan at steady state. Head movement was compensated by using coregistration between frames (FBF) and 3 methods using MT measurements of head position acquired with a commercially available optical tracking system. All methods of realignment improved test-retest reliability and noise characteristics of the raw data, with important consequences for the power to detect s...

It is generally accepted that the success of immunotherapy depends on the presence of tumor-spec... more It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8 + cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral delivery of mRNA encoding a fusion protein consisting of interferon-β and the ectodomain of the transforming growth factor-β receptor II, referred to as Fβ 2 , showed therapeutic potential. The treatment efficacy was dependent on CD8 + T cells and could be improved through blockade of PD-1/PD-L1 interactions. In vitro studies revealed that administration of Fβ 2 to tumor cells resulted in a reduced proliferation and increased expression of MHC I but also PD-L1. Importantly, Fβ 2 enhanced the antigen presenting capacity of dendritic cells, whilst reducing the suppressive activity of myeloid-derived suppressor cells. In conclusion, these data suggest that intratumoral delivery of mRNA encoding soluble proteins, such as Fβ 2 , can modulate the tumor microenvironment, leading to effective antitumor T cell responses, which can be further potentiated through combination therapy.

Genes of the MAGE, BAGE, GAGE, and LAGE-1/NY-ESO-1 families encode antigenic peptides that are pr... more Genes of the MAGE, BAGE, GAGE, and LAGE-1/NY-ESO-1 families encode antigenic peptides that are presented by HLA class I molecules and that are recognized on human tumors by autologous cytolytic T lymphocytes. These genes are expressed in many solid tumor types but not in normal tissues, except male germline cells. Because the latter cells are devoid of HLA molecules, the derived antigens are strictly tumor-specific and should constitute safe immunogens for cancer immunotherapy. We detected a significant expression of these genes in a high proportion of bone marrow samples from patients with advanced multiple myeloma. This observation provides a basis for clinical trials aimed at inducing a cellular immune response directed at malignant plasma cells in advanced myeloma patients.