Current Treatment Options for Renal Cell Carcinoma: Focus on Cell-Based Immunotherapy.

Renal cell carcinoma (RCC) affects over 400,000 patients globally each year, and 30% of patients present with metastatic disease. Current standard of care therapy for metastatic RCC involve TKIs and ICIs, including combinatorial strategies, but this offers only modest clinical benefit. Novel treatment approaches are warranted, and cell-based immunotherapies for RCC hold significant promise. These are currently being tested in the pre-clinical setting and in early phase clinical trials. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies, with a particular focus on defining the current best antigenic targets, the range of cell therapy products being explored in RCC, and how advanced engineering solutions may further enhance these therapies in the RCC space.

The role of maintenance therapy following autologous stem cell transplantation in newly diagnosed multiple myeloma: Considerations on behalf of the Chronic Malignancies Working Party of the EBMT.

Recent treatment advancements in multiple myeloma have led to significant improvements in patient outcomes. Maintenance therapy following autologous haematopoietic stem cell transplantation (AHCT) is now standard of care and has been demonstrated to prolong and deepen treatment responses. Currently, lenalidomide remains the single agent that has been approved for maintenance post-AHCT in Europe and the USA which, if tolerated, is continued until disease progression. The treatment landscape is rapidly expanding however, and the optimal personalised maintenance approach for a patient is becoming more complex. Treatment outcomes for patients with high-risk disease remain poor and choice of maintenance in this population also remains unclear. This review article evaluates up-to-date literature regarding established maintenance approaches. It further analyses ongoing studies exploring maintenance regimens using combination and novel agents, approaches to maintenance in patients with cytogenetic high-risk disease and minimal residual disease response-adapted strategies that reflect the current evolving treatment paradigm.

Meeting Summary: Global Vaccine and Immunization Research Forum, 2021.

The 2021 Global Vaccine and Immunization Research Forum highlighted the considerable advances and recent progress in research and development for vaccines and immunization, critically reviewed lessons learned from COVID-19 vaccine programs, and looked ahead to opportunities for this decade. For COVID-19, decades of investments in basic and translational research, new technology platforms, and vaccines targeting prototype pathogens enabled a rapid, global response. Unprecedented global coordination and partnership have played an essential role in creating and delivering COVID-19 vaccines. More improvement is needed in product attributes such as deliverability, and in equitable access to vaccines. Developments in other priority areas included: the halting of two human immunodeficiency virus vaccine trials due to lack of efficacy in preventing infection; promising efficacy results in Phase 2 trials of two tuberculosis vaccines; pilot implementation of the most advanced malaria vaccine candidate in three countries; trials of human papillomavirus vaccines given in single-dose regimens; and emergency use listing of a novel, oral poliomyelitis type 2 vaccine. More systematic, proactive approaches are being developed for fostering vaccine uptake and demand, aligning on priorities for investment by the public and private sectors, and accelerating policy making. Participants emphasized that addressing endemic disease is intertwined with emergency preparedness and pandemic response, so that advances in one area create opportunities in the other. In this decade, advances made in response to the COVID-19 pandemic should accelerate availability of vaccines for other diseases, contribute to preparedness for future pandemics, and help to achieve impact and equity under Immunization Agenda 2030.

Accelerating access for all through research and innovation in immunization: Recommendations from Strategic Priority 7 of the Immunization Agenda 2030.

Research and innovation have been fundamental to many of the successes in immunization thus far, and will play important roles in the future success of Immunization Agenda 2030 (IA2030). Strategic Priority 7 (SP7) of IA2030, which addresses research and innovation, is explicitly informed by country needs and priorities, and aims to strengthen the innovation ecosystem through capacity building and collaboration at country, regional, and global levels. SP7 identifies four key focus areas: (1) "needs-based innovation", (2) "new and improved products, services, and practices", (3) "evidence for implementation", and (4) "local capacity". Strategic interventions in these key focus areas apply the lessons of the Global Vaccine Action Plan and the "Decade of Vaccines" to emphasize local innovation, promote the use of research by countries to improve program performance and impact, and encourage capacity building for the development and implementation of innovations. The proposed approach will maintain a focus on the development of new vaccines and the improvement of existing vaccines, and increase attention to innovation in service delivery. Monitoring and evaluation will foster evidence-based priority setting at the country level and help to ground the global research and development (R&D) agenda in the needs of communities. Together, these approaches are intended to harness the power of research and innovation more effectively, to meet the challenges of the future and achieve the ambitious goals of IA2030.

Improving access to human papillomavirus vaccines: A case study in the IA2030 core principle of partnership.

Partnerships are fundamental to progress in immunization, and this is especially true for human papillomavirus (HPV) vaccination, which must be delivered in the context of a broader immunization, sexual and reproductive health, and cervical cancer prevention programs. Starting from the discovery and development of HPV vaccines, through to implementation and improvement of the program's resilience, partnerships have played a critical role. In May 2018, the Global Strategy to Accelerate the Elimination of Cervical Cancer set a target for 90 % of girls to be fully vaccinated with HPV vaccine by age 15 years. This will require effective partnership and multisectoral collaboration among current and future partners to ensure alignment of interests, efficient execution, and the establishment of mechanisms to resolve emerging challenges and pre-empt foreseeable risks. In ramping up this partnering approach, HPV can provide a template for other health and immunization programs.

Pharmacogenomics cascade testing (PhaCT): a novel approach for preemptive pharmacogenomics testing to optimize medication therapy.

The implementation of pharmacogenomics (PGx) has come a long way since the dawn of utilizing pharmacogenomic data in clinical patient care. However, the potential benefits of sharing PGx results have yet to be explored. In this paper, we explore the willingness of patients to share PGx results, as well as the inclusion of family medication history in identifying potential family members for pharmacogenomics cascade testing (PhaCT). The genetic similarities in families allow for identifying potential gene variants prior to official preemptive testing. Once a candidate patient is determined, PhaCT can be initiated. PhaCT recognizes that further cascade testing throughout a family can serve to improve precision medicine. In order to make PhaCT feasible, we propose a novel shareable HIPAA-compliant informatics platform that will enable patients to manage not only their own test results and medications but also those of their family members. The informatics platform will be an external genomics system with capabilities to integrate with patients' electronic health records. Patients will be given the tools to provide information to and work with clinicians in identifying family members for PhaCT through this platform. Offering patients the tools to share PGx results with their family members for preemptive testing could be the key to empowering patients. Clinicians can utilize PhaCT to potentially improve medication adherence, which may consequently help to distribute the burden of health management between patients, family members, providers, and payers.

Artificial Intelligence-Powered Smartphone App to Facilitate Medication Adherence: Protocol for a Human Factors Design Study.

BACKGROUND: Medication Guides consisting of crucial interactions and side effects are extensive and complex. Due to the exhaustive information, patients do not retain the necessary medication information, which can result in hospitalizations and medication nonadherence. A gap exists in understanding patients' cognition of managing complex medication information. However, advancements in technology and artificial intelligence (AI) allow us to understand patient cognitive processes to design an app to better provide important medication information to patients. OBJECTIVE: Our objective is to improve the design of an innovative AI- and human factor-based interface that supports patients' medication information comprehension that could potentially improve medication adherence. METHODS: This study has three aims. Aim 1 has three phases: (1) an observational study to understand patient perception of fear and biases regarding medication information, (2) an eye-tracking study to understand the attention locus for medication information, and (3) a psychological refractory period (PRP) paradigm study to understand functionalities. Observational data will be collected, such as audio and video recordings, gaze mapping, and time from PRP. A total of 50 patients, aged 18-65 years, who started at least one new medication, for which we developed visualization information, and who have a cognitive status of 34 during cognitive screening using the TICS-M test and health literacy level will be included in this aim of the study. In Aim 2, we will iteratively design and evaluate an AI-powered medication information visualization interface as a smartphone app with the knowledge gained from each component of Aim 1. The interface will be assessed through two usability surveys. A total of 300 patients, aged 18-65 years, with diabetes, cardiovascular diseases, or mental health disorders, will be recruited for the surveys. Data from the surveys will be analyzed through exploratory factor analysis. In Aim 3, in order to test the prototype, there will be a two-arm study design. This aim will include 900 patients, aged 18-65 years, with internet access, without any cognitive impairment, and with at least two medications. Patients will be sequentially randomized. Three surveys will be used to assess the primary outcome of medication information comprehension and the secondary outcome of medication adherence at 12 weeks. RESULTS: Preliminary data collection will be conducted in 2021, and results are expected to be published in 2022. CONCLUSIONS: This study will lead the future of AI-based, innovative, digital interface design and aid in improving medication comprehension, which may improve medication adherence. The results from this study will also open up future research opportunities in understanding how patients manage complex medication information and will inform the format and design for innovative, AI-powered digital interfaces for Medication Guides. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/21659.

The inclusion of health data standards in the implementation of pharmacogenomics systems: a scoping review.

Background: Despite potential benefits, the practice of incorporating pharmacogenomics (PGx) results in clinical decisions has yet to diffuse widely. In this study, we conducted a review of recent discussions on data standards and interoperability with a focus on sharing PGx test results among health systems. Materials & methods: We conducted a literature search for PGx clinical decision support systems between 1 January 2012 and 31 January 2020. Thirty-two out of 727 articles were included for the final review. Results: Nine of the 32 articles mentioned data standards and only four of the 32 articles provided solutions for the lack of interoperability. Discussions: Although PGx interoperability is essential for widespread implementation, a lack of focus on standardized data creates a formidable challenge for health information exchange. Conclusion: Standardization of PGx data is essential to improve health information exchange and the sharing of PGx results between disparate systems. However, PGx data standards and interoperability are often not addressed in the system-level implementation.

Choosing Evolution over Extinction: Integrating Direct Patient Care Services and Value-Based Payment Models into the Community-Based Pharmacy Setting.

The American healthcare payment model introduced Pharmacy Benefit Managers (PBMs) into a position of power that currently puts into question the state of the pharmacy profession, especially in the community field. Reimbursement plans had been designed to benefit all stakeholders and save patients money but have only been shown to increase costs for these involved parties. There exist unresolved gaps in care as a result of the healthcare structure and underutilized skills of trained pharmacists who do not have the federal means to provide clinical services. Four collaborative payment models have been proposed, offering methods to quell the monetary problems that exist and are predicted to continue with the closure of community pharmacies and sustained influence of PBMs. These models may additionally allow the expansion of pharmacy career paths and improve healthcare benefits for patients. With a reflective perspective on the healthcare structure and knowledge of positive impacts with the inclusion of pharmacists, solutions to payment challenges could present a progressive approach to an outdated system. The impact of the COVID-19 pandemic highlights a dependency on pharmacists and community settings. This outlook on pharmacists may persist and an established expansion of services could prove beneficial to all healthcare stakeholders.

Global Vaccine Action Plan Lessons Learned II: Stakeholder Perspectives.

INTRODUCTION: The Global Vaccine Action Plan (GVAP), unanimously endorsed by the World Health Assembly in 2012, defined an ambitious strategy to improve immunization. At the end of the decade, significant progress has been made but four of the five GVAP goals are likely to be missed. This report describes a set of surveys and interviews relating to GVAP, conducted to inform the immunization strategy for the next decade. METHODS: Three surveys and two sets of semi-structured interviews were conducted from 2017 to 2019. Respondents consisted of immunization stakeholders at global, regional, and country levels, and included individuals who had been involved in the development and implementation of GVAP or its monitoring, evaluation and accountability (M&E/A) process; national immunization managers; academics; and personnel from non-governmental organizations and civil society organizations. RESULTS: The surveys and interviews gave consistent results. They highlighted the value of GVAP in increasing visibility for immunization and the benefits of the GVAP M&E/A framework. The main limitations of GVAP were identified as the limited ownership by countries and other stakeholders leading to incomplete implementation of the strategy and poor accountability for achieving GVAP targets. DISCUSSION: These results informed the review of GVAP and the development of its successor strategy, the Immunization Agenda 2030. In addition, these surveys and interviews identified two challenges in assessing the value of GVAP: the need to rely exclusively on stakeholder perspectives and difficulties in attributing benefits. These challenges are inherent in evaluating an over-arching strategy such as GVAP and should be factored into interpretation of the results.

Global Vaccine Action Plan lessons learned III: Monitoring and evaluation/accountability framework.

INTRODUCTION: The Monitoring & Evaluation/Accountability (M&E/A) framework of the Global Vaccine Action Plan (GVAP) was used to report progress annually to the World Health Assembly (WHA). METHODS: Stakeholder feedback was obtained through five reviews consisting of surveys and semi-structured interviews conducted from 2017 to 2019. Participants consisted of individuals involved in the development and implementation of GVAP or its M&E/A process, national immunization managers, academics, representatives of non-governmental organizations, and civil society organizations. RESULTS: The feedback was mixed and contradictory for some components, though most participants reported that the M&E/A process was a highlight of GVAP and a step in the right direction. Several of the goals and targets were considered aspirational and unrealistic for many countries. There were mixed responses on whether it promoted accountability, especially at the country level. DISCUSSION: The mixed and contradictory views on the M&E/A processes and its impact suggested a failure of communication about its scope and intent. Though the process, especially the annual reporting to the WHA, kept immunization high on the global agenda, it failed to fully meet the expectations in promoting accountability. Engaging with countries to capture the local context in setting global goals and targets and promoting local M&E/A processes will be important to achieve accountability in the next decade.

Eliminating Meningococcal Epidemics From the African Meningitis Belt: The Case for Advanced Prevention and Control Using Next-Generation Meningococcal Conjugate Vaccines.

The introduction and rollout of a meningococcal serogroup A conjugate vaccine, MenAfriVac, in the African meningitis belt has eliminated serogroup A meningococcal infections for >300 million Africans. However, serogroup C, W, and X meningococci continue to circulate and have been responsible for focal epidemics in meningitis belt countries. Affordable multivalent meningococcal conjugate vaccines are being developed to prevent these non-A epidemics. This article describes the current epidemiologic situation and status of vaccine development and highlights questions to be addressed to most efficiently use these new vaccines.

Meeting report: Global vaccine and immunization research forum, 2018.

Every two years, the Global Vaccine and Immunization Research Forum takes stock of global research in vaccines and immunization. As in prior years, the 2018 meeting addressed vaccine discovery, development, decision-making, and deployment. This time, however, it also featured two overarching themes: "Innovating for Equity" and "End-to-End Integration." Significant advances have been made in the last two years, but participants noted that some important goals of the Global Vaccine Action Plan are not being met and called urgently for innovation in improving access to vaccines. Two factors were highlighted as crucial to improving coverage: a focus on equity and sustainability throughout the immunization ecosystem, and an enabling political environment that prioritizes health and immunization.

Meeting report: Global vaccine and immunization research forum.

Building on the success of the first Global Vaccine and Immunization Research Forum (GVIRF), the World Health Organization, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health in the United States of America, and the Bill & Melinda Gates Foundation convened the second GVIRF in March 2016. Leading scientists, vaccine developers, and public health officials from around the world discussed scientific advances and innovative technologies to design and deliver vaccines as well as novel tools and approaches to increase the uptake of vaccines throughout the world. This report summarizes the discussions and conclusions from the forum participants.

Redox-Triggered Release of Moxifloxacin from Mesoporous Silica Nanoparticles Functionalized with Disulfide Snap-Tops Enhances Efficacy Against Pneumonic Tularemia in Mice.

Effective and rapid treatment of tularemia is needed to reduce morbidity and mortality of this potentially fatal infectious disease. The etiologic agent, Francisella tularensis, is a facultative intracellular bacterial pathogen which infects and multiplies to high numbers in macrophages. Nanotherapeutics are particularly promising for treatment of infectious diseases caused by intracellular pathogens, whose primary host cells are macrophages, because nanoparticles preferentially target and are avidly internalized by macrophages. A mesoporous silica nanoparticle (MSN) has been developed functionalized with disulfide snap-tops that has high drug loading and selectively releases drug intracellularly in response to the redox potential. These nanoparticles, when loaded with Hoechst fluorescent dye, release their cargo exclusively intracellularly and stain the nuclei of macrophages. The MSNs loaded with moxifloxacin kill F. tularensis in macrophages in a dose-dependent fashion. In a mouse model of lethal pneumonic tularemia, MSNs loaded with moxifloxacin prevent weight loss, illness, and death, markedly reduce the burden of F. tularensis in the lung, liver, and spleen, and are significantly more efficacious than an equivalent amount of free drug. An important proof-of-principle for the potential therapeutic use of a novel nanoparticle drug delivery platform for the treatment of infectious diseases is provided.

Global Vaccine and Immunization Research Forum: Opportunities and challenges in vaccine discovery, development, and delivery.

The World Health Organization, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Bill & Melinda Gates Foundation convened the first Global Vaccine and Immunization Research Forum (GVIRF) in March 2014. This first GVIRF aimed to track recent progress of the Global Vaccine Action Plan research and development agenda, identify opportunities and challenges, promote partnerships in vaccine research, and facilitate the inclusion of all stakeholders in vaccine research and development. Leading scientists, vaccine developers, and public health officials from around the world discussed scientific and technical challenges in vaccine development, research to improve the impact of immunization, and regulatory issues. This report summarizes the discussions and conclusions from the forum participants.

Tuberculosis: pH-Responsive Isoniazid-Loaded Nanoparticles Markedly Improve Tuberculosis Treatment in Mice (Small 38/2015).

On page 5066, J. I. Zink, M. A. Horwitz, and co-workers use confocal microscopy to demonstrate the avid uptake of RITC-labeled mesoporous silica nanoparticles loaded with the anti-tuberculosis drug isoniazid (shown here in red) by human macrophages (nuclei stained blue with DAPI) infected with GFP-expressing Mycobacterium tuberculosis (shown here in green).

pH-Responsive Isoniazid-Loaded Nanoparticles Markedly Improve Tuberculosis Treatment in Mice.

Tuberculosis is a major global health problem for which improved therapeutics are needed to shorten the course of treatment and combat emergence of drug resistance. Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is an intracellular pathogen of mononuclear phagocytes. As such, it is an ideal pathogen for nanotherapeutics because macrophages avidly ingest nanoparticles even without specific targeting molecules. Hence, a nanoparticle drug delivery system has the potential to target and deliver high concentrations of drug directly into M. tuberculosis-infected cells-greatly enhancing efficacy while avoiding off-target toxicities. Stimulus-responsive mesoporous silica nanoparticles of two different sizes, 100 and 50 nm, are developed as carriers for the major anti-tuberculosis drug isoniazid in a prodrug configuration. The drug is captured by the aldehyde-functionalized nanoparticle via hydrazone bond formation and coated with poly(ethylene imine)-poly(ethylene glycol) (PEI-PEG). The drug is released from the nanoparticles in response to acidic pH at levels that naturally occur within acidified endolysosomes. It is demonstrated that isoniazid-loaded PEI-PEG-coated nanoparticles are avidly ingested by M. tuberculosis-infected human macrophages and kill the intracellular bacteria in a dose-dependent manner. It is further demonstrated in a mouse model of pulmonary tuberculosis that the nanoparticles are well tolerated and much more efficacious than an equivalent amount of free drug.

Functional nanovalves on protein-coated nanoparticles for in vitro and in vivo controlled drug delivery.

A multifunctional mesoporous drug delivery system that contains fluorescent imaging molecules, targeting proteins, and pH-sensitive nanovalves is developed and tested. Three nanovalve-mesoporous silica nanoparticle (NV-MSN) systems with varied quantities of nanovalves on the surface are synthesized. These systems are characterized and tested to optimize the trade-off between the coverage of nanovalves on the MSNs to effectively trap and deliver cargo, and the remaining underivatized silanol groups that can be used for protein attachments. The NV-MSN system that has satisfactory coverage for high loading and spare silanols is chosen, and transferrin (Tf) is integrated into the system. Abiotic studies are performed to test the operation of the nanovalve in the presence of the protein. In vitro studies are carried out to demonstrate the autonomous activation and function of the nanovalves in the system under biological conditions. Enhanced cellular uptake of the Tf-modified MSNs is seen using fluorescence microscopy and flow cytometry in MiaPaCa-2 cells. The MSNs are then tested using SCID mice, which show that both targeted and untargeted NV-MSN systems are fully functional to effectively deliver cargo. These new multifunctional nanoparticles serve proof of concept of nanovalve functionality in the presence of large proteins and demonstrate another dimension of MSN-based theranostic platforms.