A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade.

Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations. MCLA-145 potently activates T cells at sub-nanomolar concentrations, even under suppressive conditions, and enhances T cell priming, differentiation and memory recall responses. In vivo, MCLA-145 anti-tumor activity is superior to immune checkpoint inhibitor comparators and linked to recruitment and intra-tumor expansion of CD8 + T cells. No graft-versus-host-disease is observed in contrast to other antibodies inhibiting the PD-1 and PD-L1 pathway. Non-human primates treated with 100 mg/kg/week of MCLA-145 show no adverse effects. The conditional activation of CD137 signaling by MCLA-145, triggered by neighboring cells expressing >5000 copies of PD-L1, may provide both safety and potency advantages.

Parsaclisib Is a Next-Generation Phosphoinositide 3-Kinase δ Inhibitor with Reduced Hepatotoxicity and Potent Antitumor and Immunomodulatory Activities in Models of B-Cell Malignancy.

The clinical use of first-generation phosphoinositide 3-kinase (PI3K)δ inhibitors in B-cell malignancies is hampered by hepatotoxicity, requiring dose reduction, treatment interruption, and/or discontinuation of therapy. In addition, potential molecular mechanisms by which resistance to this class of drugs occurs have not been investigated. Parsaclisib (INCB050465) is a potent and selective next-generation PI3Kδ inhibitor that differs in structure from first-generation PI3Kδ inhibitors and has shown encouraging anti-B-cell tumor activity and reduced hepatotoxicity in phase 1/2 clinical studies. Here, we present preclinical data demonstrating parsaclisib as a potent inhibitor of PI3Kδ with over 1000-fold selectivity against other class 1 PI3K isozymes. Parsaclisib directly blocks PI3K signaling-mediated cell proliferation in B-cell lines in vitro and in vivo and indirectly controls tumor growth by lessening immunosuppression through regulatory T-cell inhibition in a syngeneic lymphoma model. Diffuse large B-cell lymphoma cell lines overexpressing MYC were insensitive to proliferation blockade via PI3Kδ signaling inhibition by parsaclisib, but their proliferative activities were reduced by suppression of MYC gene transcription. Molecular structure analysis of the first- and next-generation PI3Kδ inhibitors combined with clinical observation suggests that hepatotoxicity seen with the first-generation inhibitors could result from a structure-related off-target effect. Parsaclisib is currently being evaluated in multiple phase 2 clinical trials as a therapy against various hematologic malignancies of B-cell origin (NCT03126019, NCT02998476, NCT03235544, NCT03144674, and NCT02018861). SIGNIFICANCE STATEMENT: The preclinical properties described here provide the mechanism of action and support clinical investigations of parsaclisib as a therapy for B-cell malignancies. MYC overexpression was identified as a resistance mechanism to parsaclisib in DLBCL cells, which may be useful in guiding further translational studies for the selection of patients with DLBCL who might benefit from PI3Kδ inhibitor treatment in future trials. Hepatotoxicity associated with first-generation PI3Kδ inhibitors may be an off-target effect of that class of compounds.

INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of Phosphoinositide 3-Kinase Delta (PI3Kδ).

A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδ inhibitors, such as idelalisib (1), duvelisib (2), and INCB040093 (3, dezapelisib). Parsaclisib (20) is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.

Mobile Health Divide Between Clinicians and Patients in Cancer Care: Results From a Cross-Sectional International Survey.

BACKGROUND: Mobile technologies are increasingly being used to manage chronic diseases, including cancer, with the promise of improving the efficiency and effectiveness of care. Among the myriad of mobile technologies in health care, we have seen an explosion of mobile apps. The rapid increase in digital health apps is not paralleled by a similar trend in usage statistics by clinicians and patients. Little is known about how much and in what ways mobile health (mHealth) apps are used by clinicians and patients for cancer care, what variables affect their use of mHealth, and what patients' and clinicians' expectations of mHealth apps are. OBJECTIVE: This study aimed to describe the patient and clinician population that uses mHealth in cancer care and to provide recommendations to app developers and regulators to generally increase the use and efficacy of mHealth apps. METHODS: Through a cross-sectional Web-based survey, we explored the current utilization rates of mHealth in cancer care and factors that explain the differences in utilization by patients and clinicians across the United States and 5 different countries in Europe. In addition, we conducted an international workshop with more than 100 stakeholders and a roundtable with key representatives of international organizations of clinicians and patients to solicit feedback on the survey results and develop insights into mHealth app development practices. RESULTS: A total of 1033 patients and 1116 clinicians participated in the survey. The proportion of cancer patients using mHealth (294/1033, 28.46%) was far lower than that of clinicians (859/1116, 76.97%). Accounting for age and salary level, the marginal probabilities of use at means are still significantly different between the 2 groups and were 69.8% for clinicians and 38.7% for patients using the propensity score-based regression adjustment with weighting technique. Moreover, our analysis identified a gap between basic and advanced users, with a prevalent use for activities related to the automation of processes and the interaction with other individuals and a limited adoption for side-effect management and compliance monitoring in both groups. CONCLUSIONS: mHealth apps can provide access to clinical and economic data that are low cost, easy to access, and personalized. The benefits can go as far as increasing patients' chances of overall survival. However, despite its potential, evidence on the actual use of mobile technologies in cancer care is not promising. If the promise of mHealth is to be fulfilled, clinician and patient usage rates will need to converge. Ideally, cancer apps should be designed in ways that strengthen the patient-physician relationship, ease physicians' workload, be tested for validity and effectiveness, and fit the criteria for reimbursement.

Interprofessional education and practice guide: interprofessional team writing to promote dissemination of interprofessional education scholarship and products.

Collaborations to develop, implement, evaluate, replicate, and write about interprofessional education (IPE) activities within and across institutions are wonderful opportunities to experience teamwork, team communication, ethics and values, and the roles and responsibilities of interprofessional team writing. Just as effective communication in interprofessional team-based care is essential for providing safe, high-quality health care, similar communication strategies are necessary to produce high-quality scholarship of IPE curricula and activities. Relationship and communication issues that affect health care teams' abilities to work together effectively (e.g., hierarchy, exclusion, assumptions, non-responsiveness, biases, stereotypes and poor hand-offs of information) can also occur in interprofessional team writing. Between 1970 and 2010, interprofessional practice research publications increased by 2293%. Although there has been tremendous growth in the IPE literature, especially of articles that require collaborative writing, there have not been any papers addressing the challenges of interprofessional team writing. As more teams collaborate to develop IPE, there is a need to establish principles and strategies for effective interprofessional team writing. In this education and practice guide, a cross-institutional team of faculty, staff, and graduate students who have collaborated on externally funded IPE grants, conferences, products, and workshops will share lessons learned for successfully collaborating in interprofessional team writing.

Preclinical characterization of INCB053914, a novel pan-PIM kinase inhibitor, alone and in combination with anticancer agents, in models of hematologic malignancies.

The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine protein kinases are overexpressed in many hematologic and solid tumor malignancies and play central roles in intracellular signaling networks important in tumorigenesis, including the Janus kinase-signal transducer and activator of transcription (JAK/STAT) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. The three PIM kinase isozymes (PIM1, PIM2, and PIM3) share similar downstream substrates with other key oncogenic kinases and have differing but mutually compensatory functions across tumors. This supports the therapeutic potential of pan-PIM kinase inhibitors, especially in combination with other anticancer agents chosen based on their role in overlapping signaling networks. Reported here is a preclinical characterization of INCB053914, a novel, potent, and selective adenosine triphosphate-competitive pan-PIM kinase inhibitor. In vitro, INCB053914 inhibited proliferation and the phosphorylation of downstream substrates in cell lines from multiple hematologic malignancies. Effects were confirmed in primary bone marrow blasts from patients with acute myeloid leukemia treated ex vivo and in blood samples from patients receiving INCB053914 in an ongoing phase 1 dose-escalation study. In vivo, single-agent INCB053914 inhibited Bcl-2-associated death promoter protein phosphorylation and dose-dependently inhibited tumor growth in acute myeloid leukemia and multiple myeloma xenografts. Additive or synergistic inhibition of tumor growth was observed when INCB053914 was combined with selective PI3Kδ inhibition, selective JAK1 or JAK1/2 inhibition, or cytarabine. Based on these data, pan-PIM kinase inhibitors, including INCB053914, may have therapeutic utility in hematologic malignancies when combined with other inhibitors of oncogenic kinases or standard chemotherapeutics.

INCB040093 Is a Novel PI3Kδ Inhibitor for the Treatment of B Cell Lymphoid Malignancies.

Phosphatidylinositol 3-kinase delta (PI3Kδ) is a critical signaling molecule in B cells and is considered a target for development of therapies against various B cell malignancies. INCB040093 is a novel PI3Kδ small-molecule inhibitor and has demonstrated promising efficacy in patients with Hodgkin's lymphoma in clinical studies. In this study, we disclose the chemical structure and the preclinical activity of the compound. In biochemical assays, INCB040093 potently inhibits the PI3Kδ kinase, with 74- to >900-fold selectivity against other PI3K family members. In vitro and ex vivo studies using primary B cells, cell lines from B cell malignancies, and human whole blood show that INCB040093 inhibits PI3Kδ-mediated functions, including cell signaling and proliferation. INCB040093 has no significant effect on the growth of nonlymphoid cell lines and was less potent in assays that measure human T and natural killer cell proliferation and neutrophil and monocyte functions, suggesting that the impact of INCB040093 on the human immune system will likely be restricted to B cells. INCB040093 inhibits the production of macrophage-inflammatory protein-1ß (MIP-1beta) and tumor necrosis factor-ß (TNF-beta) from a B cell line, suggesting a potential effect on the tumor microenvironment. In vivo, INCB040093 demonstrates single-agent activity in inhibiting tumor growth and potentiates the antitumor growth effect of the clinically relevant chemotherapeutic agent, bendamustine, in the Pfeiffer cell xenograft model of non-Hodgkin's lymphoma. INCB040093 has a favorable exposure profile in rats and an acceptable safety margin in rats and dogs. Taken together, data presented in this report support the potential utility of orally administered INCB040093 in the treatment of B cell malignancies.

Effectiveness of the South African expanded program of immunization against hepatitis B in children infected with human immunodeficiency virus-1 living in a resource-limited setting of Kwazulu-Natal.

Prevalence of Human-Immunodeficiency-Virus/Hepatitis-B-virus (HIV/HBV) coinfection and HBV vaccination response in children are unknown in Kwazulu-Natal. This study included 183 HIV-infected and 108 HIV-uninfected children aged between 5 and 15 years screened for HBV infection and vaccination. HBV infection occurred in 2.1% and 0% of HIV-infected and uninfected children respectively. Serological response to immunization was shown in 15.8% and 61.1% of HIV-infected and uninfected children, respectively (P < 0.001). Even if prevalence of HBV infection was low in these cohorts, HIV-infected children will stay at risk of infection if the vaccine schedule is not adapted. J. Med. Virol. 89:182-185, 2017. © 2016 Wiley Periodicals, Inc.

Findings from a mixed-methods study of an interprofessional faculty development program.

Forty faculty members from eight schools participated in a year-long National Faculty Development Program (NFDP) conducted in 2012-2013, aimed at developing faculty knowledge and skills for interprofessional education (IPE). The NFDP included two live conferences. Between conferences, faculty teams implemented self-selected IPE projects at their home institutions and participated in coaching and peer-support conference calls. This paper describes program outcomes. A mixed methods approach was adopted. Data were gathered through online surveys and semi-structured interviews. The study explored whether faculty were satisfied with the program, believed the program was effective in developing knowledge and skills in designing, implementing, and evaluating IPE, and planned to continue newly-implemented IPE and faculty development (FD). Peer support and networking were two of the greatest perceived benefits. Further, this multi-institutional program appears to have facilitated early organizational change by bringing greater contextual understanding to assumptions made at the local level that in turn could influence hidden curricula and networking. These findings may guide program planning for future FD to support IPE.

The cancer experience map: an approach to including the patient voice in supportive care solutions.

The perspective of the patient, also called the "patient voice", is an essential element in materials created for cancer supportive care. Identifying that voice, however, can be a challenge for researchers and developers. A multidisciplinary team at a health information company tasked with addressing this issue created a representational model they call the "cancer experience map". This map, designed as a tool for content developers, offers a window into the complex perspectives inside the cancer experience. Informed by actual patient quotes, the map shows common overall themes for cancer patients, concerns at key treatment points, strategies for patient engagement, and targeted behavioral goals. In this article, the team members share the process by which they created the map as well as its first use as a resource for cancer support videos. The article also addresses the broader policy implications of including the patient voice in supportive cancer content, particularly with regard to mHealth apps.

Interprofessional Education and Practice Guide No. 1: developing faculty to effectively facilitate interprofessional education.

With the growth of interprofessional education (IPE) and practice in health professional schools, faculty members are being asked to assume new roles in leading or delivering interprofessional curriculum. Many existing faculty members feel ill-prepared to face the challenges of this curricular innovation. From 2012-2013, University of Missouri - Columbia and University of Washington partnered with six additional academic health centers to pilot a faculty development course to prepare faculty leaders for IPE. Using a variety of techniques, including didactic teaching, small group exercises, immersion participation in interprofessional education, local implementation of new IPE projects, and peer learning, the program positioned each site to successfully introduce an interprofessional innovation. Participating faculty confirmed the value of the program, and suggested that more widespread similar efforts were worthwhile. This guide briefly describes this faculty development program and identifies key lessons learned from the initiative. Peer learning arising from a faculty development community, adaptation of curricula to fit local context, experiential learning, and ongoing coaching/mentoring, especially as it related to actual participation in IPE activities, were among the key elements of this successful faculty development activity.

A model to support shared decision making in electronic health records systems.

Shared decision making (SDM) is an approach to medical care based on collaboration between provider and patient, with both sharing in medical decisions. When patients' values and preferences are incorporated in decision making, care is more appropriate, ethically sound, and often lower in cost. However, SDM is difficult to implement in routine practice because of the time required for SDM methods, the lack of integration of SDM approaches into electronic health record (EHR) systems, and absence of explanatory mechanisms for providers on the results of patients' use of decision aids. This article discusses potential solutions, including the concept of a "personalize button" for EHRs. Leveraging a 4-phase clinical model for SDM, this article describes how computer decision support (CDS) technologies integrated into EHRs can help ensure that health care is delivered in a way that is respectful of those preferences. The architecture described herein, called CDS for SDM, is built on recognized standards that are currently integrated into certification requirements for EHRs as part of meaningful use regulations. While additional work is needed on modeling of preferences and on techniques for rapid communication models of preferences to clinicians, unless EHRs are redesigned to support SDM around and during clinical encounters, they are likely to continue to be an unintended barrier to SDM. With appropriate development, EHRs could be a powerful tool to promote SDM by reminding providers of situations for SDM and monitoring ongoing care to ensure treatments are consistent with patients' preferences.

Broad-range direct detection and identification of fungi by use of the PLEX-ID PCR-electrospray ionization mass spectrometry (ESI-MS) system.

The PLEX-ID system is a novel technology that couples PCR amplification and electrospray ionization-mass spectrometry to identify pathogens directly in clinical specimens. The analytical performance of the PLEX-ID Broad Fungal assay was compared with that of traditional culture identification by using 91 characterized fungal culture isolates (64 manufacturer-claimed and 27 nonclaimed organisms) and directly by using 395 respiratory specimens. Discordant results were resolved by D2 large-subunit ribosomal DNA fungal sequencing. Environmental studies were performed to monitor for potential contamination. The PLEX-ID Broad Fungal assay correctly identified 95.6% (87/91) and 81.3% (74/91) of the culture isolates to the genus and species levels, respectively. Of the manufacturer-claimed organisms, 100% (64/64) and 92.2% (59/64) were correctly identified to the genus and species levels, respectively. Direct analysis of respiratory specimens resulted in 67.6% (267/395) and 66.6% (263/395) agreement with culture results to the genus and species levels, respectively, with 16.2% (64/395) of the results discordant with culture and 16.2% (64/395) not detected by the system. The majority (>95%) of the isolates not detected directly by the PLEX-ID system ultimately grew in low quantities in culture (≤ 20 colonies). In 20.3% (35/172) of the respiratory specimens where no growth was observed in culture, the PLEX-ID system identified a fungus, suggesting a potential increase in sensitivity over culture in some instances. The PLEX-ID system provides a rapid method for the detection of a broad array of fungi directly in respiratory specimens and has the potential of impacting turnaround times and patient care by reducing the need to wait for the growth of an organism in culture.

Evaluation of the Sensititre MycoTB plate for susceptibility testing of the Mycobacterium tuberculosis complex against first- and second-line agents.

The Sensititre MycoTB plate (TREK Diagnostic Systems, Cleveland, OH) uses a microtiter plate MIC format for susceptibility testing of Mycobacterium tuberculosis complex isolates against first- and second-line antituberculosis agents. Categorical agreement versus the agar proportion method for 122 M. tuberculosis complex isolates was 94% to 100%.

The second victim of adverse health care events.

Nurses and other professionals drawn to health care by their desire to help others may be traumatized because they are involved in situations that bring harm rather than healing to patients. Health systems should develop early warning systems to alert unit or team leaders when health workers are at risk of harm from adverse events. This article focuses on health professionals who become second victims of adverse events that occur to patients.

Formic acid-based direct, on-plate testing of yeast and Corynebacterium species by Bruker Biotyper matrix-assisted laser desorption ionization-time of flight mass spectrometry.

An on-plate testing method using formic acid was evaluated on the Bruker Biotyper matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry system using 90 yeast and 78 Corynebacterium species isolates, and 95.6 and 81.1% of yeast and 96.1 and 92.3% of Corynebacterium isolates were correctly identified to the genus and species levels, respectively. The on-plate method using formic acid yielded identification percentages similar to those for the conventional but more laborious tube-based extraction.

Evaluation of the Yeast Traffic Light PNA FISH probes for identification of Candida species from positive blood cultures.

The Yeast Traffic Light PNA FISH kit (YTL) correctly identified Candida spp. in 207/216 (96%) positive blood cultures. Discordant results were seen with known cross-reacting species and cultures containing Candida lambica and Rhodotorula mucilaginosa. The YTL provides rapid, reliable identification of the five common Candida species found in blood cultures.

A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3.

PURPOSE: The c-MET receptor tyrosine kinase plays important roles in the formation, progression, and dissemination of human cancer and presents an attractive therapeutic target. This study describes the preclinical characterization of INCB28060, a novel inhibitor of c-MET kinase. EXPERIMENTAL DESIGN: Studies were conducted using a series of in vitro and in vivo biochemical and biological experiments. RESULTS: INCB28060 exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10,000-fold selectivity over a large panel of human kinases. This inhibitor potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET-dependent tumor cell lines. As a result, INCB28060 potently inhibits c-MET-dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro. Oral dosing of INCB28060 results in time- and dose-dependent inhibition of c-MET phosphorylation and tumor growth in c-MET-driven mouse tumor models, and the inhibitor is well tolerated at doses that achieve complete tumor inhibition. In a further exploration of potential interactions between c-MET and other signaling pathways, we found that activated c-MET positively regulates the activity of epidermal growth factor receptors (EGFR) and HER-3, as well as expression of their ligands. These effects are reversed with INCB28060 treatment. Finally, we confirmed that circulating hepatocyte growth factor levels are significantly elevated in patients with various cancers. CONCLUSIONS: Activated c-MET has pleiotropic effects on multiple cancer-promoting signaling pathways and may play a critical role in driving tumor cell growth and survival. INCB28060 is a potent and selective c-MET kinase inhibitor that may have therapeutic potential in cancer treatment.

Dermatophyte identification using matrix-assisted laser desorption ionization-time of flight mass spectrometry.

The performance of the Bruker Biotyper matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometer (MS) for the identification of dermatophytes from clinical cultures was compared to that of dermatophyte identification using 28S rRNA gene sequencing. The MALDI Biotyper library (MBL; version 3.0) was used alone and in combination with a supplemented library containing an additional 20 dermatophyte spectra (S-MBL). Acquired spectra were interpreted using both the manufacturer-recommended scores (genus, ≥1.7; species, ≥2.0) and adjusted cutoff values established by this study (genus, ≥1.5; species, ≥1.7); identifications required a minimum 10% difference in scores between the top two different organisms to be considered correct. One hundred well-characterized, archived dermatophyte isolates and 71 fresh dermatophyte cultures were evaluated using both libraries and both sets of cutoff criteria. Collectively, the S-MBL significantly outperformed the MBL at both the genus (93% versus 37.4%; P < 0,0001) and species (59.6% versus 20.5%; P < 0.0001) levels when using the adjusted score criteria. Importantly, application of the lowered cutoff values significantly improved genus (P = 0.005)- and species (P < 0.0001)-level identification for the S-MBL, without leading to an increase in misidentifications. MALDI-TOF MS is a cost-effective and rapid alternative to traditional or molecular methods for dermatophyte identification, provided that the reference library is supplemented to sufficiently encompass clinically relevant, intraspecies strain diversity.