Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It is critical to develop novel therapeutic options to add to the treatment arsenal to overcome IMiD resistance.
View Article and Find Full Text PDFAt the heart of the DNA/ALVAC/gp120/alum vaccine's efficacy in the absence of neutralizing antibodies is a delicate balance of pro- and anti-inflammatory immune responses that effectively decreases the risk of SIV acquisition in macaques. Vaccine efficacy is linked to antibodies recognizing the V2 helical conformation, DC-10 tolerogenic dendritic cells eliciting the clearance of apoptotic cells via efferocytosis, and CCR5 downregulation on vaccine-induced gut homing CD4 cells. RAS activation is also linked to vaccine efficacy, which prompted the testing of IGF-1, a potent inducer of RAS activation with vaccination.
View Article and Find Full Text PDFBackground/aim: Gonadotropin-releasing hormone 2 (GNRH2) is a poorly-studied peptide hormone that is widely distributed in the central nervous system and expressed in peripheral tissues of mammals. The non-synonymous rs6051545 variant in GNRH2 (A16V) has been linked to higher serum testosterone concentrations. This study investigated whether the A16V variant is associated with altered androgen-deprivation therapy (ADT) progression-free survival (PFS) and overall survival (OS).
View Article and Find Full Text PDFBackground: Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies.
View Article and Find Full Text PDFThe human immunodeficiency virus epidemic continues in sub-Saharan Africa, and particularly affects adolescent girls and women who have limited access to antiretroviral therapy. Here we report that the risk of vaginal simian immunodeficiency virus (SIV) acquisition is reduced by more than 90% using a combination of a vaccine comprising V1-deleted (V2 enhanced) SIV envelope immunogens with topical treatment of the zinc-finger inhibitor SAMT-247. Following 14 weekly intravaginal exposures to the highly pathogenic SIV, 80% of a cohort of 20 macaques vaccinated and treated with SAMT-247 remained uninfected.
View Article and Find Full Text PDFThe development of an effective vaccine to protect against HIV acquisition will be greatly bolstered by in-depth understanding of the innate and adaptive responses to vaccination. We report here that the efficacy of DNA/ALVAC/gp120/alum vaccines, based on V2-specific antibodies mediating apoptosis of infected cells (V2-ADCC), is complemented by efferocytosis, a cyclic AMP (cAMP)-dependent antiphlogistic engulfment of apoptotic cells by CD14 monocytes. Central to vaccine efficacy is the engagement of the CCL2/CCR2 axis and tolerogenic dendritic cells producing IL-10 (DC-10).
View Article and Find Full Text PDFPosttransplantation cyclophosphamide (PTCy), given on days +3 and +4, reduces graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT), but its immunologic underpinnings are not fully understood. In a T-cell-replete, major histocompatibility complex-haploidentical murine HCT model (B6C3F1→B6D2F1), we previously showed that PTCy rapidly induces suppressive mechanisms sufficient to prevent GVHD induction by non-PTCy-exposed donor splenocytes infused on day +5. Here, in PTCy-treated mice, we found that depleting Foxp3+ regulatory T cells (Tregs) in the initial graft but not the day +5 splenocytes did not worsen GVHD, yet depleting Tregs in both cellular compartments led to fatal GVHD induced by the day +5 splenocytes.
View Article and Find Full Text PDFLMB-100 is a novel immune-conjugate (immunotoxin) that targets mesothelin. A phase 1/2 clinical trial was conducted (NCT02810418) with primary objectives assessing the safety and efficacy of LMB-100 ± nab-paclitaxel. Participant blood samples were analyzed for changes in serum cytokines and circulating immune cell subsets associated with response or toxicity.
View Article and Find Full Text PDFRelapse limits the therapeutic efficacy both of chimeric antigen receptor (CAR) T cells and allogeneic hematopoietic cell transplantation (allo-HCT). Patients may undergo these therapies sequentially to prevent or treat relapsed malignancy. However, direct integration of the 2 therapies has been avoided over concerns for potential induction of graft-versus-host disease (GVHD) by allogeneic CAR T cells.
View Article and Find Full Text PDFContext: The skeletal phenotype of patients with MEN2B has been described but fracture risk in these patients has not yet been evaluated.
Objective: This work aims to better delineate fracture risk in patients with multiple endocrine neoplasia type 2B (MEN2B).
Methods: This case series with chart review was conducted at the National Institutes of Health, Pediatric Oncology Branch.
Background: Selumetinib was recently approved for the treatment of inoperable symptomatic plexiform neurofibromas (PNs) in children with neurofibromatosis type 1 (NF1). This parallel phase II study determined the response rate to selumetinib in children with NF1 PN without clinically significant morbidity.
Methods: Children with NF1 and inoperable PNs, which were not yet causing clinically significant morbidity but had the potential to cause symptoms, received selumetinib at 25 mg/m2 orally twice daily (1 cycle = 28 days).
Purpose: Bintrafusp alfa is a bifunctional agent consisting of an anti-human PD-L1 antibody linked to two TGFβRII. It is designed to act both as a checkpoint inhibitor and to 'trap' TGFβ in the tumor microenvironment. Phase I and II clinical studies demonstrated clinical activity in patients with a range of human papillomavirus (HPV)-associated cancers.
View Article and Find Full Text PDFPost-transplantation cyclophosphamide (PTCy) reduces the incidence and severity of graft-versus-host disease (GVHD), thereby improving the safety and accessibility of allogeneic hematopoietic cell transplantation (HCT). We have shown that PTCy works by inducing functional impairment and suppression of alloreactive T cells. We also have identified that reduced proliferation of alloreactive CD4 T cells at day +7 and preferential recovery of CD4CD25Foxp3 regulatory T cells (T) at day +21 are potential biomarkers associated with optimal PTCy dosing and timing in our B6C3F1→B6D2F1 MHC-haploidentical murine HCT model.
View Article and Find Full Text PDFCurrent single-cell epigenome analyses are designed for single use. The cell is discarded after a single use, preventing analysis of multiple epigenetic marks in a single cell and requiring data from other cells to distinguish signal from experimental background noise in a single cell. This paper describes a method to reuse the same single cell for iterative epigenomic analyses.
View Article and Find Full Text PDFAs demonstrated by the recent COVID pandemic, vaccines can reduce the burden arising from infectious agents. Adenoviruses (Ads) with deletion of the early region 1B55K (ΔE1B Ad) are currently being explored for use in vaccine delivery. Δ Ads are different from Ads with deletions in early region 1 and early region 3 (ΔE1/E3) used in most Ad vaccine vectors in that they contain the Ad early region 1A (E1A), and therefore the ability to replicate.
View Article and Find Full Text PDFDietary therapy may be beneficial in alleviating symptoms of chronic fatigue syndrome (CFS), a disorder that is characterized by extreme fatigue and other symptoms, but the cause of which remains unclear. The aim of this study was to evaluate the protective effect of a botanical product containing cistanche ( [Schenk] Wight) and ginkgo (.) extracts on adults with CFS in a randomized, double-blind, placebo-controlled clinical trial.
View Article and Find Full Text PDFDurability of SARS-CoV-2 Spike antibody responses after infection provides information relevant to understanding protection against COVID-19 in humans. We report the results of a sequential evaluation of anti-SARS-CoV-2 antibodies in convalescent patients with a median follow-up of 14 months (range 12.4-15.
View Article and Find Full Text PDFAdrenocortical carcinoma (ACC) is a rare malignancy with an overall unfavorable prognosis. Clinicians treating patients with ACC have noted accelerated growth in metastatic liver lesions that requires rapid intervention compared to other metastatic locations. This study measured and compared the growth rates of metastatic ACC lesions in the lungs, liver, and lymph nodes using volumetric segmentation.
View Article and Find Full Text PDFThe speed of development, versatility and efficacy of mRNA-based vaccines have been amply demonstrated in the case of SARS-CoV-2. DNA vaccines represent an important alternative since they induce both humoral and cellular immune responses in animal models and in human trials. We tested the immunogenicity and protective efficacy of DNA-based vaccine regimens expressing different prefusion-stabilized Wuhan-Hu-1 SARS-CoV-2 Spike antigens upon intramuscular injection followed by electroporation in rhesus macaques.
View Article and Find Full Text PDFSubstandard use of N95 masks, sometimes combined with dry heat decontamination, lacks safety data. We evaluated the impact of these practices on the fitness of N95 masks. This is a non-human subject research conducted from July to October 2020.
View Article and Find Full Text PDFSARS-CoV-2 virus causes upper and lower respiratory diseases including pneumonia, and in some cases, leads to lethal pulmonary failure. Angiotensin converting enzyme-2 (ACE2), the receptor for cellular entry of SARS-CoV-2 virus, has been shown to protect against severe acute lung failure. Here, we provide evidence that SARS-CoV-2 spike protein S1 reduced the mRNA expression of ACE2 and type I interferons in primary cells of lung bronchoalveolar lavage (BAL) from naïve rhesus macaques.
View Article and Find Full Text PDFEffective SARS-CoV-2 vaccines are urgently needed. Although most vaccine strategies have focused on systemic immunization, here we compared the protective efficacy of 2 adjuvanted subunit vaccines with spike protein S1: an intramuscularly primed/boosted vaccine and an intramuscularly primed/intranasally boosted mucosal vaccine in rhesus macaques. The intramuscular-alum-only vaccine induced robust binding and neutralizing antibody and persistent cellular immunity systemically and mucosally, whereas intranasal boosting with nanoparticles, including IL-15 and TLR agonists, elicited weaker T cell and Ab responses but higher dimeric IgA and IFN-α.
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