Among violence prevention educators and researchers, there is growing interest in sexual, dating, and intimate partner violence (SV/DV/IPV) prevention programs for males because of evidence showing ...that boys and men are more likely than girls and women to perpetrate SV as well as more severe forms of DV/IPV. To date, comprehensive guidance on the content, structure, delivery, and effectiveness of such programs is limited. We reviewed randomized controlled studies that evaluated SV/DV/IPV perpetration prevention programs for boys and men. Searches yielded 5,249 potential documents for review of which 10 met inclusion criteria—representing 9 unique studies of 7 distinct programs. Two reviewers independently reviewed and abstracted data from these studies regarding program setting and target audience; type of violence addressed; number and length of program sessions; program duration, topics, activities, and delivery mode; and implementer details. Study characteristics were also examined (sample size, participant characteristics, recruitment, randomization, comparison/control condition, data collection protocols, attrition, measures of violence perpetration, and perpetration findings). The Cochrane Risk of Bias Tool was used to assess study design quality. Results show considerable heterogeneity among program content and delivery strategies, study designs, and outcome measurement. Study sample size ranged widely, and most used cluster-randomized designs, recruited undergraduate college students, and evaluated a multisession program delivered via group sessions. Only one program reduced men’s self-reported SV perpetration. Accordingly, critical gaps exist around “what works” for SV/DV/IPV perpetration prevention programs for boys and men.
There is an increased call for research on promising prevention programs already embedded in communities (“homegrown interventions”). Unfortunately, there is limited guidance to help researchers ...prepare these types of interventions for rigorous evaluation. To address this need, this article presents our team’s process for revising a promising community-based sexual violence prevention intervention for rigorous research. Our extensive and iterative process of reviewing and revising the intervention was guided by evaluability assessment (EA) approaches, implementation science, and a close collaboration with our community partners. Our EA process allowed us to specify the intervention’s core components and develop a “research ready” standardized curriculum with implementation fidelity assessments. We offer four lessons learned from our process: (1) even with existing materials and an extensive history of community-based delivery, community-developed programs are not necessarily research-ready; (2) close collaboration and a trusting relationship between researchers and community partners throughout the revision process ensures the integrity of core program components are maintained and implementation in diverse community settings is feasible; (3) observations of program implementation are a crucial part of the revision process; and (4) it is important to budget adequate time and resources for such revisions.
Objective:This study examined correlates of use of outpatient and inpatient mental health services and psychotropic medication in a large, nationally representative sample of young adults ages 18–26 ...with mental illness (N=22,600).Methods:Data were from the 2008–2012 National Survey on Drug Use and Health, an annual nationally representative survey of the civilian, noninstitutionalized U.S. population. Separate logistic regression models examined past-year use of three mental health service types (outpatient services, inpatient services, and psychotropic medication). Correlates included demographic characteristics, factors developmentally relevant to young adults, and general medical and mental health status.Results:Within this sample of young adults with mental illness, 20.4% used outpatient services, 3.6% used inpatient services, and 25.4% used psychotropic medication. Variables associated with use of one or more types of mental health services included being female (outpatient and medication), one to two moves in the past year (medication), having health insurance (all types), past-year criminal justice involvement (all types), poor health (inpatient and medication), substance use disorders (inpatient and medication), and mental illness with severe impairment (all types). Non-Hispanic blacks, Asians, and Hispanics were less likely than non-Hispanic whites to receive outpatient mental health services or psychotropic medications. Surprisingly, young adults employed full-time were less likely than those who were unemployed to receive services, and living with a partner (versus living alone) was not associated with a likelihood of using outpatient services.Conclusions:Results support the unique nature of young adulthood and the need to tailor mental health services to close gaps in service use during this developmental period.
Racialized mass incarceration is associated with racial/ethnic disparities in HIV and other sexually transmitted infections (STIs) in the US. The purpose of this longitudinal qualitative study was to ...learn about the processes through which partner incarceration affects African-American women’s sexual risk. Four waves of in-depth qualitative interviews were conducted in 2010–2011 with 30 women in Atlanta, Georgia (US) who had recently incarcerated partners. Approximately half the sample misused substances at baseline. Transcripts were analyzed using grounded theory. For over half the sample (
N
= 19), partner incarceration resulted in destitution, and half of this group (
N
= 9) developed new partnerships to secure shelter or food; most misused substances. Other women (
N
= 9) initiated casual relationships to meet emotional or sexual needs. When considered with past research, these findings suggest that reducing incarceration rates among African-American men may reduce HIV/STIs among African-American women, particularly among substance-misusing women, as might rapidly linking women with recently incarcerated partners to housing and economic support and drug treatment.
This NIH-funded longitudinal qualitative study explored pathways through which partner incarceration affected substance misuse among African American women. Four waves of semi-structured interviews ...were conducted with 17 substance-misusing African American women whose partners had recently been incarcerated. Data were collected in Atlanta, Georgia, during 2010-2011. Transcripts were analyzed using grounded theory methods. Analyses suggest that partner incarceration initially precipitated multiple crises in women's lives (e.g., homelessness); over time, and with formal and informal support, women got their lives "back on track." Substance misuse declined over time, though spiked for some women during the crisis period. We discuss implications for research and interventions.
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DOBA, FSPLJ, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Overexpression of CD74, a type II transmembrane glycoprotein involved in MHC class II antigen presentation, has been reported in many B-cell non-Hodgkin lymphomas (NHLs) and in multiple myeloma (MM). ...STRO-001 is a site-specific, predominantly single-species antibody-drug conjugate (ADC) that targets CD74 and has demonstrated efficacy in xenograft models of MM and tolerability in non-human primates. Here we report results of preclinical studies designed to elucidate the potential role of STRO-001 in B-cell NHL. STRO-001 displayed nanomolar and sub-nanomolar cytotoxicity in 88% (15/17) of cancer cell lines tested. STRO-001 showed potent cytotoxicity on proliferating B cells while limited cytotoxicity was observed on naïve human B cells. A linear dose-response relationship was demonstrated
for DLBCL models SU-DHL-6 and U2932. Tumor regression was induced at doses less than 5 mg/kg, while maximal activity with complete cures were observed starting at 10 mg/kg. In MCL Mino and Jeko-1 xenografts, STRO-001 starting at 3 mg/kg significantly prolonged survival or induced tumor regression, respectively, leading to tumor eradication in both models. In summary, high CD74 expression levels in tumors, nanomolar cellular potency, and significant anti-tumor in DLBCL and MCL xenograft models support the ongoing clinical study of STRO-001 in patients with B-cell NHL.
STRO-001 is a site-specific, predominantly single-species, fully human, aglycosylated anti-CD74 antibody-drug conjugate incorporating a non-cleavable linker-maytansinoid warhead with a drug-antibody ...ratio of 2 which was produced by a novel cell-free antibody synthesis platform. We examined the potential pharmacodynamics and anti-tumor effects of STRO-001 in multiple myeloma (MM). CD74 expression was assessed in MM cell lines and primary bone marrow (BM) MM biopsies. CD74 mRNA was detectable in CD138+ enriched plasma cells from 100% (892/892) of patients with newly diagnosed MM. Immunohistochemistry confirmed CD74 expression in 35/36 BM biopsies from patients with newly diagnosed and relapsed/refractory MM. Cytotoxicity assays demonstrated nanomolar STRO-001 potency in 4/6 MM cell lines. In ARP-1 and MM.1S tumor-bearing mice, repeat STRO-001 dosing provided significant antitumor activity with eradication of malignant hCD138+ BM plasma cells and prolonged survival. In a luciferase-expressing MM.1S xenograft model, dose-dependent STRO-001 efficacy was confirmed using bioluminescent imaging and BM tumor burden quantification. Consistent with the intended pharmacodynamic effect, STRO-001 induced dose-responsive, reversible B-cell and monocyte depletion in cynomolgus monkeys, up to a maximum tolerated 10 mg/kg, with no evidence of off-target toxicity. Collectively, these data suggest that STRO-001 is a promising therapeutic agent for the treatment of MM.
Abstract
There is growing evidence that tumor-targeted cytotoxins can also enhance anti-tumor immunity by inducing immunogenic cell death (ICD) in tumor cells and promoting recruitment of immune ...effector cells. We sought to investigate the immune stimulating potential of STRO-002, an antibody drug conjugate (ADC) composed of an anti-Folate receptor alpha (FolRα) antibody conjugated to a tubulin-targeting hemiasterlin warhead via a cleavable linker. FolRα is a single chain glycosylphosphatidylinositol-anchored membrane receptor glycoprotein with minimal expression in normal tissues. Its overexpression in several cancer indications has been described, including in ovarian, endometrial, non-small cell lung carcinoma (NSCLC), and triple negative breast cancer (TNBC), thus making it an ideal ADC target. We have previously demonstrated potent in vitro and in vivo activity of STRO-002 in several FolRα expressing models. Here we show that the hemiasterlin warhead, SC209, and STRO-002 ADC induced ICD in vitro as evidenced by presentation of cell-surface calreticulin and release of HMGB1 and ATP. As a result of ICD, STRO-002 treated FolRα positive cancer cells induced antigen-dependent monocyte activation, as well as, increased phagocytic activity in PBMCs co-cultured with tumor cells. To determine if these immunogenic properties could improve therapeutic efficacy, we evaluated STRO-002 in combination with the immune checkpoint inhibitor Avelumab (anti-PD-L1) in a mouse syngeneic MC38 model engineered to express human FolRα (MC38-hFolRα). Results showed that STRO-002 and Avelumab alone inhibited tumor growth and could induce complete responses (e.g. no palpable tumors) at low frequency (< 15%), while co-administration of STRO-002 and Avelumab significantly enhanced efficacy leading to complete response in the majority of animals. Furthermore, when animals that initially achieved complete response were re-challenged with MC38-hFolRα cells, they showed durable anti-tumor immunity, indicating formation of immunological memory. Immunohistochemical analysis conducted seven days after treatment revealed a significant increase in tumor-infiltrating cytotoxic CD8+ T cells in animals treated with combination of STRO-002 + Avelumab versus either monotherapy. Cumulatively, these results suggest that STRO-002 synergizes with Avelumab to enhance anti-tumor response by inducing ICD in tumor cells, which in turn, promote T cell recruitment. These data support the rationale for combining STRO-002 with immune checkpoint inhibitors to potentially enhance their clinical efficacy.
Citation Format: Millicent Embry, Sihong Zhou, Christine Cheng, Janice Yu, Cristina L. Abrahams, Xioafan Li, Jeff Hanson, Cuong Tran, Gang Yin, Shamim Ahmad, Krishna Bajjuri, Venita DeAlmeida, Mark Lupher, Trevor Hallam. STRO-002, an anti-FolRαADC, demonstrates immune-modulating properties and potentiates PD-L1 blockade abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2250.
CD74 is a transmembrane glycoprotein involved in MHC II protein formation and transport. STRO-001 is a novel antibody drug conjugate (ADC) comprised of a human aglycosylated anti-CD74 IgG1 antibody ...(SP7219) genetically incorporating the non-natural amino acid para-azidomethy-L-phenyalanine (pAMF) to enable the site-specific conjugation of a non-cleavable maytansinoid linker-warhead. Highly efficient and precise site-specific conjugation enabled by Sutro's cell-free antibody synthesis technology produced a well-defined homogeneous ADC with a drug-antibody ratio (DAR) of 2. Conjugation sites were selected based on the highest in vitro and in vivo stability.
Biotinylated SP7219 was used for immunohistochemistry (IHC). Bone marrow (BM) biopsy samples from patients with multiple myeloma (MM) from the UCSF Dept. of Laboratory Medicine were used after appropriate permissions were obtained. CD74 expression in plasma cells was measured as follows: 0, no staining; 1+, weak staining; 2+, moderate staining; 3+, strong staining (Figure 1A). Plasma cells were identified based on morphology and paired CD138+ staining. Two pathologists blinded to the patient's clinical history and pathology results independently reviewed IHC specimens. SP7219 conjugated to a fluorescent dye (DBCO-Alexa647) was used for detection and quantitation of CD74 expression on MM cell lines. STRO-001 was used to determine the EC50 and the proportion of MM cells killed (span killing) in an in vitro viability assay. The anti-tumor activity of STRO-001 was evaluated in the disseminated ARP-1 and MM.1S MM models. In vivo bioluminescence imaging (BLI) for animals bearing luciferase-expressing MM.1s (MM.1s-luc) cells was performed using an IVIS Spectrum. BLI images were collected 7, 14, 21, and 28 days post-tumor cell inoculation.
Overall, CD74 expression levels were not significantly different between newly diagnosed MM (n=13) and relapsed or refractory MM (n=24) (Figure 1B). Of 37 total samples analyzed, only 1 sample lacked detectable CD74 and the majority (67%) of relapsed/refractory patients expressed CD74 levels higher than 1+ by IHC (Figure 1C). In vitro cytotoxicity assays show nanomolar potency of STRO-001 in five MM cell lines: MC/CAR (EC50 0.8 nM), ARD (EC50 ~7.0 nM), MM.1S (EC50 10-11 nM), U266B1 (EC50 8.5-9.3 nM), and ARP-1 (EC50 4.3-22 nM). CD74 cell surface expression is required for STRO-001 cytotoxic activity but expression level, measured by antibody-binding capacity, does not correlate strongly with in vitro potency (R2=0.5837 for MM cell lines). STRO-001 inhibits the growth of CD138+ plasma cells in BM and formation of visceral tumors (p=0.002 for kidney; p<0.0001 for ovary) after 4 weekly doses of 3 mg/kg in the ARP-1 disseminated MM xenograft model in severe combined immune deficient (SCID) mice. STRO-001 dosed at 3 mg/kg and 10 mg/kg weekly x 3 also eradicates malignant BM plasma cells by day 32 post-inoculation (p<0.0001) and prolongs survival in the MM.1S disseminated model in NOD SCID gamma (NSG) mice. At termination of the study, 129 days post-inoculation, 100% of the STRO-001 treated animals survived and showed no evidence of disease with no CD138+ cells in their BM, while mean survival of control animals was 35 days with almost 50% of their BM containing myeloma cells. Additionally, BLI enabled noninvasive quantitation of tumor burden in MM.1S-luc-bearing NSG mice. Single doses of 1, 3, and 10 mg/kg STRO-001 (administered on day 7 post-inoculation) resulted in eradication of myeloma by day 28 based on BLI (Figure 2A and 2B) and quantification of CD138+ cells in BM (p<.0001) (Figure 2C).
CD74 expression was detected in most MM samples examined in this study. Expression is heterogeneous and observed in treatment-naïve and heavily pre-treated patients. STRO-001 demonstrates potent in vitro cytotoxicity in MM cell lines and reduces tumor burden in MM xenograft models, including prolongation of survival in the MM.1S model. Based on these encouraging observations, STRO-001 is advancing to the clinic for the treatment of myeloma and other B-cell malignancies.
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Embry:Sutro Biopharma: Employment. Li:Sutro Biopharma: Employment. Yu:Sutro Biopharma: Employment. Abrahams:Sutro Biopharma: Employment. DeAlmeida:Sutro Biopharma: Employment. Krimm:Sutro Biopharma: Employment. Matheny:Sutro Biopharma: Employment. Kline:Sutro Biopharma: Employment. Yam:Sutro Biopharma: Employment. Stafford:Sutro Biopharma: Employment. Wiita:Sutro Biopharma: Research Funding; TeneoBio, Inc.: Research Funding. Hallam:Sutro Biopharma: Employment. Lupher:Sutro Biopharma: Employment. Molina:Sutro Biopharma: Employment.
Introduction: STRO-001 is a novel CD74-targeting ADC comprised of an anti-CD74 human IgG1 antibody (SP7219) genetically incorporating the non-natural amino acid para-azidomethyl-L-phenylalanine ...(pAMF) with a non-cleavable dibenzocyclooctyne (DBCO)-maytansinoid linker-warhead. Highly efficient and precise site-specific conjugation enabled by cell-free antibody synthesis technology produced a well-defined homogeneous ADC with a drug-antibody ratio (DAR) of 2. Conjugation sites were selected based on highest stability both in vitro and in vivo . The aim of this study was to investigate the expression of CD74 in NHL and explore the therapeutic potential of STRO-001 in B-cell NHL cell lines and xenografts.
Methods: The binding affinity of SP7219 to recombinant human CD74 ECD (extracellular domain) and cynomolgus monkey (cyno) CD74 ECD was measured by SPR using a Biacore T200. Biotinylated SP7219 was used for immunohistochemistry (IHC) in NHL tumor specimens. Flow cytometry was used for measuring CD74 expression in NHL cell lines. STRO-001 was used to determine the EC50 and percent span of killing in NHL cell lines. The anti-tumor activity of STRO-001 in NHL xenografts in severe combined immune deficient (SCID) mice was examined.
Results: Anti-CD74 antibody SP7219 binds to both human and cyno CD74 ECD with high affinity (KD=0.85nM for human, KD=2.4nM for cyno). Tissue samples from the Department of Pathology at Stanford University were used to evaluate CD74 expression by IHC after appropriate permissions were obtained. Medium to high CD74 expression in >70% of cells was observed in 118/118 (100%) diffuse large B-cell lymphoma (DLBCL), 148/151 (98%) follicular lymphoma and 19/21 (90%) mantle cell lymphoma (MCL) samples. In vitro cytotoxicity assays show potent activity of STRO-001 in a diverse panel of B-cell tumor lines with EC50 values ranging from 0.17-13 nM (Table 1). CD74 cell surface expression is required for STRO-001 cytotoxicity but expression level does not correlate highly with in vitro potency (R2 = 0.4154). STRO-001 exhibits dose-dependent tumor growth inhibition in rituximab-resistant germinal center B-cell-like (GCB)-DLBCL SU-DHL-6 xenografts starting at 2.5 mg/kg weekly x 3 doses. STRO-001 + bendamustine/rituximab (BR) further improves tumor suppression in SU-DHL-6 xenografts compared to vehicle (p = 0.002) or BR alone (p = 0.02). In the activated B-cell (ABC)-DLBCL U2932 model, single doses of STRO-001 produce dose-dependent growth inhibition at 1 and 3 mg/kg and complete tumor regression at 10 mg/kg in 7/7 animals with no tumor re-growth up to > 90 days post-treatment (Figure 1). Studies with an MCL model, Jeko-1, demonstrate robust STRO-001 anti-tumor activity compared to vehicle (p < 0.0001) starting at a single 3 mg/kg dose, with a single 10 mg/kg dose resulting in tumor regression for up to 64 days post treatment (Figure 2). STRO-001 treatment 14 days post tumor inoculation was used to evaluate disease progression in the disseminated Mino MCL model. Vehicle-treated animals developed advanced progressive disease, with median survival of 81 days. In contrast, all Mino xenografts treated with STRO-001 at 3 mg/kg or 10 mg/kg were alive and disease-free at the time of sacrifice 135 days post tumor inoculation (Figure 3).
Conclusions: CD74 is expressed with high frequency and intensity in DLBCL, follicular lymphoma and MCL, supporting the investigation of novel biologics targeting this antigen. STRO-001 demonstrates potent in vitro cytotoxicity in multiple NHL cell lines and anti-tumor activity in GCB-DLBCL, ABC-DLBCL and mantle cell lymphoma xenograft models, including prolongation of survival in the disseminated Mino MCL model and prevention of tumor regrowth in the U2932 ABC-DLBCL and Jeko-1 MCL subcutaneous models. Clinical studies of this novel ADC for treatment of B-cell malignancies are under development.
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Yu:Sutro Biopharma: Employment. Abrahams:Sutro Biopharma: Employment. Embry:Sutro Biopharma: Employment. Li:Sutro Biopharma: Employment. Zhao:Stanford University School of Medicine: Employment. Henningsen:Sutro Biopharma: Employment. DeAlmeida:Sutro Biopharma: Employment. Matheny:Sutro Biopharma: Employment. Kline:Sutro Biopharma: Employment. Yam:Sutro Biopharma: Employment. Stafford:Sutro Biopharma: Employment. Natkunam:Stanford University School of Medicine: Employment. Hallam:Sutro Biopharma: Employment. Lupher:Sutro Biopharma: Employment. Molina:Sutro Biopharma: Employment.
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