Background: Despite immunization, patients on antineoplastic and immunomodulating agents have a heightened risk of COVID-19 infection. However, accurately attributing this risk to specific medications remains challenging.
Methods: An observational cohort study from December 11, 2020 to September 22, 2022, within a large healthcare system in San Diego, California, USA was designed to identify medications associated with greatest risk of postimmunization SARS-CoV-2 infection.
The maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions.
View Article and Find Full Text PDFBackground: Oncogenes act in a cell-intrinsic way to promote tumorigenesis. Whether oncogenes also have a cell-extrinsic effect on suppressing the immune response to cancer is less well understood.
Methods: We use an expression screen of known cancer-associated somatic mutations in mouse syngeneic tumor models treated with checkpoint blockade to identify oncogenes that promote immune evasion.
Aim: This study investigated the humoral response against SARS-CoV-2 in patients needing intensive care unit (ICU) care compared with those on general medicine wards.
Materials & Methods: The authors retrospectively reviewed 113 hospitalized patients with COVID-19. They assessed antibody response against five SARS-CoV-2 epitopes at 6-14 days post symptom onset in these patients.
J Immunother Cancer
January 2021
Background: Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies.
View Article and Find Full Text PDFCoronavirus Disease 2019 infections among healthcare workers were widely reported in China and Europe as the pandemic expanded to the United States. In order to examine the infection rate among these essential workers, we combined results of SARS-CoV-2 serology testing offered free to healthcare workers at two large San Diego health systems when the antibody assays first became available.
View Article and Find Full Text PDFTransplant Proc
April 2021
Although interest in the role of donor-specific antibodies (DSAs) in kidney transplant rejection, graft survival, and histopathological outcomes is increasing, their impact on steroid avoidance or minimization in renal transplant populations is poorly understood. Primary outcomes of graft survival, rejection, and histopathological findings were assessed in 188 patients who received transplants between 2012 and 2015 at the Scripps Center for Organ Transplantation, which follows a steroid avoidance protocol. Analyses were performed using data from the United Network for Organ Sharing.
View Article and Find Full Text PDFA defining feature of protracted sepsis is development of immunosuppression that is thought to be a major driving force in the morbidity and mortality associated with the syndrome. The immunosuppression that occurs in sepsis is characterized by profound apoptosis-induced depletion of CD4 and CD8 T cells and severely impaired T cell function. OX40, a member of the TNF receptor superfamily, is a positive co-stimulatory molecule expressed on activated T cells.
View Article and Find Full Text PDFDespite the promising clinical benefit of targeted and immune checkpoint blocking therapeutics, current strategies have limited success in breast cancer, indicating that additional inhibitory pathways are required to complement existing therapeutics. TAM receptors (Tyro-3, Axl, and Mertk) are often correlated with poor prognosis because of their capacities to sustain an immunosuppressive environment. Here, we ablate Axl on tumor cells using CRISPR/Cas9 gene editing, and by targeting Mertk in the tumor microenvironment (TME), we observed distinct functions of TAM as oncogenic kinases, as well as inhibitory immune receptors.
View Article and Find Full Text PDFCo-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood.
View Article and Find Full Text PDFPurpose: The success of checkpoint blockade has led to a significant increase in the development of a broad range of immunomodulatory molecules for the treatment of cancer, including agonists against T-cell costimulatory receptors, such as OX40. Unlike checkpoint blockade, where complete and sustained receptor saturation may be required for maximal activity, the optimal dosing regimen and receptor occupancy for agonist agents is less well understood and requires further study.
Experimental Design: We integrated both preclinical and clinical biomarker data sets centered on dose, exposure, receptor occupancy, receptor engagement, and downstream pharmacodynamic changes to model the optimal dose and schedule for the OX40 agonist antibody BMS-986178 alone and in combination with checkpoint blockade.
Purpose: Radiotherapy (RT) traditionally has been used for local tumor control in the treatment of cancer. The recent discovery that radiotherapy can have anticancer effects on the immune system has led to recognition of its ability to sensitize the tumor microenvironment to immunotherapy. However, radiation can also prompt adverse immunosuppressive effects that block aspects of systemic response at other tumor sites.
View Article and Find Full Text PDFFollowing publication of the original article [1], the author reported that an author name, Roberta Zappasodi, was missed in the authorship list.
View Article and Find Full Text PDFTumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines.
View Article and Find Full Text PDFTyro3, Axl, and Mertk (TAM) represent a family of homologous tyrosine kinase receptors known for their functional role in phosphatidylserine (PS)-dependent clearance of apoptotic cells and also for their immune modulatory functions in the resolution of inflammation. Previous studies in our laboratory have shown that Gas6/PS-mediated activation of TAM receptors on tumor cells leads to subsequent upregulation of PD-L1, defining a putative PS→TAM receptor→PD-L1 inhibitory signaling axis in the cancer microenvironment that may promote tolerance. In this study, we tested combinations of TAM inhibitors and PD-1 mAbs in a syngeneic orthotopic E0771 murine triple-negative breast cancer model, whereby tumor-bearing mice were treated with pan-TAM kinase inhibitor (BMS-777607) or anti-PD-1 alone or in combination.
View Article and Find Full Text PDFPurpose: A recent systematic review indicated that higher sunlight exposure increased risk of AMD. The Beaver Dam study and the Pathologies Oculaires Liées à L'âge study both noted that wearing hats and/or sunglasses significantly decrease some AMD lesions, suggesting that reduced retinal light dose (RLD) may be related to reduced AMD risk. Given that myopes also have reduced AMD risk, we hypothesize its link to decreased RLD.
View Article and Find Full Text PDFThe digestibility of starch in foods, which is influenced by the ingredients, formulation and preparation conditions, is a major determinant of glycaemic response. The terms rapidly digestible starch (RDS) and slowly digestible starch (SDS) along with the associated analytical methodology were developed by Englyst to characterise this nutritionally relevant food attribute. The measurement uncertainty of this starch digestibility method is evaluated here with an inter-laboratory trial.
View Article and Find Full Text PDFEfficacious antitumor immune responses must overcome multiple suppressive mechanisms in the tumor microenvironment to control cancer progression. In this study, we demonstrate that dual targeting of suppressive myeloid populations by inhibiting CSF-1/CSF-1R signaling and activation of antigen-presenting cells with agonist anti-CD40 treatment confers superior antitumor efficacy and increased survival compared with monotherapy treatment in preclinical tumor models. Concurrent CSF-1R blockade and CD40 agonism lead to profound changes in the composition of immune infiltrates, causing an overall decrease in immunosuppressive cells and a shift toward a more inflammatory milieu.
View Article and Find Full Text PDFImmunol Cell Biol
April 2017
The use of antibody therapy for cancer has steadily increased in recent years and has become standard treatment for numerous tumor types. It is now appreciated that the clinical activity of these antibodies relies upon their specific interactions with Fc receptors in addition to the well-studied target-binding region. The interactions mediated by antibody Fc domains can strongly affect the functional outcome of antibody therapy.
View Article and Find Full Text PDFThe monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results.
View Article and Find Full Text PDFBackground: Rapid diagnostics for bloodstream infections have been shown to improve outcomes. Most studies have focused on rapid diagnostics for a single pathogen and have been conducted in academic medical centers. The Verigene Gram-Positive Blood Culture Test (BC-GP) identifies 12 gram-positive organisms and 3 genetic markers of antibiotic resistance from positive blood culture media in 2.
View Article and Find Full Text PDFAntitumor activity of CTLA-4 antibody blockade is thought to be mediated by interfering with the negative regulation of T-effector cell (Teff) function resulting from CTLA-4 engagement by B7-ligands. In addition, a role for CTLA-4 on regulatory T cells (Treg), wherein CTLA-4 loss or inhibition results in reduced Treg function, may also contribute to antitumor responses by anti-CTLA-4 treatment. We have examined the role of the immunoglobulin constant region on the antitumor activity of anti-CTLA-4 to analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies.
View Article and Find Full Text PDFT cells are activated by antigen (Ag)-bearing dendritic cells (DCs) in lymph nodes in three phases. The duration of the initial phase of transient, serial DC-T cell interactions is inversely correlated with Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessary for full-fledged T cell activation.
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