Flanaganlerche0760

CAR19 T cells provide an optimal cell therapy platform with well understood inherent persistence and fitness characteristics.Metastasis is the major cause of mortality in breast cancer patients. Many signaling pathways have been linked to cancer invasiveness, but blockade of few protein components has succeeded in reducing metastasis. Thus, identification of proteins contributing to invasion that are manipulable by small molecules may be valuable in inhibiting spread of the disease. The protein kinase WNK1 (with no lysine (K) 1) has been suggested to induce migration of cells representing a range of cancer types. Analyses of mouse models and patient data have implicated WNK1 as one of a handful of genes uniquely linked to invasive breast cancer. Here we present evidence that inhibition of WNK1 slows breast cancer metastasis. We show that depletion or inhibition of WNK1 reduces migration of several breast cancer cell lines in wound healing assays and decreases invasion in collagen matrices. Furthermore, WNK1 depletion suppresses expression of AXL, a tyrosine kinase implicated in metastasis. Finally, we demonstrate that WNK inhibition in mice attenuates tumor progression and metastatic burden. These data showing reduced migration, invasion, and metastasis upon WNK1 depletion in multiple breast cancer models suggest that WNK1 contributes to the metastatic phenotype and that WNK1 inhibition may offer a therapeutic avenue for attenuating progression of invasive breast cancers.Temozolomide is a DNA-methylating agent used in cancer chemotherapy, notably for glioblastoma multiforme (GBM) where it is applied as a front-line drug. One of the DNA alkylation products is the minor lesion O6-methylguanine (O6MeG), which is responsible for nearly all genotoxic, cytotoxic and cytostatic effects of TMZ in the low-dose range relevant for cancer therapy. Here, we addressed the question of how many O6MeG adducts are required to elicit cytotoxic responses. Adduct quantification revealed that O6MeG increases linearly with dose. The same was observed for DNA double-strand breaks (DSBs) and p53ser15. Regarding apoptosis, hockeystick modeling indicated a possible threshold for A172 cells at 2.5 µM TMZ, while for LN229 cells no threshold was detected. Cellular senescence, which is the main cellular response, also increased linearly, without a threshold. Using a dose of 20 µM, which is achievable in a therapeutic setting, we determined that 14,000 adducts give rise to 32 DSBs (γH2AX foci) in A172 cells. This leads to 12% cell death and 35% of cells entering senescence. In LN229 cells, 20 µM TMZ induced 20,600 O6MeG adducts, 66 DSBs (γH2AX foci), 24% apoptosis and 52% senescence. The linear dose-response and the genotoxic and cytotoxic effects observed at therapeutically relevant dose levels makes it very likely that the TMZ target concentration triggers a significant cytotoxic and cytostatic effect in vivo. Despite a linear increase in the O6MeG adduct level, DSBs and p53 activation, the low curative effect of TMZ results presumably from the low rate of apoptosis compared to senescence.T cell Dependent Bispecific antibodies (TDBs) have been a major advancement in the the treatment of cancer that allow for improved targeting and efficacy for large molecule therapeutics. TDBs are comprised of one arm targeting a surface antigen on a cancer cell and another targeting an engaging surface antigen on a cytotoxic T cell. In order to impart this function, the antibody must be in a bispecific format as opposed to the more conventional bivalent format. Through in vitro and in vivo studies, we sought to determine the impact of changing antibody valency on solid tumor distribution and catabolism. A bivalent anti-HER2 antibody exhibited higher catabolism than its full-length monovalent binding counterpart in vivo by both invasive tissue harvesting and non-invasive SPECT-CT imaging despite similar systemic exposures for the two molecules. In order to determine what molecular factors drove in vivo distribution and uptake, we developed a mechanistic model for binding and catabolism of monovalent and bivalent HER2 antibodies in KPL4 cells. This model suggests that observed differences in cellular uptake of monovalent and bivalent antibodies are caused by the change in apparent affinity conferred by avidity as well as differences in internalization and degradation rates of receptor bound antibodies. To our knowledge, this is the first study to directly compare the targeting abilities of monovalent and bivalent full-length antibodies. These findings may inform diverse antibody therapeutic modalities including T cell redirecting therapies and drug delivery strategies relying upon receptor internalization.B-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma (MM) and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody-drug-conjugate approved for the treatment of relapsed/refractory MM. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation in vitro and in vivo. GSK2857916 treatment enhances intra-tumor immune cell infiltration and activation, delays tumor growth and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA). Responding mice are immune to re-challenge with EL4 parental and EL4-hBCMA cells, suggesting engagement of an adaptive immune response, immunologic memory, and tumor antigen spreading, which are abrogated upon depletion of endogenous CD8+ T-cells. Combinations with OX40/OX86, an immune agonist antibody, significantly enhance anti-tumor activity and increase durable complete responses, providing a strong rationale for clinical evaluation of GSK2857916 combinations with immunotherapies targeting adaptive immune responses, including T-cell-directed checkpoint modulators.Background Donor-specific HLA antibody (DSA) is present in many kidney transplant patients whose biopsies are classified as no-rejection (NR). We explored whether in some NR kidneys DSA has subtle effects that are not currently being recognized. Methods We used microarrays to examine the relationship between standard-of-care DSA and rejection-related transcript increases in 1679 kidney transplant indication biopsies in the INTERCOMEX study (ClinicalTrials.gov NCT01299168), focusing on biopsies classified as NR by automatically assigned archetypal clustering. DSA testing results were available for 835 NR biopsies and were positive in 271 (32%). Results DSA-positivity in NR biopsies was associated with mildly increased expression of ABMR-related transcripts, particularly IFNG-inducible and NK cell transcripts. We developed a machine learning DSA probability (DSAProb) classifier based on transcript expression in biopsies from DSA-positive vs. DSA-negative patients, assigning scores using 10-fold cross-validation. This DSAProb classifier was very similar to a previously described "ABMR probability" classifier trained on histologic ABMR in transcript associations and prediction of molecular or histologic ABMR. Plotting the biopsies using Uniform Manifold Approximation and Projection revealed a gradient of increasing molecular ABMR-like transcript expression in NR biopsies, associated with increased DSA (P less then 2E-16). In biopsies with no molecular or histologic rejection, increased DSAProb or ABMR probability scores were associated with increased risk of kidney failure over three years. Conclusions Many biopsies currently considered to have no molecular or histologic rejection have mild increases in expression of ABMR-related transcripts, associated with increasing frequency of DSA. Thus mild molecular ABMR-related pathology is more common than previously realized.COVID-19 represents one of the most challenging global health issues in modern times. However, as epidemics have affected humans since our origins, many before us have described how significantly they compromise human lives. Leaving apart the aspects more linked to medicine and health sciences, we focus here on analysing how epidemics force people to change their habits, what type of emotions and behaviours they promote, and which roles are played by different social actors. For such a purpose, especially if we wish to draw some parallels between past epidemics and COVID-19, historical records seemed to be more suitable than literary works. Nonetheless, we have taken this approach relying on La Peste (Albert Camus, 1947), a novel based on a fictional epidemic of plague in the Algerian town of Oran. Far from creating a barrier separating fiction from reality, this reading allowed us to establish several links with our current situation. Recognising that context and solutions vary widely between the two scenarios, core matters concerning epidemics seemed to remain invariable. The important role of data and statistics, the leadership acquired by health authorities, the separations of relatives or the negative effects on trade and business are some issues which took place in Oran as well as nowadays. Besides that, epidemics also affect humans at an individual level, and certain thoughts and feelings in La Peste's main characters may make us identify with our own fears and desires.

CMML is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies. CMML cells are uniquely hypersensitive to GM-CSF and robustly engraft in immunocompromised mice that secrete human cytokines. To leverage these unique biologic features, we conducted an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that potently downregulates intracellular GM-CSF signaling.

A total of 50 patients with WHO-defined CMML were enrolled in this open-label, multi-institution phase 1/2 clinical study, with a ruxolitinib dose of 20mg twice daily studied in phase 2. selleck In parallel, 49 patient-derived xenografts (PDX) derived from 13 study participants were generated and randomized to receive ruxolitinib or vehicle control.

The most common grade 3/4 treatment-related toxicities observed were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38% by MDS/MPN IWG criteria and 43% of patients with baseline splenomegaly achieved a spleen response.s of patients treated on clinical trial and represents a novel correlative study that corroborates clinical efficacy seen in humans.

CX-072, a PD-L1-targeting Probody therapeutic, is engineered to be activated by tumor proteases that remove a masking peptide. To study effects on biodistribution and pharmacokinetics, we performed

Zr-CX-072 positron emission tomography (PET) imaging.

Patients received ∼1 mg, 37 MBq

Zr-CX-072 plus 0, 4, or 9 mg unlabeled CX-072 and PET scans at days 2, 4, and 7. After that, treatment comprised 10 mg/kg CX-072 q2 weeks (

= 7) + 3 mg/kg ipilimumab q3w 4× (

= 1). Normal organ tracer uptake was expressed as standardized uptake value (SUV)

and tumor uptake as SUV

. PD-L1 expression was measured immunohistochemically in archival tumor tissue.

Three of the eight patients included received 10-mg protein dose resulting in a blood pool mean SUV

± SD of 4.27 ± 0.45 on day 4, indicating sufficient available tracer. Tumor uptake was highest at day 7, with a geometric mean SUV

5.89 (

= 113) and present in all patients. The median follow-up was 12 weeks (4-76+). One patient experienced stable disease and two patients a partial response.