Immunotherapy of Multiple Myeloma: Current Status as Prologue to the Future.

The landscape of therapeutic measures to treat multiple myeloma has undergone a seismic shift since the dawn of the current century. This has been driven largely by the introduction of new classes of small molecules, such as proteasome blockers (e.g., bortezomib) and immunomodulators (e.g., lenalidomide), as well as by immunotherapeutic agents starting with the anti-CD38 monoclonal antibody daratumumab in 2015. Recently, other immunotherapies have been added to the armamentarium of drugs available to fight this malignancy. These include the bispecifics teclistamab, talquetamab, and elranatamab, and the chimeric antigen receptor (CAR) T-cell products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). While the accumulated benefits of these newer agents have resulted in a more than doubling of the disease's five-year survival rate to nearly 60% and improved quality of life, the disease remains incurable, as patients become refractory to the drugs and experience relapse. This review covers the current scope of antimyeloma immunotherapeutic agents, both those in clinical use and in development. Included in the discussion are additional monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), bi- and multitargeted mAbs, and CAR T-cells and emerging natural killer (NK) cells, including products intended for "off-the-shelf" (allogeneic) applications. Emphasis is placed on the benefits of each along with the challenges that need to be surmounted if MM is to be cured.

Recent Advances in the Applications of Small Molecules in the Treatment of Multiple Myeloma.

Therapy for multiple myeloma (MM), a hematologic neoplasm of plasma cells, has undergone remarkable changes over the past 25 years. Small molecules (molecular weight of less than one kDa), together with newer immunotherapies that include monoclonal antibodies, antibody-drug conjugates, and most recently, chimeric antigen receptor (CAR) T-cells, have combined to double the disease's five-year survival rate to over 50% during the past few decades. Despite these advances, the disease is still considered incurable, and its treatment continues to pose substantial challenges, since therapeutic refractoriness and patient relapse are exceedingly common. This review focuses on the current pipeline, along with the contemporary roles and future prospects for small molecules in MM therapy. While small molecules offer prospective benefits in terms of oral bioavailability, cellular penetration, simplicity of preparation, and improved cost-benefit considerations, they also pose problems of toxicity due to off-target effects. Highlighted in the discussion are recent developments in the applications of alkylating agents, immunomodulators, proteasome inhibitors, apoptosis inducers, kinesin spindle protein inhibitors, blockers of nuclear transport, and drugs that affect various kinases involved in intracellular signaling pathways. Molecular and cellular targets are described for each class of agents in relation to their roles as drivers of MM.

Immunotherapy of Multiple Myeloma: Promise and Challenges.

Whereas the treatment of MM was dependent solely on alkylating agents and corticosteroids during the prior three decades, the landscape of therapeutic measures to treat the disease began to expand enormously early in the current century. The introduction of new classes of small-molecule drugs, such as proteasome blockers (bortezomib and carfilzomib), immunomodulators (lenalidomide and pomalidomide), nuclear export inhibitors (selinexor), and histone deacetylase blockers (panobinostat), as well as the application of autologous stem cell transplantation (ASCT), resulted in a seismic shift in how the disease is treated. The picture changed dramatically once again starting with the 2015 FDA approval of two monoclonal antibodies (mAbs) - the anti-CD38 daratumumab and the anti-SLAMF7 elotuzumab. Daratumumab, in particular, has had a great impact on MM therapy and today is often included in various regimens to treat the disease, both in newly diagnosed cases and in the relapse/refractory setting. Recently, other immunotherapies have been added to the arsenal of drugs available to fight this malignancy. These include isatuximab (also anti-CD38) and, in the past year, the antibody-drug conjugate (ADC) belantamab mafodotin and the chimeric antigen receptor (CAR) T-cell product idecabtagene vicleucel (ide-cel). While the accumulated benefits of these newer agents have resulted in a doubling of the disease's five-year survival rate to more than 5 years and improved quality of life, the disease remains incurable. Almost without exception patients experience relapse and/or become refractory to the drugs used, making the search for innovative therapies all the more essential. This review covers the current scope of anti-myeloma immunotherapeutic agents, both those in clinical use and on the horizon, including naked mAbs, ADCs, bi- and multi-targeted mAbs, and CAR T-cells. Emphasis is placed on the benefits of each along with the challenges that need to be overcome if MM is to be considered curable in the future.

B-Cell Maturation Antigen (BCMA) as a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma.

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, has approximately doubled the disease's five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug's effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.

Longitudinal changes in EEG power, sleep cycles and behaviour in a tau model of neurodegeneration.

BACKGROUND: Disturbed sleep is associated with cognitive decline in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). The progressive sequence of how neurodegeneration affects aspects of sleep architecture in conjunction with behavioural changes is not well understood. METHODS: We investigated changes in sleep architecture, spectral power and circadian rhythmicity in the tet-off rTg4510 mouse overexpressing human P301L tau within the same subjects over time. Doxycycline-induced transgene-suppressed rTg4510 mice, tTa carriers and wild-type mice were used as comparators. Spectral power and sleep stages were measured from within the home cage environment using EEG electrodes. In addition, locomotor activity and performance during a T-maze task were measured. RESULTS: Spectral power in the delta and theta bands showed a time-dependent decrease in rTg4510 mice compared to all other groups. After the initial changes in spectral power, wake during the dark period increased whereas NREM and number of REM sleep bouts decreased in rTg4510 compared to wild-type mice. Home cage locomotor activity in the dark phase significantly increased in rTg4510 compared to wild-type mice by 40 weeks of age. Peak-to-peak circadian rhythm amplitude and performance in the T-maze was impaired throughout the experiment independent of time. At 46 weeks, rTG4510 mice had significant degeneration in the hippocampus and cortex whereas doxycycline-treated rTG4510 mice were protected. Pathology significantly correlated with sleep and EEG outcomes, in addition to locomotor and cognitive measures. CONCLUSIONS: We show that reduced EEG spectral power precedes reductions in sleep and home cage locomotor activity in a mouse model of tauopathy. The data shows increasing mutant tau changes sleep architecture, EEG properties, behaviour and cognition, which suggest tau-related effects on sleep architecture in patients with neurodegenerative diseases.

Willingness to pay for policies to reduce future deaths from climate change: evidence from a British survey.

OBJECTIVES: Without urgent action, climate change will put the health of future populations at risk. Policies to reduce these risks require support from today's populations; however, there are few studies assessing public support for such policies. Willingness to pay (WtP), a measure of the maximum a person is prepared to pay for a defined benefit, is widely used to assess public support for policies. We used WtP to investigate whether there is public support to reduce future health risks from climate change and if individual and contextual factors affect WtP, including perceptions of the seriousness of the impacts of climate change. STUDY DESIGN: A cross-sectional British survey. METHODS: Questions about people's WtP for policies to reduce future climate change-related deaths and their perceptions of the seriousness of climate change impacts were included in a British survey of adults aged 16 years and over (n=1859). We used contingent valuation, a survey-based method for eliciting WtP for outcomes like health which do not have a direct market value. RESULTS: The majority (61%) were willing to pay to reduce future increases in climate change-related deaths in Britain. Those regarding climate change impacts as not at all serious were less willing to pay than those regarding the impacts as extremely serious (OR 0.04, 95% CI 0.02-0.09). Income was also related to WtP; the highest-income group were twice as likely to be willing to pay as the lowest-income group (OR 2.14, 95% CI 1.40-3.29). CONCLUSIONS: There was public support for policies to address future health impacts of climate change; the level of support varied with people's perceptions of the seriousness of these impacts and their financial circumstances. Our study adds to evidence that health, including the health of future populations, is an outcome that people value and suggests that framing climate change around such values may help to accelerate action.

Monoclonal Antibodies for the Treatment of Multiple Myeloma: An Update.

The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation. Immunotherapeutic approaches to MM treatment using monoclonal antibodies (mAbs), while long in development, began to reap success with the identification of CD38 and SLAMF7 as suitable targets for development, culminating in the 2015 Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, respectively. This review highlights additional mAbs now in the developmental pipeline. Isatuximab, another anti-CD38 mAb, currently is under study in four phase III trials and may offer certain advantages over daratumumab. Several antibody-drug conjugates (ADCs) in the early stages of development are described, including JNJ-63723283, which has attained FDA breakthrough status for MM. Other mAbs described in this review include denosumab, recently approved for myeloma-associated bone loss, and checkpoint inhibitors, although the future status of the latter combined with immunomodulators has been clouded by unacceptably high death rates that caused the FDA to issue clinical holds on several of these trials. Also highlighted are the therapies based on the B Cell Maturation Antigen (BCMA), another very promising target for anti-myeloma development.

The Multiple Myeloma Drug Pipeline-2018: A Review of Small Molecules and Their Therapeutic Targets.

Treatment of multiple myeloma (MM), a neoplasm of plasma cells, formerly dependent on alkylating drugs, corticosteroids, and autologous stem cell transplantation, has changed dramatically in the past 20 years because 3 new classes of small molecule drugs (arbitrarily defined as having a molecular weight of < 900 kDa)-immunomodulators, proteasome inhibitors, and histone deacetylase blockers-have been introduced for the disease. Therapeutic options for MM expanded further in 2015 when 2 new monoclonal antibodies (daratumumab and elotuzumab) were approved by the Food and Drug Administration for MM. Although MM remains incurable, the cumulative effect of these advances has resulted in a near-doubling of the 5-year survival rate since the late 1980s. Despite these advances, therapy for MM continues to pose substantial challenges because resistance to therapy frequently develops, and relapse and recurrence are all too common. The present review focused on the pipeline for new small molecules in various stages of development and their associated cellular targets. In addition to newer versions of alkylators, immunomodulators, proteasome inhibitors, and histone deacetylase inhibitors, the present review considered the prospects for adding new classes of small molecules to the MM armamentarium, which offer the potential for oral efficacy, relative simplicity of preparation, and prospects for improvement in the cost-to-benefit ratio. Included are agents that affect myeloma epigenetics and the ubiquitination-proteasome system and the unfolded protein response, apoptotic mechanisms, chromosomal abnormalities, nuclear protein transport, and various kinases involved in cellular signaling pathways.

What a Difference a Stochastic Process Makes: Epidemiological-Based Real Options Models of Optimal Treatment of Disease.

The real options approach has been used within environmental economics to investigate the impact of uncertainty on the optimal timing of control measures to minimise the impacts of invasive species, including pests and diseases. Previous studies typically model the growth in infected area using geometric Brownian motion (GBM). The advantage of this simple approach is that it allows for closed form solutions. However, such a process does not capture the mechanisms underlying the spread of infection. In particular the GBM assumption does not respect the natural upper boundary of the system, which is determined by the maximum size of the host species, nor the deceleration in the rate of infection as this boundary is approached. We show how the stochastic process describing the growth in infected area can be derived from the characteristics of the spread of infection. If the model used does not appropriately capture uncertainty in infection dynamics, then the excessive delay before treatment implies that the full value of the option to treat is not realised. Indeed, when uncertainty is high or the disease is fast spreading, ignoring the mechanisms of infection spread can lead to control never being deployed. Thus the results presented here have important implications for the way in which the real options approach is applied to determine optimal timing of disease control given uncertainty in future disease progression.

Kinase inhibitors as potential agents in the treatment of multiple myeloma.

Recent years have witnessed a dramatic increase in the number of therapeutic options available for the treatment of multiple myeloma (MM) - from immunomodulating agents to proteasome inhibitors to histone deacetylase (HDAC) inhibitors and, most recently, monoclonal antibodies. Used in conjunction with autologous hematopoietic stem cell transplantation, these modalities have nearly doubled the disease's five-year survival rate over the last three decades to about 50%. In spite of these advances, MM still is considered incurable as resistance and relapse are common. While small molecule protein kinase inhibitors have made inroads in the therapy of a number of cancers, to date their application to MM has been less than successful. Focusing on MM, this review examines the roles played by a number of kinases in driving the malignant state and the rationale for target development in the design of a number of kinase inhibitors that have demonstrated anti-myeloma activity in both in vitro and in vivo xenograph models, as well as those that have entered clinical trials. Among the targets and their inhibitors examined are receptor and non-receptor tyrosine kinases, cell cycle control kinases, the PI3K/AKT/mTOR pathway kinases, protein kinase C, mitogen-activated protein kinase, glycogen synthase kinase, casein kinase, integrin-linked kinase, sphingosine kinase, and kinases involved in the unfolded protein response.

Human pluripotent stem cells for modeling toxicity.

The development of xenobiotics, driven by the demand for therapeutic, domestic and industrial uses continues to grow. However, along with this increasing demand is the risk of xenobiotic-induced toxicity. Currently, safety screening of xenobiotics uses a plethora of animal and in vitro model systems which have over the decades proven useful during compound development and for application in mechanistic studies of xenobiotic-induced toxicity. However, these assessments have proven to be animal-intensive and costly. More importantly, the prevalence of xenobiotic-induced toxicity is still significantly high, causing patient morbidity and mortality, and a costly impediment during drug development. This suggests that the current models for drug safety screening are not reliable in toxicity prediction, and the results not easily translatable to the clinic due to insensitive assays that do not recapitulate fully the complex phenotype of a functional cell type in vivo. Recent advances in the field of stem cell research have potentially allowed for a readily available source of metabolically competent cells for toxicity studies, derived using human pluripotent stem cells harnessed from embryos or reprogrammed from mature somatic cells. Pluripotent stem cell-derived cell types also allow for potential disease modeling in vitro for the purposes of drug toxicology and safety pharmacology, making this model possibly more predictive of drug toxicity compared with existing models. This article will review the advances and challenges of using human pluripotent stem cells for modeling metabolism and toxicity, and offer some perspectives as to where its future may lie.

The stress of starvation: glucocorticoid restraint of beta cell development.

Developmental insults during gestation, such as under-nutrition, are known to restrict the number of beta cells that form in the fetal pancreas and are maintained in adulthood, leading to increased risk of type 2 diabetes. There are now substantial data indicating that glucocorticoids mediate this effect of under-nutrition on beta cell mass and that even at physiological levels they restrain fetal beta cell development in utero. There are emerging clues that this occurs downstream of endocrine commitment by neurogenin 3 but prior to terminal beta cell differentiation. Deciphering the precise mechanism will be important as it might unveil new pathways by which to manipulate beta cell mass that could be exploited as novel therapies for patients with diabetes.

Chronological expression of Ciliated Bronchial Epithelium 1 during pulmonary development.

Ciliated Bronchial Epithelium (CBE) 1 is a novel gene, which is expressed in ciliated cells. As cilia are important during embryogenesis, the present authors characterised the murine homologue of CBE1 (Cbe1) and compared its temporal expression during murine and human lung development. Cbe1 cDNA was cloned and characterised using sequencing, standard PCR and Western blotting. Mouse and human embryonic/fetal lungs (HELs) were harvested for mRNA analysis and protein localisation in vivo and in vitro using RT-PCR and immunohistochemistry. The Cbe1 amino acid sequence was >75% identical with CBE1 and its alternative splicing and tissue distribution were highly conserved. Pulmonary expression of Cbe1 mRNA was increased at embryonic day (E)16, 1 day later than Foxj1, which is consistent with a role in ciliogenesis. In HELs, CBE1 mRNA was detectable at 8-9 weeks post-conception and increased in explant culture. CBE1 protein expression was weak at 10 weeks post-conception but strong at 12.3 weeks post-conception, in parallel with cilia formation. Additionally, Cbe1 mRNA was expressed at E11 (4-5 weeks post-conception in HELs) in the absence of Foxj1, implying a distinct role in early development. Chronological regulation of CBE1/Cbe1 expression during pulmonary differentiation suggests involvement in ciliogenesis, with an additional role during early lung development.

Human embryo and early fetus research.

Studies of human embryos and fetuses have highlighted developmental differences between humans and model organisms. In addition to describing the normal biology of our own species, a justification in itself, studies of early human development have aided identification of candidate disease genes mapped by positional cloning strategies, understanding pathophysiology, where human disorders are not faithfully reproduced by models in other species, and, more recently, potential therapies based on human embryonic stem and embryonic germ cells. In this article, we review these applications. We also discuss when and how to study human embryo and early fetuses and some of the regulations of this research.

Beta cell differentiation during early human pancreas development.

Understanding gene expression profiles during early human pancreas development is limited by comparison to studies in rodents. In this study, from the inception of pancreatic formation, embryonic pancreatic epithelial cells, approximately half of which were proliferative, expressed nuclear PDX1 and cytoplasmic CK19. Later, in the fetal pancreas, insulin was the most abundant hormone detected during the first trimester in largely non-proliferative cells. At sequential stages of early fetal development, as the number of insulin-positive cell clusters increased, the detection of CK19 in these cells diminished. PDX1 remained expressed in fetal beta cells. Vascular structures were present within the loose stroma surrounding pancreatic epithelial cells during embryogenesis. At 10 weeks post-conception (w.p.c.), all clusters containing more than ten insulin-positive cells had developed an intimate relationship with these vessels, compared with the remainder of the developing pancreas. At 12-13 w.p.c., human fetal islets, penetrated by vasculature, contained cells independently immunoreactive for insulin, glucagon, somatostatin and pancreatic polypeptide (PP), coincident with the expression of maturity markers prohormone convertase 1/3 (PC1/3), islet amyloid polypeptide, Chromogranin A and, more weakly, GLUT2. These data support the function of fetal beta cells as true endocrine cells by the end of the first trimester of human pregnancy.

Serotonin and the neuroendocrine regulation of the hypothalamic--pituitary-adrenal axis in health and disease.

Serotonin (5-hydroxytryptamine, 5-HT)-containing neurons in the midbrain directly innervate corticotropin-releasing hormone (CRH)-containing cells located in paraventricular nucleus of the hypothalamus. Serotonergic inputs into the paraventricular nucleus mediate the release of CRH, leading to the release of adrenocorticotropin, which triggers glucocorticoid secretion from the adrenal cortex. 5-HT1A and 5-HT2A receptors are the main receptors mediating the serotonergic stimulation of the hypothalamic-pituitary-adrenal axis. In turn, both CRH and glucocorticoids have multiple and complex effects on the serotonergic neurons. Therefore, these two systems are interwoven and communicate closely. The intimate relationship between serotonin and the hypothalamic-pituitary-adrenal axis is of great importance in normal physiology such as circadian rhythm and stress, as well as pathophysiological disorders such as depression, anxiety, eating disorders, and chronic fatigue.