NKG2D-bispecific enhances NK and CD8+ T cell antitumor immunity.

BACKGROUND: Cancer immunotherapy approaches that elicit immune cell responses, including T and NK cells, have revolutionized the field of oncology. However, immunosuppressive mechanisms restrain immune cell activation within solid tumors so additional strategies to augment activity are required. METHODS: We identified the co-stimulatory receptor NKG2D as a target based on its expression on a large proportion of CD8+ tumor infiltrating lymphocytes (TILs) from breast cancer patient samples. Human and murine surrogate NKG2D co-stimulatory receptor-bispecifics (CRB) that bind NKG2D on NK and CD8+ T cells as well as HER2 on breast cancer cells (HER2-CRB) were developed as a proof of concept for targeting this signaling axis in vitro and in vivo. RESULTS: HER2-CRB enhanced NK cell activation and cytokine production when co-cultured with HER2 expressing breast cancer cell lines. HER2-CRB when combined with a T cell-dependent-bispecific (TDB) antibody that synthetically activates T cells by crosslinking CD3 to HER2 (HER2-TDB), enhanced T cell cytotoxicity, cytokine production and in vivo antitumor activity. A mouse surrogate HER2-CRB (mHER2-CRB) improved in vivo efficacy of HER2-TDB and augmented NK as well as T cell activation, cytokine production and effector CD8+ T cell differentiation. CONCLUSION: We demonstrate that targeting NKG2D with bispecific antibodies (BsAbs) is an effective approach to augment NK and CD8+ T cell antitumor immune responses. Given the large number of ongoing clinical trials leveraging NK and T cells for cancer immunotherapy, NKG2D-bispecifics have broad combinatorial potential.

IL-15/IL-15Rα-Fc fusion protein XmAb24306 potentiates activity of CD3 bispecific antibodies through enhancing T cell expansion.

Insufficient quantity of functional T cells is a likely factor limiting clinical activity of T cell bispecific antibodies, especially in solid tumor indications. We hypothesized that XmAb24306 (efbalropendekin alfa), a lymphoproliferative interleukin (IL)-15/IL-15 receptor α (IL-15Rα) Fc-fusion protein, may potentiate the activity of T cell dependent (TDB) antibodies. Activation of human peripheral T cells by cevostamab, an anti-FcRH5/CD3 TDB, or anti-HER2/CD3 TDB resulted in upregulation of IL-2/15Rß (CD122) receptor subunit in nearly all CD8+ and majority of CD4+ T cells, suggesting that TDB treatment may sensitize T cells to the IL-15. XmAb24306 enhanced T cell bispecific antibody induced CD8+ and CD4+ T cell proliferation and expansion. In vitro combination of XmAb24306 with cevostamab or anti-HER2/CD3 TDB resulted in significant enhancement of tumor cell killing, which was reversed when T cell numbers were normalized, suggesting that T cell expansion is the main mechanism for the observed benefit. Pre-treatment of immune competent mice with a mouse-reactive surrogate of XmAb24306 (mIL-15-Fc) resulted in significant increase of T cells in blood, spleen and in tumors and converted transient anti-HER2/CD3 TDB responses to complete durable responses. In summary, our results support the hypothesis where the number of tumor infiltrating T cells is rate limiting for the activity of solid tumor targeting TDBs. Upregulation of CD122 by TDB treatment and the observed synergy with XmAb24306 and T cell bispecific antibodies supports clinical evaluation of this novel immunotherapy combination.

Effectiveness of nurse-led interventions versus usual care to manage hypertension and lifestyle behaviour: a systematic review and meta-analysis.

AIMS: This review aimed to investigate the effectiveness of nurse-led interventions vs. usual care on hypertension management, lifestyle behaviour, and patients' knowledge of hypertension and associated risk factors. METHODS: A systematic review with meta-analysis was conducted following Joanna Briggs Institute (JBI) guidelines. MEDLINE (Ovid), EmCare (Ovid), CINAHL (EBSCO), Cochrane library, and ProQuest (Ovid) were searched from inception to 15 February 2022. Randomized controlled trials (RCTs) examining the effect of nurse-led interventions on hypertension management were identified. Title and abstract, full text screening, assessment of methodological quality, and data extraction were conducted by two independent reviewers using JBI tools. A statistical meta-analysis was conducted using STATA version 17.0. RESULTS: A total of 37 RCTs and 9731 participants were included. The overall pooled data demonstrated that nurse-led interventions may reduce systolic blood pressure (mean difference -4.66; 95% CI -6.69, -2.64; I2 = 83.32; 31 RCTs; low certainty evidence) and diastolic blood pressure (mean difference -1.91; 95% CI -3.06, -0.76; I2 = 79.35; 29 RCTs; low certainty evidence) compared with usual care. The duration of interventions contributed to the magnitude of blood pressure reduction. Nurse-led interventions had a positive impact on lifestyle behaviour and effectively modified diet and physical activity, but the effect on smoking and alcohol consumption was inconsistent. CONCLUSION: This review revealed the beneficial effects of nurse-led interventions in hypertension management compared with usual care. Integration of nurse-led interventions in routine hypertension treatment and prevention services could play an important role in alleviating the rising global burden of hypertension. REGISTRATION: PROSPERO: CRD42021274900.

Health System Enablers and Barriers to Continuity of Care for First Nations Peoples Living with Chronic Disease.

Introduction: Failings in providing continuity of care following an acute event for a chronic disease contribute to care inequities for First Nations Peoples in Australia, Canada, and Aotearoa (New Zealand). Methods: A rapid narrative review, including primary studies published in English from Medline, Embase, PsycINFO, and Cochrane Central, concerning chronic diseases (cancer, cardiovascular disease, chronic kidney disease, diabetes, and related complications), was conducted. Barriers and enablers to continuity of care for First Nations Peoples were explored considering an empirical lens from the World Health Organization framework on integrated person-centred health services. Results: Barriers included a need for more community initiatives, health and social care networks, and coaching and peer support. Enabling strategies included care adapted to patients' cultural beliefs and behavioural, personal, and family influences; continued and trusting relationships among providers, patients, and caregivers; and provision of flexible, consistent, adaptable care along the continuum. Discussion: The support and co-creation of care solutions must be a dialogical participatory process adapted to each community. Conclusions: Health and social care should be harmonised with First Nations Peoples' cultural beliefs and family influences. Sustainable strategies require a co-design commitment for well-funded flexible care plans considering coaching and peer support across the lifespan.

When Cancer and Cardiovascular Disease Intersect: The Challenge and the Opportunity of Cardio-Oncology.

Cancer and cardiovascular disease (CVD) commonly coexist, with increasing evidence that long-term cancer survivors are more likely to die from CVD than the general population. Effective management of CVD and its risk factors requires identification of patients at increased risk who may benefit from early intervention and their appropriate monitoring across the disease trajectory. Improving outcomes requires new models of multidisciplinary cancer care supported by care pathways. Such pathways require a clear delineation of the roles and responsibilities of all team members and provision of appropriate enablers for their delivery. These include accessible point-of-care tools/risk calculators, patient resources, and the provision of tailored training opportunities for health care providers.

Cardiac rehabilitation, physical activity, and the effectiveness of activity monitoring devices on cardiovascular patients: an umbrella review of systematic reviews.

AIMS: To consolidate the evidence on the effectiveness of activity-monitoring devices and mobile applications on physical activity and health outcomes of patients with cardiovascular disease who attended cardiac rehabilitation (CR) programmes. METHODS AND RESULTS: An umbrella review of published randomized controlled trials, systematic reviews, and meta-analyses was conducted. Nine databases were searched from inception to 9 February 2022. Search and data extraction followed the JBI methodology for umbrella reviews and PRISMA guidelines. Nine systematic reviews met the inclusion criteria, comparing outcomes of participants in CR programmes utilizing devices/applications, to patients without access to CR with devices/applications. A wide range of physical, clinical, and behavioural outcomes were reported, with results from 18 712 participants. Meta-analyses reported improvements in physical activity, minutes/week [standardized mean difference (SMD) 0.23, 95% confidence interval (CI) 0.10-0.35] and activity levels (SMD 0.29, 95% CI 0.07-0.51), and a reduction in sedentariness [risk ratio (RR) 0.54, 95% CI 0.39-0.75] in CR participants, compared with usual care. Of clinical outcomes, the risk of re-hospitalization reduced significantly (RR 0.49, 95% CI 0.27-0.89), and there was reduction (non-significant) in mortality (RR 0.27, 95% CI 0.05-1.54). From the behavioural outcomes, reviews reported improvements in smoking behaviour (RR 0.87, 95% CI 0.67-1.13) and total diet quality intake (RR 0.79, 95% CI 0.66-0.94) among CR patients. CONCLUSIONS: The use of devices/applications was associated with increase in activity, healthy behaviours, and reductions in clinical indicators. Although most effect sizes indicate limited clinical benefits, the broad consistency of the narrative suggests devices/applications are effective at improving CR patients' outcomes.

T cell-dependent bispecific antibodies alter organ-specific endothelial cell-T cell interaction.

Preclinical and clinical studies demonstrate that T cell-dependent bispecific antibodies (TDBs) induce systemic changes in addition to tumor killing, leading to adverse events. Here, we report an in-depth characterization of acute responses to TDBs in tumor-bearing mice. Contrary to modest changes in tumors, rapid and substantial lymphocyte accumulation and endothelial cell (EC) activation occur around large blood vessels in normal organs including the liver. We hypothesize that organ-specific ECs may account for the differential responses in normal tissues and tumors, and we identify a list of genes selectively upregulated by TDB in large liver vessels. Using one of the genes as an example, we demonstrate that CD9 facilitates ICAM-1 to support T cell-EC interaction in response to soluble factors released from a TDB-mediated cytotoxic reaction. Our results suggest that multiple factors may cooperatively promote T cell infiltration into normal organs as a secondary response to TDB-mediated tumor killing. These data shed light on how different vascular beds respond to cancer immunotherapy and may help improve their safety and efficacy.

Novel Anti-LY6G6D/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Colorectal Cancer.

New therapeutics and combination regimens have led to marked clinical improvements for the treatment of a subset of colorectal cancer. Immune checkpoint inhibitors have shown clinical efficacy in patients with mismatch-repair-deficient or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). However, patients with microsatellite-stable (MSS) or low levels of microsatellite instable (MSI-L) colorectal cancer have not benefited from these immune modulators, and the survival outcome remains poor for the majority of patients diagnosed with mCRC. In this article, we describe the discovery of a novel T-cell-dependent bispecific antibody (TDB) targeting tumor-associated antigen LY6G6D, LY6G6D-TDB, for the treatment of colorectal cancer. RNAseq analysis showed that LY6G6D was differentially expressed in colorectal cancer with high prevalence in MSS and MSI-L subsets, whereas LY6G6D expression in normal tissues was limited. IHC confirmed the elevated expression of LY6G6D in primary and metastatic colorectal tumors, whereas minimal or no expression was observed in most normal tissue samples. The optimized LY6G6D-TDB, which targets a membrane-proximal epitope of LY6G6D and binds to CD3 with high affinity, exhibits potent antitumor activity both in vitro and in vivo. In vitro functional assays show that LY6G6D-TDB-mediated T-cell activation and cytotoxicity are conditional and target dependent. In mouse xenograft tumor models, LY6G6D-TDB demonstrates antitumor efficacy as a single agent against established colorectal tumors, and enhanced efficacy can be achieved when LY6G6D-TDB is combined with PD-1 blockade. Our studies provide evidence for the therapeutic potential of LY6G6D-TDB as an effective treatment option for patients with colorectal cancer.

Implementation and prospective evaluation of the Country Heart Attack Prevention model of care to improve attendance and completion of cardiac rehabilitation for patients with cardiovascular diseases living in rural Australia: a study protocol.

INTRODUCTION: Despite extensive evidence of its benefits and recommendation by guidelines, cardiac rehabilitation (CR) remains highly underused with only 20%-50% of eligible patients participating. We aim to implement and evaluate the Country Heart Attack Prevention (CHAP) model of care to improve CR attendance and completion for rural and remote participants. METHODS AND ANALYSIS: CHAP will apply the model for large-scale knowledge translation to develop and implement a model of care to CR in rural Australia. Partnering with patients, clinicians and health service managers, we will codevelop new approaches and refine/expand existing ones to address known barriers to CR attendance. CHAP will codesign a web-based CR programme with patients expanding their choices to CR attendance. To increase referral rates, CHAP will promote endorsement of CR among clinicians and develop an electronic system that automatises referrals of in-hospital eligible patients to CR. A business model that includes reimbursement of CR delivered in primary care by Medicare will enable sustainable access to CR. To promote CR quality improvement, professional development interventions and an accreditation programme of CR services and programmes will be developed. To evaluate 12-month CR attendance/completion (primary outcome), clinical and cost-effectiveness (secondary outcomes) between patients exposed (n=1223) and not exposed (n=3669) to CHAP, we will apply a multidesign approach that encompasses a prospective cohort study, a pre-post study and a comprehensive economic evaluation. ETHICS AND DISSEMINATION: This study was approved by the Southern Adelaide Clinical Human Research Ethics Committee (HREC/20/SAC/78) and by the Department for Health and Wellbeing Human Research Ethics Committee (2021/HRE00270), which approved a waiver of informed consent. Findings and dissemination to patients and clinicians will be through a public website, online educational sessions and scientific publications. Deidentified data will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: ACTRN12621000222842.

Towards a unifying caring life-course theory for better self-care and caring solutions: A discussion paper.

AIM: To present the first iteration of the caring life-course theory. BACKGROUND: Despite requiring care from birth to death, a person's universal or fundamental care needs and the subsequent care provision, either by self or others, has yet to be presented within a life-course perspective. Accurately describing the care people require across their lifespan enables us to identify who, what type, how and where this care should be provided. This novel perspective can help to legitimise a person's care needs and the support they require from wider care systems and contexts. DESIGN: Discussion paper outlines theory development. We adopted an inductive approach to theory development, drawing upon existing literature and the team's diverse experiences. Our theoretical insights were refined through a series of collaborative meetings to define the theory's constructs, until theoretical saturation was reached. DISCUSSION: Fourteen constructs are identified as essential to the theory. We propose it is possible, using these constructs, to generate caring life-course trajectories and predict divergences in these trajectories. The novel contribution of the theory is the interplay between understanding a person's care needs and provision within the context of their lifespan and personal histories, termed their care biography, and understanding a person's care needs and provision at specific points in time within a given care network and socio-political context. IMPACT FOR NURSING: The caring life-course theory can provide a roadmap to inform nursing and other care industry sectors, providing opportunities to integrate and deliver care from the perspective of the person and their care history, trajectories and networks, with those of professional care teams. It can help to shape health, social and economic policy and involve individuals, families and communities in more constructive ways of talking about the importance of care for improved quality of life and healthy societies.

Anti-LYPD1/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Ovarian Cancer.

Ovarian cancer is a diverse class of tumors with very few effective treatment options and suboptimal response rates in early clinical studies using immunotherapies. Here we describe LY6/PLAUR domain containing 1 (LYPD1) as a novel target for therapeutic antibodies for the treatment of ovarian cancer. LYPD1 is broadly expressed in both primary and metastatic ovarian cancer with ∼70% prevalence in the serous cancer subset. Bispecific antibodies targeting CD3 on T cells and a tumor antigen on cancer cells have demonstrated significant clinical activity in hematologic cancers. We have developed an anti-LYPD1/CD3 T-cell-dependent bispecific antibody (TDB) to redirect T-cell responses to LYPD1 expressing ovarian cancer. Here we characterize the nonclinical pharmacology of anti-LYPD1/CD3 TDB and show induction of a robust polyclonal T-cell activation and target dependent killing of LYPD1 expressing ovarian cancer cells resulting in efficient in vivo antitumor responses in PBMC reconstituted immune-deficient mice and human CD3 transgenic mouse models. Anti-LYPD1/CD3 TDB is generally well tolerated at high-dose levels in mice, a pharmacologically relevant species, and showed no evidence of toxicity or damage to LYPD1 expressing tissues.

Late mortality in people with cancer: a population-based Australian study.

OBJECTIVES: To investigate causes of death of people with cancer alive five years after diagnosis, and to compare mortality rates for this group with those of the general population. DESIGN, SETTING, PARTICIPANTS: Retrospective cohort study; analysis of South Australian Cancer Registry data for all people diagnosed with cancer during 1990-1999 and alive five years after diagnosis, with follow-up to 31 December 2016. MAIN OUTCOME MEASURES: All-cause and cancer cause-specific mortality, by cancer diagnosis; standardised mortality ratios (study group v SA general population) by sex, age at diagnosis, follow-up period, and index cancer. RESULTS: Of 32 646 people with cancer alive five years after diagnosis, 30 309 were of European background (93%) and 16 400 were males (50%); the mean age at diagnosis was 60.3 years (SD, 15.7 years). The median follow-up time was 17 years (IQR, 11-21 years); 17 268 deaths were recorded (53% of patients; mean age, 80.6 years; SD, 11.4 years): 7845 attributed to cancer (45% of deaths) and 9423 attributed to non-cancer causes (55%). Ischaemic heart disease was the leading cause of death (2393 deaths), followed by prostate cancer (1424), cerebrovascular disease (1175), and breast cancer (1118). The overall standardised mortality ratio (adjusted for age, sex, and year of diagnosis) was 1.24 (95% CI, 1.22-1.25). The cumulative number of cardiovascular deaths exceeded that of cancer cause-specific deaths from 13 years after cancer diagnosis. CONCLUSIONS: Mortality among people with cancer who are alive at least five years after diagnosis was higher than for the general population, particularly cardiovascular disease-related mortality. Survivorship care should include early recognition and management of risk factors for cardiovascular disease.

Target arm affinities determine preclinical efficacy and safety of anti-HER2/CD3 bispecific antibody.

Systemic cytokine release and on-target/off-tumor toxicity to normal tissues are the main adverse effects limiting the clinical utility of T cell-redirecting therapies. This study was designed to determine how binding affinity for CD3 and tumor target HER2 impact the efficacy and nonclinical safety of anti-HER2/CD3 T cell-dependent antibodies (TDBs). Affinity was found to be a major determinant for the overall tolerability. Higher affinity for CD3 associated with rapidly elevated peripheral cytokine concentrations, weight loss in mice, and poor tolerability in cynomolgus monkeys. A TDB with lower CD3 affinity was better tolerated in cynomolgus monkeys compared with a higher CD3-affinity TDB. In contrast to tolerability, T cell binding affinity had only limited impact on in vitro and in vivo antitumor activity. High affinity for HER2 was critical for the tumor-killing activity of anti-HER2/CD3 TDBs, but higher HER2 affinity also associated with a more severe toxicity profile, including cytokine release and damage to HER2-expressing tissues. The tolerability of the anti-HER2/CD3 was improved by implementing a dose-fractionation strategy. Fine-tuning the affinities for both the tumor target and CD3 is likely a valuable strategy for achieving maximal therapeutic index of CD3 bispecific antibodies.

Differences in the health, mental health and health-promoting behaviours of rural versus urban cancer survivors in Australia.

PURPOSE: People affected by cancer who live in rural Australia experience inferior survival compared to their urban counterparts. This study determines whether self-reported physical and mental health, as well as health-promoting behaviours, also differ between rural and urban Australian adults with a history of cancer. METHODS: Weighted, representative population data were collected via the South Australian Monitoring and Surveillance System between 1 January 2010 and 1 June 2015. Data for participants with a history of cancer (n = 4295) were analysed with adjustment for survey year, gender, age group, education, income, family structure, work status, country of birth and area-level relative socioeconomic disadvantage (SEIFA). RESULTS: Cancer risk factors and co-morbid physical and mental health issues were prevalent among cancer survivors regardless of residential location. In unadjusted analyses, rural survivors were more likely than urban survivors to be obese and be physically inactive. They were equally likely to experience other co-morbidities (diabetes, chronic obstructive pulmonary disease, cardiovascular disease, arthritis or osteoporosis). With adjustment for SEIFA, rural/urban differences in obesity and physical activity disappeared. Rural survivors were more likely to have trust in their communities, less likely to report high/very high distress, but equally likely to report a mental health condition, both with and without adjustment for SEIFA. CONCLUSIONS: There is a need for deeper understanding of the impact of relative socioeconomic disadvantage on health (particularly physical activity and obesity) in rural settings and the development of accessible and culturally appropriate interventions to address rural cancer survivors' specific needs and risk factors.

CD3 bispecific antibody-induced cytokine release is dispensable for cytotoxic T cell activity.

T cell-retargeting therapies have transformed the therapeutic landscape of oncology. Regardless of the modality, T cell activating therapies are commonly accompanied by systemic cytokine release, which can progress to deadly cytokine release syndrome (CRS). Because of incomplete mechanistic understanding of the relationship between T cell activation and systemic cytokine release, optimal toxicity management that retains full therapeutic potential remains unclear. Here, we report the cell type-specific cellular mechanisms that link CD3 bispecific antibody-mediated killing to toxic cytokine release. The immunologic cascade is initiated by T cell triggering, whereas monocytes and macrophages are the primary source of systemic toxic cytokine release. We demonstrate that T cell-generated tumor necrosis factor-α (TNF-α) is the primary mechanism mediating monocyte activation and systemic cytokine release after CD3 bispecific treatment. Prevention of TNF-α release is sufficient to impair systemic release of monocyte cytokines without affecting antitumor efficacy. Systemic cytokine release is only observed upon initial exposure to CD3 bispecific antibody not subsequent doses, indicating a biological distinction between doses. Despite impaired cytokine release after second exposure, T cell cytotoxicity remained unaffected, demonstrating that cytolytic activity of T cells can be achieved in the absence of cytokine release. The mechanistic uncoupling of toxic cytokines and T cell cytolytic activity in the context of CD3 bispecifics provides a biological rationale to clinically explore preventative treatment approaches to mitigate toxicity.

Cardiotoxicity after cancer treatment: a process map of the patient treatment journey.

BACKGROUND/AIM: Cardiotoxicity is a potential complication of anticancer therapy. While guidelines have been developed to assist practitioners, an effective, evidence based clinical pathway for the treatment of cardiotoxicity has not yet been developed. The aim of this study was to describe the journey of patients who developed cardiotoxicity through the healthcare system in order to establish baseline data to inform the development and implementation of a patient-centred, evidence-based clinical pathway. METHODS: Mixed-methods design with quantitative and qualitative components using process mapping at 3 large medical centres in 2 states between 2010 and 2015. RESULTS: Fifty (50) confirmed cases of cardiotoxicity were reviewed (39 medical record reviews, 7 medical record review and interviews and 4 internview only). The mean age at cancer diagnosis of this group was 53.3 years (range 6-89 years); 50% female; 30% breast cancer, 23% non-Hodgkin's lymphoma; mean chemotherapy cycles 5.2 (median 6; range 1-18); 49 (89%) presented to chemotherapy with pre-existing cardiovascular risk factors; 39 (85%) had at least one modifiable risk factor and 11 (24%) had more than 4; 44 (96%) were diagnosed by echocardiogram and 27 (57%) were referred to a cardiologist (only 7 (15%) before chemotherapy). Post chemotherapy, 22 (48%) patients were referred to a multidisciplinary heart failure clinic; 8 (17%) to cardiac rehabilitation; 1 (2%) to cancer survivorship clinic and 10 (22%) to a palliative care service. There were 16 (34%) deaths during the timeframe of the study; 4 (25%) cardiac-related, 6 (38%) cancer-related, 4 (25%) due to sepsis and 2 (12%) other causes not recorded. The main concerns participants raised during the interviews were cancer professionals not discussing the potential for cardiotoxicity with them prior to treatment, nor risk modification strategies; a need for health education, particularly regarding risks for developing heart failure related to cancer treatment; and a lack of collaboration between oncologists and cardiologists. CONCLUSIONS: Our results demonstrate that the clinical management of cancer patients with cardiotoxicity was variable and fragmented and not patient centered. This audit establishes practice gaps that can be addressed through the design of an evidence-based clinical pathway for cancer patients with, or at risk, of cardiotoxicity.

Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3.

A primary barrier to the success of T cell-recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, we developed an anti-HER2/CD3 T cell-dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab-immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell-directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.

Recommendations and practices for the screening of depression and anxiety in acute coronary syndrome: a scoping review protocol.

OBJECTIVE: The objective of this scoping review is to identify and map current recommendations and practices for the screening of depression and anxiety in acute coronary syndrome patients in the acute care setting.Specifically, the review questions are.

Evaluation of the effectiveness of an interactive avatar-based education application for improving heart failure patients' knowledge and self-care behaviours: A pragmatic randomized controlled trial protocol.

AIM: The aim of this study was to evaluate the effectiveness of an avatar-based education application for improving knowledge and self-care behaviour in patients with heart failure (HF). BACKGROUND: Avatar-based technologies for supporting education are an innovative approach for patients with low literacy, low health literacy and English as a second language. The use of avatar technologies for patient education has shown benefits in improving knowledge, self-care behaviours and quality of life in chronic diseases such as cancer, diabetes and depression. Research has demonstrated positive outcomes in clinical practice. However, the effectiveness of this technology has not been evaluated among patients with HF. DESIGN: A multi-centred, non-blinded randomized, two-armed parallel pragmatic, controlled trial. METHOD: Eighty-eight participants will be recruited from the HF clinics at three public hospitals and randomized into either control or intervention groups. The intervention group will receive the avatar-based education plus usual care. The control group will receive usual care. The primary outcome is HF knowledge, secondary outcomes include; improved self-care behaviours, readmission and satisfaction. Data will be collected at the baseline and at 1- and 3-month follow-ups. DISCUSSION: This study will measure the effectiveness of avatar-based education on patients' knowledge and self-care behaviours following HF. The evidence will be evaluated in terms of the reduction in patients' readmission.

Relative Target Affinities of T-Cell-Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model.

Anti-HER2/CD3, a T-cell-dependent bispecific antibody (TDB) construct, induces T-cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. Although therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen-binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy. To our knowledge, no distribution studies have been published using preclinical models wherein the T-cell-targeting arm of the TDB is actively bound to T cells. We used a combined approach involving radiochemistry, invasive biodistribution, and noninvasive single-photon emission tomographic (SPECT) imaging to measure TDB distribution and catabolism in transgenic mice with human CD3ε expression on T cells. Using CD3 affinity variants, we assessed the impact of CD3 affinity on short-term pharmacokinetics, tissue distribution, and cellular uptake. Our experimental approach determined the relative effects of (i) CD3 targeting to normal tissues, (ii) HER2 targeting to HER2-expressing tumors, and (iii) relative HER2/CD3 affinity, all as critical drivers for TDB distribution. We observed a strong correlation between CD3 affinity and distribution to T-cell-rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T-cell-containing tissues. These observations have important implications for clinical translation of bispecific antibodies for cancer immunotherapy. Mol Cancer Ther; 17(4); 776-85. ©2018 AACR.