STEAP1-4 (Six-Transmembrane Epithelial Antigen of the Prostate 1-4) and Their Clinical Implications for Prostate Cancer

Six-Transmembrane Epithelial Antigen of the Prostate 1-4 (STEAP1-4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed, while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1-4 are well documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1-4 as potential biomarkers and therapeutic targets for prostate cancer. In particular, STEAP1 is the target of many emerging immunotherapies. Herein, we give an overview of the structure, physiology, and pathophysiology of STEAP1-4 to provide context for past and current efforts to translate STEAP1-4 into the clinic

Environmental and microbial factors influencing methane and nitrous oxide fluxes in Mediterranean cork oak woodlands: trees make a difference

Original Researchinfo:eu-repo/semantics/publishedVersio

Minimal residual disease level predicts outcome in adults with Ph-negative Bprecursor acute lymphoblastic leukemia

Institut Germans Tries i PujolObjectives: Detectable minimal residual disease (MRD) after therapy for acute lymphoblastic leukemia (ALL) is the strongest predictor of hematologic relapse. This study evaluated outcomes of patients with B-cell precursor ALL with MRD of ≥10−4. Methods: Study population was from ALL study groups in Europe managed in national study protocols 2000-2014. MRD was measured by polymerase chain reaction or flow cytometry. Patients were age ≥15 years at initial ALL diagnosis. Patients were excluded if exposed to blinatumomab within 18 months of baseline or prior alloHSCT. Results: Of 272 patients in CR1, baseline MRD was ≥10−1, 10−2 to <10−1, 10−3 to <10−2, and 10−4 to <10−3 in 15 (6%), 71 (26%), 109 (40%), and 77 (28%) patients, respectively. Median duration of complete remission (DoR) was 18.5 months (95% confidence interval [CI], 11.9-27.2), median relapse-free survival (RFS) was 12.4 months (95% CI, 10.0-19.0) and median overall survival (OS) was 32.5 months (95% CI, 23.6-48.0). Lower baseline MRD level (P ≤ .0003) and white blood cell count <30,000/μL at diagnosis (P ≤ .0053) were strong predictors for better RFS and DoR. Allogeneic hematopoietic stem cell transplantation (alloHSCT) was associated with longer RFS (hazard ratio [HR], 0.59; 95% CI, 0.41-0.84) and DoR (HR, 0.43; 95% CI, 0.29-0.64); the association with OS was not significant (HR, 0.72; 95% CI, 0.50-1.05). Discussion: In conclusion, RFS, DoR, and OS are relatively short in patients with MRD-positive ALL, particularly at higher MRD levels. AlloHSCT may improve survival but has limitations. Alternative approaches are needed to improve outcomes in MRD-positive ALL

Generation and Characterization of different Antibody-based Therapeutics for Treatment of CD19-positive Leukemia

Die Heilungschancen lymphoider Neoplasien haben sich in den letzten Jahren nicht zuletzt durch Transplantationen und Antikörper-basierte Therapeutika stark verbessert. Dennoch stellen Rezidive weiterhin ein großes Problem dar. Aufgrund dessen besteht ein großer Bedarf an innovativen Therapieoptionen. Chimäre Antikörper gegen CD19 auf B-lymphoiden Zellen haben sich als ein effizienter Ansatz zur Eliminierung primärer B-Vorläufer ALL Zellen über NK-Zell vermittelte Lyse erwiesen. Dabei ist bekannt, dass die N-gebundenen Oligosaccharide der IgG schweren Kette das zytolytische Potential der Antikörper beeinflussen. Ein chimärer CD19 Antikörper wurde sowohl in Sf21 Insektenzellen, humanen 293T Zellen als auch in glykosylierungsmodifizierten 293T Zellen exprimiert, was zu unterschiedlichen Glykosylierungsmustern der Fc Region des Antikörpers führen sollte. Die N-gebundenen Oligosaccharidstrukturen und die Zytotoxizität der drei chimären CD19 Antikörper Varianten wurden direkt miteinander verglichen. Der in humanen Zellen produzierte chimäre Antikörper wies nur eine sehr geringe Zytotoxizität auf, obwohl das Glykosylierungsmuster mit dem, humaner Serum IgG Antikörper vergleichbar war. Der glykosylierungsmodifizierte Antikörper trug im Gegensatz dazu einen erhöhten Prozentsatz an bisecting N-Acetylglucosaminen und induzierte starke Antikörper-abhängige zelluläre Zytotoxizität. Der in Sf21 Zellen exprimierte chimäre CD19 Antikörper mit paucimannosidischen Oligosacchariden, vermittelte sehr effizient Lyse sowohl von Zelllinien als auch primären Blasten pädiatrischer Leukämie-Patienten. Die Lyse-Raten waren vergleichbar mit dem glykosylierungsmodifizierten chimären CD19 Antikörper. Darüber hinaus verlängerte eine Behandlung mit dem Insektenzell-produzierten chimären CD19 Antikörper das Überleben von NOD/Scid Mäusen, welche mit humanen Nalm-6 Leukämiezellen transplantiert wurden, signifikant. Die selektive Induktion von Apoptose über den tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) stellt einen viel versprechenden Ansatz zur Eliminierung von Krebszellen dar. Das pro-apoptotische Potential eines neuen TRAIL Fusionsproteins, bestehend aus einem CD19-spezifischen single-chain Fv Antikörper-Fragment und der löslichen extrazellulären Domäne von TRAIL (sTRAIL), wurde untersucht. ScFvCD19:sTRAIL induzierte potente Apoptose von CD19-positiven Leukämie Zelllinien und primären Zellen von Patienten mit akuter B-lymphoblastischer und chronischer B-lymphozytischer Leukämie. Hohe synergistische Apoptoseraten wurden durch gleichzeitige Behandlung von Zelllinien und primären B-CLL Zellen mit scFvCD19:sTRAIL und Valproinsäure oder CyclosporinA erzielt. Des Weiteren verhinderte scFvCD19:sTRAIL auch das Anwachsen von Nalm-6 Zellen in Mäusen. Die Resultate verdeutlichen, dass eine effiziente Eliminierung von Leukämiezellen über CD19 durch Induktion von Apoptose mittels scFvCD19:sTRAIL oder über chimäre CD19 Antikörper möglich ist. Dabei ist das zytolytische Potential der chimären CD19 Antikörper stark vom Expressionssystem und den dadurch an die Fc-Region angefügten N-Glykanen abhängig. Folglich ist es gerechtfertigt, CD19-gerichtete Antikörper-basierte Therapeutika im Hinblick auf eine mögliche klinische Anwendung weiterhin zu studieren.Treatment outcome of lymphoid malignancies has improved in recent years by optimization of transplantation and the introduction of antibody-based therapeutics. Nevertheless, relapse remains a major problem. Therefore, new therapeutic options are urgently needed. Whole antibodies directed against CD19 on B-lymphoid cells have proven to efficiently eliminate primary B-cell precoursor ALL cells via NK-cell mediated lysis. N-linked oligosaccharides of the IgG heavy chain are known to influence the cytolytic potential of antibodies. A chimeric CD19 antibody was expressed in Sf21 insect cells, human 293T cells and glycosylation-engineered 293T cells, all expected to attach different oligosaccharides to the Fc region. The N-glycan structures and the cytolytic potential of the three distinct chimeric CD19 antibody variants were directly com-pared. The cytolytic potential of the chimeric antibody produced in human cells was only minimal, despite a glycosylation-pattern comparable to human serum IgG. In contrast, the glyco-engineered antibody, carrying a high percentage of bisecting N-acetylglucosamine, induced strong antibody-dependent cellular cytotoxicity. The Sf21 expressed antibody, with N-glycans of the paucimannosidic type, triggered highly efficient lysis of cell lines and primary blasts from pediatric leukemia patients. In conclusion, the cytotolytic potential of the chimeric CD19 antibody from insect cells was comparable to the lytic activity of the glyco-engineered chimeric CD19 antibody. Moreover, treatment with the insect cell produced chimeric CD19 antibody prolonged survival of NOD/Scid mice transplanted with human Nalm-6 leukemia cells. One promising approach to eliminate cancer cells is the selective induction of apoptosis by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The pro-apoptotic potential of a novel TRAIL fusion protein designated scFvCD19:sTRAIL, consisting of a CD19-specific single-chain Fv antibody fragment fused to the soluble extracellular domain of TRAIL (sTRAIL), was investigated. ScFvCD19:sTRAIL induced potent apoptosis in CD19-positive leukemia cell lines and primary acute B-lymphoblastic and chronic B-lymphocytic leukemia cells. Simul-taneous treatment with scFvCD19:sTRAIL and valproic acid or CyclosporinA caused strongly synergistic apoptosis both in cell lines and primary B-CLL cells. In addition, scFvCD19:sTRAIL prevented engraftment of Nalm-6 cells in mice. The data presented here demonstrate that leukemic cells can be efficiently elimi-nated by targeting CD19 with the potent apoptosis inducing agent scFvCD19:sTRAIL and chimeric CD19 antibodies. Thereby the cytolytic potential of CD19 antibodies is strongly dependent on the N-glycan attached to the Fc region by the respective expression cell lines. Thus, further investigation of CD19-directed antibody-based therapeutics for potential clinical application in leukemia is warranted

Concepts in immuno-oncology: tackling B cell malignancies with CD19-directed bispecific T cell engager therapies

The B cell surface antigen CD19 is a target for treating B cell malignancies, such as B cell precursor acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma. The BiTE® immuno-oncology platform includes blinatumomab, which is approved for relapsed/refractory B cell precursor acute lymphoblastic leukemia and B cell precursor acute lymphoblastic leukemia with minimal residual disease. Blinatumomab is also being evaluated in combination with other agents (tyrosine kinase inhibitors, checkpoint inhibitors, and chemotherapy) in various treatment settings, including frontline protocols. An extended half-life BiTE molecule is also under investigation. Patients receiving blinatumomab may experience cytokine release syndrome and neurotoxicity; however, these events may be less frequent and severe than in patients receiving other CD19-targeted immunotherapies, such as chimeric antigen receptor T cell therapy. We review BiTE technology for treating malignancies that express CD19, analyzing the benefits and limitations of this bispecific T cell engager platform from clinical experience with blinatumomab

Concepts in immuno-oncology: tackling B cell malignancies with CD19-directed bispecific T cell engager therapies

The B cell surface antigen CD19 is a target for treating B cell malignancies, such as B cell precursor acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma. The BiTE® immuno-oncology platform includes blinatumomab, which is approved for relapsed/refractory B cell precursor acute lymphoblastic leukemia and B cell precursor acute lymphoblastic leukemia with minimal residual disease. Blinatumomab is also being evaluated in combination with other agents (tyrosine kinase inhibitors, checkpoint inhibitors, and chemotherapy) in various treatment settings, including frontline protocols. An extended half-life BiTE molecule is also under investigation. Patients receiving blinatumomab may experience cytokine release syndrome and neurotoxicity; however, these events may be less frequent and severe than in patients receiving other CD19-targeted immunotherapies, such as chimeric antigen receptor T cell therapy. We review BiTE technology for treating malignancies that express CD19, analyzing the benefits and limitations of this bispecific T cell engager platform from clinical experience with blinatumomab

STEAP1&ndash;4 (Six-Transmembrane Epithelial Antigen of the Prostate 1&ndash;4) and Their Clinical Implications for Prostate Cancer

Six-Transmembrane Epithelial Antigen of the Prostate 1&ndash;4 (STEAP1&ndash;4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed, while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1&ndash;4 are well documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1&ndash;4 as potential biomarkers and therapeutic targets for prostate cancer. In particular, STEAP1 is the target of many emerging immunotherapies. Herein, we give an overview of the structure, physiology, and pathophysiology of STEAP1&ndash;4 to provide context for past and current efforts to translate STEAP1&ndash;4 into the clinic

Long-term outcomes after blinatumomab treatment: follow-up of a phase 2 study in patients (pts) with minimal residual disease (MRD) positive B-cell precursor acute lymphoblastic leukemia (ALL).

Introduction. MRD in ALL is defined as detection of leukemic cells in bone marrow by polymerase chain reaction (PCR) or flow cytometry with hematologic complete remission (CR). Pts with persistent/recurrent MRD after first-line induction therapy have a higher risk of relapse than those with complete MRD response (no detectable MRD with minimum sensitivity 0.01%). Interventions, including hematopoietic stem cell transplantation (HSCT), are used to improve the outcome of these pts. Blinatumomab, a bispecific T cell engager (BiTE\uae) antibody construct, redirects CD3+ T cells to CD19+ target cells, resulting in serial lysis of CD19+ B cells. In a multicenter, international phase 2 study in MRD+ ALL (Goekbuget N et al. Blood 2014;124:379), blinatumomab resulted in complete MRD response in cycle 1 in 78% of pts including multiple subgroups such as pts in second-line treatment, those with high MRD burden, and older pts. No subgroups with higher MRD complete response rates were identified. This analysis evaluated long-term outcomes, including overall survival (OS), relapse-free survival (RFS), and duration of remission (DOR). Methods. Adults ( 6518 years) with B-cell precursor ALL with hematologic CR (<5% blasts in bone marrow) and MRD 6510-3 after 653 intensive chemotherapy treatments were eligible. Pts with CNS pathology or extramedullary disease, previous allogeneic HSCT, or Philadelphia-chromosome positive (Ph+) ALL eligible for tyrosine kinase inhibitors were excluded. Blinatumomab 15 \ub5g/m\ub2/day was given by continuous IV infusion for 4 weeks, followed by a 2-week break (1 cycle). MRD was measured by a central laboratory using PCR per EuroMRD guidelines. MRD responders in cycle 1 received up to 3 additional cycles or underwent HSCT. Pts with hematologic relapse discontinued treatment. We report here preliminary follow-up data as of 1 July 2015. Final data from the preplanned 18-mo follow-up analysis will be available for the meeting. Results. 116 pts enrolled and received blinatumomab. Median age was 45 years (range 18\u201376); 15 (13%) pts were age 6565 years. 90 (78%) pts received HSCT after blinatumomab. 62 (53%) pts were still being followed. 35 pts relapsed and 26 pts died in CR (23 of them after subsequent HSCT). Median OS, with median follow-up of 29.5 mo, was 36.5 mo (95% CI, 19.1 mo to not reached [n.r.]): 40.4 vs 12.0 (P=.001) in pts with (n=88) or without (n=24) MRD complete response in cycle 1. 110 pts were evaluable (CR at study entry, Ph-) for RFS and DOR. Median RFS was 18.9 mo (95% CI, 12.3 to 35.2 mo): 24.6 vs 11.0 (P=0.005) in pts treated in first (n=75) vs later (n=35) remission; and 35.2 vs 7.1 (P=0.002) in pts alive and relapse-free after 45 days with (n=85) or without (n=15) MRD complete response in cycle 1 (Figure). Median DOR was n.r. (95% CI, 24.6 mo to n.r.): n.r. vs 15.0 mo (P=0.002) in pts treated in first vs later remission; and n.r. vs 15.0 mo (P=0.015) in pts with DOR 65 45 days with (n=85) or without (n=13) MRD complete response in cycle 1. In time-dependent Cox model analyses, HSCT vs no HSCT were not different for OS (hazard ratio [HR], 1.39; 95% CI, 0.68 to 2.82; P=0.368) or RFS (HR, 0.89; 95% CI, 0.47 to 1.69; P=0.730); DOR (treating death as a competing risk) was longer for HSCT vs no HSCT (HR, 0.36; 95% CI, 0.17 to 0.77; P=0.008). All pts experienced at least one AE. The most clinically relevant were neurologic events, including tremor (30%), aphasia (13%) dizziness (8%), ataxia and paraesthesia (6% each), and encephalopathy (5%). Rates decreased over time (cycles 1, 2, 3, and 4) for any neurologic event (47%, 24%, 15%, and 15%) and any grade 653 neurologic event (10%, 4%, 0%, and 0%). 12 (10%) pts interrupted treatment due to grade 653 neurologic events: 5 resumed without another interruption and 2 resumed then stopped treatment for another neurologic event. Investigators reported 4 deaths as fatal AEs during follow-up (brain injury, disease progression, gastrointestinal hemorrhage, and multiorgan failure); all 4 pts received HSCT after blinatumomab. Conclusion. In this long-term follow-up analysis of the first large prospective trial with an experimental compound in MRD+ ALL, MRD complete response induced by single-agent blinatumomab treatment was associated with longer OS, RFS, and DOR compared with not achieving an MRD complete response after blinatumomab treatment. This strengthens the current strategy of MRD-based treatment in ALL before occurrence of clinical relapse

Superior activity of fusion protein scFvRit:sFasL over cotreatment with rituximab and Fas agonists

The clinical efficacy of the CD20-specific chimeric monoclonal antibody rituximab is significantly hampered by intrinsic or acquired resistance to therapy. Rituximab activates antibody-dependent cellular cytotoxicity/complement-dependent cytotoxicity-dependent lysis but also induces apoptosis by cross-linking of its target antigen CD20. Recent reports indicate that this apoptotic activity of rituximab can be synergized by cotreatment with Fas agonists. Here, we report on a strategy designed to exploit and optimize the synergy between rituximab and Fas signaling by genetically fusing a rituximab-derived antibody fragment to soluble Fas ligand (sFaSL). The resultant fusion protein, designated scFvRit:sFasL, potently induced CD20-restricted apoptosis in a panel of malignant B-cell lines (10 of 11) and primary patient-derived malignant B cells (two of two non-Hodgkin lymphoma and five of six B cell chronic lymphocytic leukemia). ScFvRit:sFasL efficiently activated CD20 and Fas apoptotic signaling, resulting in a far superior proapoptotic activity compared with cotreatment with rituximab and Fas agonists. ScFvRit:sFasL lacked activity toward normal human B cells and also lacked systemic toxicity in nude mice with no elevation of aspartate aminotransferase and alanine aminotransferase levels or liver caspase-3 activity. In conclusion, scFvRit:sFasL efficiently activates CD20 and Fas-apoptotic signaling and may be useful for the elimination of malignant B cells