Purpose: Adoptive T-cell therapy generally fails to induce meaningful anticancer responses in pat... more Purpose: Adoptive T-cell therapy generally fails to induce meaningful anticancer responses in patients with solid tumors. Here, we present a novel strategy designed to selectively enhance the tumoricidal activity of T cells by targeted delivery of TNF-related apoptosis-inducing ligand (TRAIL) to the T-cell surface.Experimental Design: We constructed two recombinant fusion proteins, anti-CD3:TRAIL and K12:TRAIL. Tumoricidal activity of T cells in the presence of these fusion proteins was assessed in solid tumor cell lines, primary patient-derived malignant cells, and in a murine xenograft model.Results: When added to T cells, K12:TRAIL and anti-CD3:TRAIL selectively bind to the T-cell surface antigens CD3 and CD7, respectively, leading to cell surface accretion of TRAIL. Subsequently, anti-CD3:TRAIL and K12:TRAIL increased the tumoricidal activity of T cells toward cancer cell lines and primary patient-derived malignant cells by more than 500-fold. Furthermore, T-cell surface deliver...
Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among oth... more Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among others due to frequent occurrence of therapy-resistant relapse after standard-of-care treatment with cytarabine (AraC). AraC triggers apoptotic cell death, a type of cell death to which AML cells often becomes resistant. Therefore, alternative therapeutic options that trigger a different type of cell death are of particular interest. We previously identified that the glycan-binding protein Galectin-9 (Gal-9) has tumor-selective and non-apoptotic cytotoxicity towards various types of cancer, which depended on autophagy inhibition. Thus, Gal-9 could be of a therapeutic interest for (AraC-resistant) AML. In the current study, we identified that Gal-9 was cytotoxic for AML cells, including for CD34+ patient-derived AML stem cells, but not for healthy cord blood-derived CD34+ stem cells. This Gal-9-mediated cytotoxicity did not rely on apoptosis but negatively associated with autophagic flux. Im...
Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among oth... more Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among others, due to frequent occurrence of therapy-resistant relapse after standard-of-care treatment with cytarabine (AraC). AraC triggers apoptotic cell death, a type of cell death to which AML cells often become resistant. Therefore, therapeutic options that trigger an alternate type of cell death are of particular interest. We previously identified that the glycan-binding protein Galectin-9 (Gal-9) has tumor-selective and non-apoptotic cytotoxicity towards various types of cancer, which depended on autophagy inhibition. Thus, Gal-9 could be of therapeutic interest for (AraC-resistant) AML. In the current study, treatment with Gal-9 was cytotoxic for AML cells, including for CD34+ patient-derived AML stem cells, but not for healthy cord blood-derived CD34+ stem cells. This Gal-9-mediated cytotoxicity did not rely on apoptosis but was negatively associated with autophagic flux. Importantly, bo...
TRAIL is een eiwitmolecuul dat in geringe hoeveelheden voorkomt op bepaalde immuuncellen en dat d... more TRAIL is een eiwitmolecuul dat in geringe hoeveelheden voorkomt op bepaalde immuuncellen en dat door deze cellen wordt gebruikt om kankercellen te doden. Tijdens het onderzoek van Valerie R. Wiersma is onderzocht of het mogelijk is om extra TRAIL moleculen op immuuncellen ‘te plakken’ om op deze wijze hun antikankeractiviteit te vergroten. Hiertoe zijn nieuwe zogenaamde TRAIL fusie-eiwitten ontwikkeld waarbij TRAIL gekoppeld werd aan een antilichaamfragment dat specifiek aan immuuncellen bindt. Bij de keuze voor het antilichaamfragment is een doelwit geselecteerd op immuuncellen dat ook kan worden gebruikt om deze cellen te activeren. Twee vliegen in een klap dus; extra TRAIL afleveren op immuuncellen en wel op zo’n manier dat het deze immuuncellen ook nog eens extra activeert. Het onderzoek laat inderdaad zien dat met behulp van deze aanpak de antikankeractiviteit van verschillende immuuncellen aanzienlijk kan worden vergroot. Mogelijk kan deze strategie in de toekomst worden ingez...
Purpose: Adoptive T-cell therapy generally fails to induce meaningful anticancer responses in pat... more Purpose: Adoptive T-cell therapy generally fails to induce meaningful anticancer responses in patients with solid tumors. Here, we present a novel strategy designed to selectively enhance the tumoricidal activity of T cells by targeted delivery of TNF-related apoptosis-inducing ligand (TRAIL) to the T-cell surface.Experimental Design: We constructed two recombinant fusion proteins, anti-CD3:TRAIL and K12:TRAIL. Tumoricidal activity of T cells in the presence of these fusion proteins was assessed in solid tumor cell lines, primary patient-derived malignant cells, and in a murine xenograft model.Results: When added to T cells, K12:TRAIL and anti-CD3:TRAIL selectively bind to the T-cell surface antigens CD3 and CD7, respectively, leading to cell surface accretion of TRAIL. Subsequently, anti-CD3:TRAIL and K12:TRAIL increased the tumoricidal activity of T cells toward cancer cell lines and primary patient-derived malignant cells by more than 500-fold. Furthermore, T-cell surface deliver...
Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among oth... more Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among others due to frequent occurrence of therapy-resistant relapse after standard-of-care treatment with cytarabine (AraC). AraC triggers apoptotic cell death, a type of cell death to which AML cells often becomes resistant. Therefore, alternative therapeutic options that trigger a different type of cell death are of particular interest. We previously identified that the glycan-binding protein Galectin-9 (Gal-9) has tumor-selective and non-apoptotic cytotoxicity towards various types of cancer, which depended on autophagy inhibition. Thus, Gal-9 could be of a therapeutic interest for (AraC-resistant) AML. In the current study, we identified that Gal-9 was cytotoxic for AML cells, including for CD34+ patient-derived AML stem cells, but not for healthy cord blood-derived CD34+ stem cells. This Gal-9-mediated cytotoxicity did not rely on apoptosis but negatively associated with autophagic flux. Im...
Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among oth... more Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among others, due to frequent occurrence of therapy-resistant relapse after standard-of-care treatment with cytarabine (AraC). AraC triggers apoptotic cell death, a type of cell death to which AML cells often become resistant. Therefore, therapeutic options that trigger an alternate type of cell death are of particular interest. We previously identified that the glycan-binding protein Galectin-9 (Gal-9) has tumor-selective and non-apoptotic cytotoxicity towards various types of cancer, which depended on autophagy inhibition. Thus, Gal-9 could be of therapeutic interest for (AraC-resistant) AML. In the current study, treatment with Gal-9 was cytotoxic for AML cells, including for CD34+ patient-derived AML stem cells, but not for healthy cord blood-derived CD34+ stem cells. This Gal-9-mediated cytotoxicity did not rely on apoptosis but was negatively associated with autophagic flux. Importantly, bo...
TRAIL is een eiwitmolecuul dat in geringe hoeveelheden voorkomt op bepaalde immuuncellen en dat d... more TRAIL is een eiwitmolecuul dat in geringe hoeveelheden voorkomt op bepaalde immuuncellen en dat door deze cellen wordt gebruikt om kankercellen te doden. Tijdens het onderzoek van Valerie R. Wiersma is onderzocht of het mogelijk is om extra TRAIL moleculen op immuuncellen ‘te plakken’ om op deze wijze hun antikankeractiviteit te vergroten. Hiertoe zijn nieuwe zogenaamde TRAIL fusie-eiwitten ontwikkeld waarbij TRAIL gekoppeld werd aan een antilichaamfragment dat specifiek aan immuuncellen bindt. Bij de keuze voor het antilichaamfragment is een doelwit geselecteerd op immuuncellen dat ook kan worden gebruikt om deze cellen te activeren. Twee vliegen in een klap dus; extra TRAIL afleveren op immuuncellen en wel op zo’n manier dat het deze immuuncellen ook nog eens extra activeert. Het onderzoek laat inderdaad zien dat met behulp van deze aanpak de antikankeractiviteit van verschillende immuuncellen aanzienlijk kan worden vergroot. Mogelijk kan deze strategie in de toekomst worden ingez...
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