Adoptive T cell therapy for the treatment of ovarian cancer

Despite de advances in surgery and chemotherapy, the outcome of ovarian cancer patients has improved very little over the last 40 years. Given that ovarian cancer is an immunogenic tumor, immunotherapies offer a great promise as treatment of this dismal disease. We show that follicle-stimulating hormone (FSH) receptor can be a very specific target that is expressed in >56% of human ovarian carcinomas and is a negative prognostic factor. Accordingly, we designed chimeric receptors expressing full-length FSH to redirect T-cell cytotoxic activity against these more aggressive tumors. In vivo, fully murine FSH-targeted T-cells and low affinity anti-mesothelin scFv-targeted Chimeric Antigen Receptor (CAR) T-cells were similarly safe and effective at increasing the survival of immunocompetent mice with established and aggressive ovarian carcinomas. Notably, both chimeric receptors enhanced the ability of endogenous, pre-existing tumor-reactive T-cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, chimeric receptor-expressing CD4 T-cells were superior contributors to these consistent therapeutic benefits, compared to their CD8 counterparts. We also found that although chimeric receptor-targeted T-cells were able to persist as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, the shedding of FSH receptor from tumor cells diverted the effector activity of chimeric receptor-transduced T-cells away from targeted tumor cells. Accordingly, although tumor cells remained sensitive to chimeric receptor-driven activities, re-directed lymphocytes ultimately disappeared from tumor beds. Thus, although tumor microenvironmental factors could limit their effectiveness against established and aggressive epithelial tumors, lymphocytes redirected against tumor cells with full-length hormones or low-affinity scFvs induce significant therapeutic benefits by boosting endogenous anti-tumor immunity and show negligible toxicity even in the presence of cognate targets in tumor-free tissues.Despite de advances in surgery and chemotherapy, the outcome of ovarian cancer patients has improved very little over the last 40 years. Given that ovarian cancer is an immunogenic tumor, immunotherapies offer a great promise as treatment of this dismal disease. We show that follicle-stimulating hormone (FSH) receptor can be a very specific target that is expressed in >56% of human ovarian carcinomas and is a negative prognostic factor. Accordingly, we designed chimeric receptors expressing full-length FSH to redirect T-cell cytotoxic activity against these more aggressive tumors. In vivo, fully murine FSH-targeted T-cells and low affinity anti-mesothelin scFv-targeted Chimeric Antigen Receptor (CAR) T-cells were similarly safe and effective at increasing the survival of immunocompetent mice with established and aggressive ovarian carcinomas. Notably, both chimeric receptors enhanced the ability of endogenous, pre-existing tumor-reactive T-cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, chimeric receptor-expressing CD4 T-cells were superior contributors to these consistent therapeutic benefits, compared to their CD8 counterparts. We also found that although chimeric receptor-targeted T-cells were able to persist as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, the shedding of FSH receptor from tumor cells diverted the effector activity of chimeric receptor-transduced T-cells away from targeted tumor cells. Accordingly, although tumor cells remained sensitive to chimeric receptor-driven activities, re-directed lymphocytes ultimately disappeared from tumor beds. Thus, although tumor microenvironmental factors could limit their effectiveness against established and aggressive epithelial tumors, lymphocytes redirected against tumor cells with full-length hormones or low-affinity scFvs induce significant therapeutic benefits by boosting endogenous anti-tumor immunity and show negligible toxicity even in the presence of cognate targets in tumor-free tissues

Validation and measurement invariance of the Scale of Positive and Negative Experience (SPANE) in a spanish general sample

Well-being has been measured based on different perspectives in positive psychology. However, it is necessary to measure affects and emotions correctly and to explore the independence of positive and negative affect. This cross-sectional study adapts and validates the Scale of Positive and Negative Experience (SPANE) with a non-probabilistic sample of 821 Spanish adults. A confirmatory factor analysis confirmed two related factors with two correlated errors. The average variance extracted was 0.502 for negative affect (SPANE-N) and 0.588 for positive affect (SPANE-P). The composite reliability was 0.791 for SPANE-N and 0.858 for SPANE-P. Measurement invariance analysis showed evidence of scalar invariance. Item-total corrected polyserial correlations showed values between 0.47 and 0.76. The path analysis used to test temporal stability, and the structural equation models used to test convergent and concurrent validity with other well-being measures, showed good fit. All path coefficients were statistically significant and over 0.480. For the validity models, the magnitude of the correlations was large and in the expected direction. The Spanish version of the SPANE show good psychometric properties. Future studies of emotional well-being in Spain can benefit from the use of this scale, and new studies must test cross-cultural invarianc

Promoting Alzheimer's Risk-Reduction through Community-Based Lifestyle Education and Exercise in Rural America: A Pilot Intervention

Introduction. Rural Americans (RA) have poorer vascular health and physical activity levels than their urban counterparts; all are dementia risk factors. Dementia risk reduction among rural individuals requires a tailored approach. The purpose of this project was to examine preliminary efficacy of a community-based physical exercise and/or dementia risk factor-reduction curriculum among rural adults 50 and older. Methods. Seventy-five rural dwelling adults 50 and older were randomized to one of three groups: 1) 10 weeks of Alzheimer’s disease risk-reduction education (ED), 2) risk-reduction education and supervised exercise (EDEX) or 3) control group (CON). Outcomes included baseline to 10-week follow-up difference in dementia knowledge (primary outcome) and physical activity, muscular endurance, healthy lifestyle engagement, and anthropometrics (secondary outcomes). Results. Sixty-nine adults successfully completed the 10-week study. Dementia knowledge increased in a Treatment Arm-dependent manner (χ2 = 6.95 (2), p = 0.03), being ED and EDEX superior to CON. Engagement in healthy lifestyle behaviors did not change statistically. However, participation specifically in physical activity increased over time (χ2 = 11.47 (2), p = 0.003) with EDEX reporting the greatest increases. No significant change in average daily steps was observed for any group. Conclusion. The results suggested dementia risk-reduction education, both with and without structured exercise, leads to improvements in dementia knowledge. When coupled with regular, supervised exercise, this education intervention also helped participants increase engagement in physical activity over 10 weeks. Tailored interventions that combine Alzheimer’s disease education and regular, supervised exercise may help reduce dementia risk in rural communities

The Longitudinal Association Between a Discrepancy Measure of Anosognosia in Patients with Dementia, Caregiver Burden and Depression

Anosognòsia; Cuidadors; Estudis longitudinalsAnosognosia; Cuidadores; Estudios longitudinalesAnosognosia; Caregivers; Longitudinal studiesBackground: According to cross-sectional studies, there is an association between anosognosia in people with dementia and caregiver’s burden and depression. Anosognosia in patients may be a cause of caregiver burden and depression. However, variability in caregiver anosognosia ratings may exist as caregivers with burden and depression may have a more pessimistic view of the patients’ health. Objective: To assess the variability of caregiver anosognosia ratings of patients with dementia using a widely used anosognosia scale and its longitudinal relationship with caregiver burden and depression. Methods: A convenience cohort of 221 consecutive dementia outpatient and caregiver dyads was followed up at 12 and 24 months. The main instruments used were the Anosognosia Questionnaire-Dementia (AQ-D), Caregiver Burden Interview, and Geriatric Depression Scale. Linear mixed models were used including time as a factor in every model. Multivariate analyses controlled for caregiver’s socio-demographic and possible confounding factors. Results: Attrition at 12 and 24 months was 24.9% and 42.5% respectively. Patients at baseline were on average 77.8 years of age, 63.3% were women, and 63.3% had < 5 years of education. In the bivariate analyses, caregiver burden, depression, and gender were associated with caregiver ratings of total, cognitive, and personality AQ-D of the patient at different time points. Multivariate analyses revealed burden as the caregiver variable most consistently associated with total, cognitive, and personality caregiver AQ-D ratings of the patient. Conclusion: Some caregiver characteristics, especially burden, are associated with caregiver ratings of AQ-D with regard to the patientPSI 2010-1901

The longitudinal association between a discrepancy measure of anosognosia in patients with dementia, caregiver burden and depression

Background: According to cross-sectional studies, there is an association between anosognosia in people with dementia and caregiver's burden and depression. Anosognosia in patients may be a cause of caregiver burden and depression. However, variability in caregiver anosognosia ratings may exist as caregivers with burden and depression may have a more pessimistic view of the patients' health. Objective: to assess the variability of caregiver anosognosia ratings of patients with dementia using a widely used anosognosia scale and its longitudinal relationship with caregiver burden and depression. Methods: A convenience cohort of 221 consecutive dementia outpatient and caregiver dyads was followed up at 12 and 24 months. The main instruments used were the Anosognosia Questionnaire-Dementia (AQ-D), Caregiver Burden Interview, and Geriatric Depression Scale. Linear mixed models were used including time as a factor in every model. Multivariate analyses controlled for caregiver's socio-demographic and possible confounding factors. Results: Attrition at 12 and 24 months was 24.9% and 42.5% respectively. Patients at baseline were on average 77.8 years of age, 63.3% were women, and 63.3% had <5 years of education. In the bivariate analyses, caregiver burden, depression, and gender were associated with caregiver ratings of total, cognitive, and personality AQ-D of the patient at different time points. Multivariate analyses revealed burden as the caregiver variable most consistently associated with total, cognitive, and personality caregiver AQ-D ratings of the patient. Conclusion: Some caregiver characteristics, especially burden, are associated with caregiver ratings of AQ-D with regard to the patient

Patient Polypharmacy use Following a Multi-Disciplinary Dementia Care Program in a Memory Clinic: A Retrospective Cohort Study

Introduction. Dementia increases the risk of polypharmacy. Timely detection and optimal care can optimize the prognosis for patients with dementia, which may in turn reduce polypharmacy. We aimed to compare the change in polypharmacy use among memory clinic patients living with dementia who participate in a dementia care program, vs those who did not. We hypothesized that patients in the dementia care program would reduce their use of polypharmacy compared to those who were not in the program. Methods. We retrospectively analyzed EMR data from a university memory clinic. The final analytic sample consisted of 381 patients: 107 in the program and 274 matched patients not in the program. We used logistic regression of outcomes (five or more concurrent medications) at follow-up, controlled for the same outcome at baseline to assess the change in polypharmacy, and stratified outcomes by prescription and over-the-counter. Results. The two groups did not differ in the use of five or more total and prescription medications at follow-up controlling for the use of 5 or more of the respective medications at baseline and covariates. Being in the program was associated with a threefold lower odds of using 5 or more over-the-counter medications at follow-up (OR=0.30; p&lt;0.001) after controlling for using 5 or more over-the-counter medications at baseline and covariates. Conclusions. Dementia care might reduce polypharmacy of over-the-counter medications, potentially reducing risky medication-medication interactions. More research is needed to infer causality and understand how to reduce prescription medication polypharmacy

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma:importance of immunoglobulin supplementation

Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received onceweekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P &lt; .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.</p

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma:importance of immunoglobulin supplementation

Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received onceweekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P &lt; .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.</p

Chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis.

BACKGROUND: Gastrointestinal mucosal injury (mucositis), commonly affecting the oral cavity, is a clinically significant yet incompletely understood complication of cancer chemotherapy. Although antineoplastic cytotoxicity constitutes the primary injury trigger, the interaction of oral microbial commensals with mucosal tissues could modify the response. It is not clear, however, whether chemotherapy and its associated treatments affect oral microbial communities disrupting the homeostatic balance between resident microorganisms and the adjacent mucosa and if such alterations are associated with mucositis. To gain knowledge on the pathophysiology of oral mucositis, 49 subjects receiving 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy were evaluated longitudinally during one cycle, assessing clinical outcomes, bacterial and fungal oral microbiome changes, and epithelial transcriptome responses. As a control for microbiome stability, 30 non-cancer subjects were longitudinally assessed. Through complementary in vitro assays, we also evaluated the antibacterial potential of 5-FU on oral microorganisms and the interaction of commensals with oral epithelial tissues. RESULTS: Oral mucositis severity was associated with 5-FU, increased salivary flow, and higher oral granulocyte counts. The oral bacteriome was disrupted during chemotherapy and while antibiotic and acid inhibitor intake contributed to these changes, bacteriome disruptions were also correlated with antineoplastics and independently and strongly associated with oral mucositis severity. Mucositis-associated bacteriome shifts included depletion of common health-associated commensals from the genera Streptococcus, Actinomyces, Gemella, Granulicatella, and Veillonella and enrichment of Gram-negative bacteria such as Fusobacterium nucleatum and Prevotella oris. Shifts could not be explained by a direct antibacterial effect of 5-FU, but rather resembled the inflammation-associated dysbiotic shifts seen in other oral conditions. Epithelial transcriptional responses during chemotherapy included upregulation of genes involved in innate immunity and apoptosis. Using a multilayer epithelial construct, we show mucositis-associated dysbiotic shifts may contribute to aggravate mucosal damage since the mucositis-depleted Streptococcus salivarius was tolerated as a commensal, while the mucositis-enriched F. nucleatum displayed pro-inflammatory and pro-apoptotic capacity. CONCLUSIONS: Altogether, our work reveals that chemotherapy-induced oral mucositis is associated with bacterial dysbiosis and demonstrates the potential for dysbiotic shifts to aggravate antineoplastic-induced epithelial injury. These findings suggest that control of oral bacterial dysbiosis could represent a novel preventive approach to ameliorate oral mucositis