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

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

STEAP1–4 (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

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

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

OBJECTIVES: 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 &lt;10-1, 10-3 to &lt;10-2, and 10-4 to &lt;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 &lt;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

Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study

ABSTRACT : Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with premedication and step dosing. Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging [49% PSA50; 24% objective response rate (ORR)], with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Xaluritamig is a novel immunotherapy for prostate cancer that has shown encouraging results supporting further development. SIGNIFICANCE : Xaluritamig demonstrated encouraging responses (PSA and RECIST) compared with historical established treatments for patients with late-line mCRPC. This study provides proof of concept for T-cell engagers as a potential treatment for prostate cancer, validates STEAP1 as a target, and supports further clinical investigation of xaluritamig in prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Nolan-Stevaux et al., p. 90. This article is featured in Selected Articles from This Issue, p. 5