Citations

AbstractRichter syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL), typically to an aggressive lymphoma. Treatment options for RS are limited and the disease is often fatal. Receptor tyrosine kinase–like orphan receptor 1 (ROR1) is expressed on CLL cells and other cancers but not on healthy adult tissues, making it an attractive, tumor-specific therapeutic target. VLS-101 is being developed as an antibody-drug conjugate (ADC) for therapy of ROR1-expressing (ROR1+) cancers. VLS-101 comprises UC-961 (a humanized immunoglobulin G1 monoclonal antibody that binds an extracellular epitope of human ROR1), a maleimidocaproyl-valine-citrulline-para-aminobenzoate linker, and the antimicrotubule cytotoxin monomethyl auristatin E (MMAE). VLS-101 binding to ROR1 results in rapid cellular internalization and delivery of MMAE to induce tumor cell death. We studied 4 RS patient-derived xenografts (RS-PDXs) with varying levels of ROR1 expression (11%, 32%, 85%, and 99% of cells). VLS-101 showed no efficacy in the lowest-expressing RS-PDX but induced complete remissions in those with higher levels of ROR1 expression. Responses were maintained during the posttherapy period, particularly after higher VLS-101 doses. In systemic ROR1+ RS-PDXs, VLS-101 dramatically decreased tumor burden in all RS-colonized tissues and significantly prolonged survival. Animals showed no adverse effects or weight loss. Our results confirm ROR1 as a target in RS and demonstrate the therapeutic potential of using an ADC directed toward ROR1 for the treatment of hematological cancers. A phase 1 clinical trial of VLS-101 (NCT03833180) is ongoing in patients with RS and other hematological malignancies.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

Background: Nonrheumatic valvular diseases are common; however, no studies have estimated their global or national burden. As part of the Global Burden of Disease Study 2017, mortality, prevalence, and disability-adjusted life-years (DALYs) for calcific aortic valve disease (CAVD), degenerative mitral valve disease, and other nonrheumatic valvular diseases were estimated for 195 countries and territories from 1990 to 2017. Methods: Vital registration data, epidemiologic survey data, and administrative hospital data were used to estimate disease burden using the Global Burden of Disease Study modeling framework, which ensures comparability across locations. Geospatial statistical methods were used to estimate disease for all countries, because data on nonrheumatic valvular diseases are extremely limited for some regions of the world, such as Sub-Saharan Africa and South Asia. Results accounted for estimated level of disease severity as well as the estimated availability of valve repair or replacement procedures. DALYs and other measures of health-related burden were generated for both sexes and each 5-year age group, location, and year from 1990 to 2017. Results: Globally, CAVD and degenerative mitral valve disease caused 102 700 (95% uncertainty interval [UI], 82 700–107 900) and 35 700 (95% UI, 30 500–42 500) deaths, and 12.6 million (95% UI, 11.4 million–13.8 million) and 18.1 million (95% UI, 17.6 million–18.6 million) prevalent cases existed in 2017, respectively. A total of 2.5 million (95% UI, 2.3 million–2.8 million) DALYs were estimated as caused by nonrheumatic valvular diseases globally, representing 0.10% (95% UI, 0.09%–0.11%) of total lost health from all diseases in 2017. The number of DALYs increased for CAVD and degenerative mitral valve disease between 1990 and 2017 by 101% (95% UI, 79%–117%) and 35% (95% UI, 23%–47%), respectively. There is significant geographic variation in the prevalence, mortality rate, and overall burden of these diseases, with highest age-standardized DALY rates of CAVD estimated for high-income countries. Conclusions: These global and national estimates demonstrate that CAVD and degenerative mitral valve disease are important causes of disease burden among older adults. Efforts to clarify modifiable risk factors and improve access to valve interventions are necessary if progress is to be made toward reducing, and eventually eliminating, the burden of these highly treatable diseases.

Background The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Methods Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm—the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. Results For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. Conclusions The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum.

Background The Global Burden of Disease Study (GBD) has historically produced estimates of causes of injury such as falls but not the resulting types of injuries that occur. The objective of this study was to estimate the global incidence, prevalence and years lived with disability (YLDs) due to facial fractures and to estimate the leading injurious causes of facial fracture. Methods We obtained results from GBD 2017. First, the study estimated the incidence from each injury cause (eg, falls), and then the proportion of each cause that would result in facial fracture being the most disabling injury. Incidence, prevalence and YLDs of facial fractures are then calculated across causes. Results Globally, in 2017, there were 7 538 663 (95% uncertainty interval 6 116 489 to 9 493 113) new cases, 1 819 732 (1 609 419 to 2 091 618) prevalent cases, and 117 402 (73 266 to 169 689) YLDs due to facial fractures. In terms of age-standardised incidence, prevalence and YLDs, the global rates were 98 (80 to 123) per 100 000, 23 (20 to 27) per 100 000, and 2 (1 to 2) per 100 000, respectively. Facial fractures were most concentrated in Central Europe. Falls were the predominant cause in most regions. Conclusions Facial fractures are predominantly caused by falls and occur worldwide. Healthcare systems and public health agencies should investigate methods of all injury prevention. It is important for healthcare systems in every part of the world to ensure access to treatment resources.

Background Past research has shown how fires, heat and hot substances are important causes of health loss globally. Detailed estimates of the morbidity and mortality from these injuries could help drive preventative measures and improved access to care. Methods We used the Global Burden of Disease 2017 framework to produce three main results. First, we produced results on incidence, prevalence, years lived with disability, deaths, years of life lost and disability-adjusted life years from 1990 to 2017 for 195 countries and territories. Second, we analysed these results to measure mortality-to-incidence ratios by location. Third, we reported the measures above in terms of the cause of fire, heat and hot substances and the types of bodily injuries that result. Results Globally, there were 8 991 468 (7 481 218 to 10 740 897) new fire, heat and hot substance injuries in 2017 with 120 632 (101 630 to 129 383) deaths. At the global level, the age-standardised mortality caused by fire, heat and hot substances significantly declined from 1990 to 2017, but regionally there was variability in age-standardised incidence with some regions experiencing an increase (eg, Southern Latin America) and others experiencing a significant decrease (eg, High-income North America). Conclusions The incidence and mortality of injuries that result from fire, heat and hot substances affect every region of the world but are most concentrated in middle and lower income areas. More resources should be invested in measuring these injuries as well as in improving infrastructure, advancing safety measures and ensuring access to care.

ROR1 is a transmembrane receptor with tightly controlled expression during development. It is present on multiple tumor types but not on normal adult tissues. Hematological malignancies are often ROR1-positive, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B cell lymphoma (DLBCL). Given its unique pattern of expression, ROR1 represents a tumor-specific therapeutic target. The anti-ROR1 antibody, UC-961, is ahumanized IgG1 monoclonal antibody (mAb) that binds with high affinity to a specific extracellular epitope of human ROR1 receptor and can block Wnt5a-induced ROR1 signaling. Nonclinical studies document that UC-961 does not react with normal adult human tissues and selectively binds to tumor cells. Because of the antibody high specificity, rapid internalization, and trafficking to lysosomes, UC-961 appears ideally suited to serve as the targeting moiety for an anti-ROR1 ADC. Accordingly, we have developed VLS-101, a UC-961-linker-monomethyl auristatin E (MMAE) ADC that preserves the high-affinity binding and specificity of UC-961 and allows for ROR1-targeted intracellular release of MMAE. RS is an aggressive lymphoma, typically of DLBCL type, arising as transformation of CLL. Despite, progressive improvements in the therapy of CLL, very few effective treatment options exist for patients with RS. Using our recently established RS patient-derived xenografts (RS-PDXs), we explored the expression and signaling properties of ROR1 in RS and investigated the ex-vivo and in vivo effects of VLS-101. When assessed by flow cytometry (FACS), immunohistochemistry (IHC), and reverse-transcriptase-polymerase chain reaction (RT-PCR), 3 of 4 RS-PDXs showed ROR1 positivity (2 highly positive: 99% and 80% of cells; 1 medium/low positive: 25% of cells by FACS). The extent of ROR1 expression correlated among the 3 assays methods and was consistent with ROR1 expression data reported for non-RS DLBCL samples. When engaged by its ligand Wnt-5a, ROR1 activated downstream targets, Rac1 and RhoA, and induced phosphorylation of the p65 subunit of NF-kB and Jnk in RS cells. When cells purified from RS-PDX tumor masses were exposed to VLS-101 ex-vivo, the drug induced time- and dose-dependent apoptosis, as shown by increases in annexin V/propidium iodide and by Caspase-3 and PARP cleavage. VLS-101 efficacy was then assessed in vivo in both subcutaneous and systemic RS-PDX models. When palpable masses had formed in subcutaneous models, mice were randomly assigned to vehicle or VLS-101, bi-weekly treated for 3 consecutive weeks, and then compared for tumor growth and survival. In the 3 ROR1-expressing RS-PDX models, VLS-101 caused highly significant disease regressions. Complete regressions were observed even in RS-PDXs without universal ROR1 expression, suggesting a MMAE bystander effect. After treatment discontinuation, VLS-101-treated animals showed no tumor regrowth for several months and had significantly extended survival. Data were confirmed in systemic ROR1-expressing RS models in which tumor cells were intravenously injected and allowed to engraft for ~14 days before starting treatment. VLS-101 was administered with the same schedule adopted for the subcutaneous model. VLS-101 eliminated RS cells in bone marrow, peripheral blood, and spleen, increasing survival in VLS-101-treated animals relative to controls (approximately 20-50 days, depending on the RS-PDX model). Of note, no in vivo VLS-101 efficacy was observed in the ROR1-negative RS-PDX, confirming the specificity of VLS-101 targeting. VLS-101 showed no adverse effects on animal well-being or body weight. Collectively, these results indicate that ROR1 is expressed on RS cells where it can transduce pro-survival signals and can be diagnostically evaluated for selective targeting. Nonclinical data document that the MMAE-containing ADC, VLS-101, can cause RS-PDX apoptosis in vitro and can safely and selectively induce complete tumor regressions in in vivo models of RS derived from patient tumors with heavy prior clinical treatment and variable levels of ROR1 expression. Building on these types of results, a Phase 1 clinical trial of VLS-101 (NCT03833180) is ongoing in patients with lymphoid cancers. Disclosures Vaisitti: VelosBio Inc.: Research Funding; Verastem Inc: Research Funding. Jessen:VelosBio Inc.: Employment. Vo:VelosBio Inc: Employment. Ko:VelosBio Inc: Employment. Allan:Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Acerta Pharma: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Bayer: Consultancy. Furman:Acerta Pharma: Consultancy; Pharmacyclics: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Oncotracker: Consultancy; Verastem: Consultancy; Abbvie: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy. Miller:VelosBio Inc.: Employment. Lanutti:VelosBio Inc.: Employment. Deaglio:iTeos Therapeutics: Research Funding; Verastem Inc: Research Funding; VelosBio Inc.: Research Funding. OffLabel Disclosure: The drug used in this project is an anti-ROR1-toxin-conjugated antibody