The Bispecific Tumor Antigen-Conditional 4-1BB x 5T4 Agonist, ALG.APV-527, Mediates Strong T-Cell Activation and Potent Antitumor Activity in Preclinical Studies.

4-1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNγ production. The ability to induce potent antitumor activity by stimulating 4-1BB on tumor-specific cytotoxic T cells makes 4-1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4-1BB function when co-engaged with the tumor-associated antigen 5T4. ALG.APV-527 was built on the basis of the ADAPTIR bispecific platform with optimized binding domains to 4-1BB and 5T4 originating from the ALLIGATOR-GOLD human single-chain variable fragment library. The epitope of ALG.APV-527 was determined to be located at domain 1 and 2 on 4-1BB using X-ray crystallography. As shown in reporter and primary cell assays in vitro, ALG.APV-527 triggers dose-dependent 4-1BB activity mediated only by 5T4 crosslinking. In vivo, ALG.APV-527 demonstrates robust antitumor responses, by inhibiting growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response. ALG.APV-527 has an antibody-like half-life in cynomolgus macaques and was well tolerated at 50.5 mg/kg. ALG.APV-527 is uniquely designed for 5T4-conditional 4-1BB-mediated antitumor activity with potential to minimize systemic immune activation and hepatotoxicity while providing efficacious tumor-specific responses in a range of 5T4-expressing tumor indications as shown by robust activity in preclinical in vitro and in vivo models. On the basis of the combined preclinical dataset, ALG.APV-527 has potential as a promising anticancer therapeutic for the treatment of 5T4-expressing tumors.

Relationship between emotional expressions and lifestyle changes among university students during COVID-19 lockdown in Lebanon.

INTRODUCTION: Emotional expressivity plays an important role in terms of communication and interpersonal relationships in the context of society. Our research aims at assessing the perception of emotional expressivity and its association with lifestyle changes during COVID-19 lockdown among university students in Lebanon. METHODOLOGY: A total of 742 participants completed an anonymous online questionnaire including socio-demographic characteristics, lifestyle habits, and emotional expression evaluated through the Berkeley Expressivity Questionnaire (BEQ). Participants also reported their perception of the relationship between emotional expressivity and lifestyle changes experienced during lockdown. RESULTS: The expression of positive emotions was decreased among students who have a weight loss from decreased eating during lockdown. Moreover, significantly lower negative emotions and increased positive emotions were found to be associated respectively with the increase in quality and quantity of distance learning, which emphasizes the psychological investment in education. In terms of extensive time spent on TV and social media, results point towards increased emotional expressivity, particularly positive emotions and impulse facets. Finally, changes in social interaction during this period impacted all facets of emotional expressivity. CONCLUSIONS: In the context of lockdown due to the pandemic, emotional aspects were associated by university students with lifestyle changes. Our research highlights the beneficial role of social networking, distance learning, physical activity, and well-balanced nutrition on emotional regulation in this particularly stressful situation, thus the importance of a global approach to emotional expressivity including the social aspects and biological ones.

Changes in the profile and therapeutic care of people who use drugs with HCV mono-infection: a retrospective study between 2015 and 2019 from a monocentric tertiary referent center in France.

BACKGROUND AND AIMS: People who use drugs (PWUDs) are the main group at risk for hepatitis C virus (HCV) transmission and a key population for hepatitis C elimination. Multidisciplinary team (MDT) meetings were set up in France in December 2014 within regional reference centers to supervise the prescriptions and delivery of direct-acting antivirals (DAAs) to optimize the management of HCV infection. The aim of this retrospective study was to analyze the changes in the profile and therapeutic care of PWUDs with HCV mono-infection according to the evolution of MDT meetings in a regional tertiary reference center. METHODS: Between 2015 and 2019, overall 1912 HCV-infected patients presented at the MDT meetings, 547 were PWUDs with HCV mono-infection treated with DAAs. Five periods were defined according to the evolution of MDT meetings. The profile and management of PWUDs were compared among these five periods. RESULTS: Over time, the frequency of advanced stage of fibrosis decreased from 90.8 to 36.3% (P < 0.001), whereas the therapeutic care of the patients in primary addictology centers and networks of general practitioners increased from 17.4 to 55% (P < 0.001). The frequency of excessive alcohol consumption varied between 9.1 and 30% (P = 0.003) and that of opioid substitution therapy between 42.5 and 70% (P < 0.001). The Sustained virologic response assessed 12 weeks after the end of treatment rate was above 95% for the five periods. CONCLUSION: Between 2015 and 2019, the changes in the profile and management of PWUDs have followed the evolution of MDT meetings concerning patients with less advanced fibrosis and more therapeutic hepatitis C care made by the primary care centers.

Characteristics and care of chronic hepatitis C treated with direct-acting antivirals in migrants.

BACKGROUND AND AIMS: Hepatitis C is poorly documented in migrants. The published studies mainly concern the screening in this population and are limited to some countries in Europe and North America. This study aimed to evaluate the characteristics and care of chronic hepatitis C in this population compared to the nonmigrant population, in the era of direct-acting antivirals (DAAs). METHOD: We performed a retrospective analysis based on data presented at the multidisciplinary team meetings of our tertiary care center between 2015 and 2019. RESULTS: We included 277 migrant- and 1390 nonmigrant patients mono-infected with hepatitis C virus (HCV) and treated with DAAs. The majority of the migrants were from Eastern European countries. In multivariable analysis, BMI classes associated with more obesity (OR = 1.84; 95% CI, 1.37-2.49; P < 0.001) and therapeutic patient education (OR = 3.91; 95% CI, 2.38-6.49; P < 0.001) were positively associated with migrant status, whereas age (OR = 0.92; 95% CI, 0.90-0.94; P < 0.001), female gender (OR = 0.46; 95% CI, 0.28-0.74; P = 0.002), modes of contamination with less drug use, transfusion history or nosocomial risk, as well more unknown mode (OR = 0.70; 95% CI, 0.50-0.96; P = 0.031), alcohol consumption (OR = 0.48; 95% CI, 0.29-0.73; P = 0.001), types of structures with less care in a general hospital or health network of general practitioners and more care in a university hospital or primary addictology center (OR = 0.78; 95% CI, 0.60-0.99; P = 0.046) and opioid substitution therapy (OR = 0.25; 95% CI, 0.08-0.68; P = 0.008) were negatively associated with migrant status. The substained virologic response 12 was close to 97% in both groups. CONCLUSION: Despite multiple differences in characteristics and therapeutic care between the two populations, the chances of healing hepatitis C were the same among migrant- compared with nonmigrant patients.

Improvement of Human Sperm Vacuolization and DNA Fragmentation Co-Cultured with Adipose-Derived Mesenchymal Stem Cell Secretome: In Vitro Effect.

BACKGROUND AND OBJECTIVES: Oxidative stress (OS) is known to be an important factor of male infertility. Adipose-derived mesenchymal stem cells (AD-MSCs) are known to have immune-modulatory and anti-oxidant effects through their secretions, hence raising the idea of their potential benefit to improve sperm parameters. This study aims at investigating the effect of AD-MSCs conditioned medium (CM) on human sperm parameters in the presence and absence of H2O2-induced OS. METHODS AND RESULTS: Sperm samples were collected from 30 healthy men and divided into two groups: non-stressed and H2O2-stressed. Isolated AD-MSCs from healthy donors undergoing liposuction were cultured and CM was collected at 24, 48 and 72 h. Both sperm groups were cultured with CM and a time course was performed followed by an evaluation of sperm parameters. The incubation of non-stressed and stressed sperm samples with AD-MSCs-CM for 24 h was found to have the optimum impact on sperm vacuolization, DNA fragmentation and OS levels in comparison to other incubation timings, while preserving motility, viability and morphology of cells. Incubation with CM improved all sperm parameters except morphology in comparison to the non-treated group, with the best effect noted with CM collected at 24 h rather than 48 or 72 h for sperm vacuolization and DNA fragmentation. When compared to fresh semen parameters (T0), samples cultured with CM 24 h showed a significant decrease in sperm vacuolization and DNA fragmentation while keeping other parameters stable. CONCLUSIONS: AD-MSCSs-CM improves sperm quality, and hence can be used in treating infertility and subsequently enhancing IVF outcomes.

Impact of alexithymia on glycemic control among Lebanese adults with type 2 diabetes.

PURPOSE: Alexithymia, defined as the inability of a person to identify, describe and express emotions, has been found to influence glycemic control in type 2 diabetes patients (D2). The characteristics and influencing factors of alexithymia and the association of this psychological construct with D2 has not yet been studied in Lebanon where 14.6% of adults are diagnosed with the disease. This study aims at evaluating the prevalence of alexithymia and its relationship with glycemic control among Lebanese adults with D2. METHODS: Alexithymia was assessed in 104 patients diagnosed with D2 and 100 healthy controls using the 20-item Toronto Alexithymia Scale (TAS-20). The impact of alexithymia on glycemic control was evaluated using HbA1c values, fasting blood glucose levels, number of severe hyperglycemic episodes and hospitalizations for hyperglycemia within the past months. RESULTS: Alexithymia prevalence was significantly higher in D2 patients compared to controls (35.5% vs 15%). Patients with alexithymia showed higher levels of HbA1c and glucose in comparison to those without alexithymia. Consistently, significant positive correlations were found between the TAS-20 total and subscale scores and both HbA1c and glucose levels. Alexithymic patients had three times more severe hyperglycemic episodes and five times more hospitalizations for hyperglycemia compared to those without alexithymia. According to multivariate regression analysis, lifestyle factors alone were not found predictive of alexithymia in D2 patients. CONCLUSION: Given the impact of alexithymia on D2 regulation, screening of alexithymia in case of D2 and appropriate psychological follow-up are important for a better prognosis, management and treatment of the disease.

Hepatocellular carcinoma is diagnosed at a later stage in alcoholic patients: Results of a prospective, nationwide study.

BACKGROUND: Recent data suggest that alcohol-related hepatocellular carcinoma (HCC) is diagnosed at a later stage. The aim of this study was to compare HCC characteristics and outcomes in an alcohol-related group (group A) and a non-alcohol-related group (group NA). METHODS: A total of 1207 patients with newly diagnosed HCC were prospectively included between May 2008 and October 2009. Patients with multiple causes (alcohol plus another cause) were excluded. Patients were followed every year for 5 years. Recorded variables, including etiologies were tested as prognostic factors of survival in a multivariate Cox model after adjustments for a lead-time bias. RESULTS: In all, 894 patients were analyzed: 582 (65.1%) were in group A, and 312 (34.9%) were in group NA. Alcohol-related HCC was more likely to be diffuse and detected in patients with a worse performance status and worse liver function. After adjustments for a lead-time bias, the median overall survival (OS) was 9.7 and 5.7 months in groups NA and A, respectively (P = .0002), and 5.8 and 5.0 months in alcohol-abstinent and alcohol non-abstinent groups, respectively (P = .09). The prognostic role of alcohol disappeared when survival was assessed at each Barcelona Clinic Liver Cancer (BCLC) stage. Patients with HCC detected during a cirrhosis follow-up program (n = 199 [22.3% of the whole cohort]) had increased lead time-adjusted median OS in comparison with patients with HCC diagnosed incidentally (11.7 vs 5.4 months; P < .0001). CONCLUSIONS: In comparison with patients with non-alcohol-related HCC, patients with alcohol-related HCC have reduced OS, mainly because of worse liver function and tumor characteristics at diagnosis, as attested by similar survival within each BCLC stage. Cancer 2018;124:1964-72. © 2018 American Cancer Society.

MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer.

Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3ε to prostate cancer cells expressing PSMA (prostate-specific membrane antigen). In vitro cross-linking of T cells with PSMA-expressing tumor cells by MOR209/ES414 triggered potent target-dependent tumor lysis and induction of target-dependent T-cell activation and proliferation. This activity occurred at low picomolar concentrations of MOR209/ES414 and was effective at low T-effector to tumor target cell ratios. In addition, cytotoxic activity was equivalent over a wide range of PSMA expression on target cells, suggesting that as few as 3,700 PSMA receptors per cell are sufficient for tumor lysis. In addition to high sensitivity and in vitro activity, MOR209/ES414 induced limited production of cytokines compared with other bispecific antibody formats. Pharmacokinetic analysis of MOR209/ES414 demonstrated a serum elimination half-life in NOD/SCID γ (NSG) mice of 4 days. Administration of MOR209/ES414 in murine xenograft models of human prostate cancer significantly inhibited tumor growth, prolonged survival, and decreased serum prostate-specific antigen levels only in the presence of adoptively transferred human T cells. On the basis of these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC. Mol Cancer Ther; 15(9); 2155-65. ©2016 AACR.

CD20-directed small modular immunopharmaceutical, TRU-015, depletes normal and malignant B cells.

PURPOSE: CD20-directed therapy with rituximab is effective in many patients with malignant lymphoma or follicular lymphoma. However, relapse frequently occurs within 1 year, and patients become increasingly refractory to retreatment. Our purpose was to produce a compact, single-chain CD20-targeting immunotherapeutic that could offer therapeutic advantages in the treatment of B-cell lymphoma. EXPERIMENTAL DESIGN: Rituximab is a chimeric antibody containing two heavy chains and two light chains. Here, we describe the properties of TRU-015, a small modular immunopharmaceutical specific for CD20, encoded by a single-chain construct containing a single-chain Fv specific for CD20 linked to human IgG1 hinge, CH2, and CH3 domains but devoid of CH1 and CL domains. RESULTS: TRU-015 mediates potent direct signaling and antibody-dependent cellular cytotoxicity but has reduced size and complement-mediated cytotoxicity activity compared with rituximab. TRU-015 is a compact dimer of 104 kDa that comigrates with albumin in size exclusion chromatography and retains a long half-life in vivo. TRU-015 induced growth arrest in multiple B lymphoma cell lines in vitro and showed effective antitumor activity against large, established subcutaneous Ramos or Daudi xenograft tumors in nude mice. TRU-015 also showed rapid, dose-dependent, and durable depletion of peripheral blood B cells following single-dose administration to nonhuman primates. CONCLUSION: These results indicate that TRU-015 may improve CD20-directed therapy by effectively depleting embedded malignant B cells and nonmalignant pathogenic B cells and do so with reduced complement activation.

The COSTIM bioassay: a novel potency test for dendritic cells.

The utility of dendritic cells (DCs) in experimental immunotherapy has driven significant advances in the manufacture of these cells. They are increasingly prepared in vitro for use in clinical trials of human disease, particularly cancer. Thus, it has become imperative that, in concert with other quality control measures, a potency test be employed for lot (batch)-release testing of DC products, both in preclinical studies and human clinical trials. The mixed lymphocyte reaction (MLR) assay has served as a 'gold standard' for evaluating the functional ability of antigen presenting cells. Alternatively, some researchers also employ immunophenotyping, a test unrelated to cellular function, as a potency-determining test. We have developed a novel method named the 'COSTIM bioassay', which, as we describe in this paper, is suitable for quality control or lot-release testing. In this method T-cells are stimulated with a sub-optimal amount of anti-CD3 antibody, such that they remain unable to proliferate unless a source of co-stimulation (accessory cells, such as DC) is added to the culture. Thus, the COSTIM bioassay is a functional test that selectively measures co-stimulatory activity, or functional potency. This method takes less than 2 days for completion and assures better quality control than the MLR.

[Long term results of treatment of hemorrhagic radiation proctitis by argon plasma coagulation]. / Résultats à long terme du traitement des rectites radiques hémorragiques par la coagulation au plasma d'argon.

AIM: To assess long term results of argon plasma coagulation (APC) treatment in hemorrhagic radiation proctitis. METHODS: Thirty patients treated with APC in 2 departments were enrolled. In 16 patients, APC was the first treatment used. A clinical scale (Chutkan) was used to assess bleeding before and after treatment. An endoscopic scale was used to assess results on mucosa appearance. RESULTS: The mean course number was 2.3 (extremes 1-5). Bleeding score decreased from 2.67 to 0.77 (P<0.001). The success rate was 26/30 patients (87%) in an intention-to-treat analysis with 2 failures (6%), 1 patient lost for follow up and 1 patient not referred after one session. Improvement in endoscopic appearance was observed in the 13 endoscopically controlled patients with a decrease of the endoscopic score from 1.61 to 0.3 (P<0.002). The overall morbidity was 47% with 3 severe complications (10%): 1 severe bleeding, 1 extensive necrosis of lower part of the rectum and 1 perforation. We also noticed 3 microrecties and 2 symptomless rectal stenosis. With regard to tolerance, we observed post treatment pain in 6 patients (20%), easily released by usual antalgics. Complications and side effects occurred, in all patients but one, when power shot was > 45 W. Mean follow up was 20 months (3 to 35 months). Hematochezia recurred in 4 patients, but were easily treated with 1 APC course. CONCLUSION: APC is an effective treatment of hemorrhagic radiation proctitis, with a success rate of 87%. Endoscopic improvement is usual. It seems to be possible to limit the risk of complications by using low power setting.