Anti-tumour immune activation by checkpoint inhibitors leads to durable responses in a variety of cancers, but combination approaches are required to extend this benefit beyond a subset of patients. ...In preclinical models tumour-derived VEGF limits immune cell activity while anti-VEGF augments intra-tumoral T-cell infiltration, potentially through vascular normalization and endothelial cell activation. This study investigates how VEGF blockade with bevacizumab could potentiate PD-L1 checkpoint inhibition with atezolizumab in mRCC. Tissue collections are before treatment, after bevacizumab and after the addition of atezolizumab. We discover that intra-tumoral CD8(+) T cells increase following combination treatment. A related increase is found in intra-tumoral MHC-I, Th1 and T-effector markers, and chemokines, most notably CX3CL1 (fractalkine). We also discover that the fractalkine receptor increases on peripheral CD8(+) T cells with treatment. Furthermore, trafficking lymphocyte increases are observed in tumors following bevacizumab and combination treatment. These data suggest that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell migration.
BackgroundAtezolizumab (anti-PD-L1) has demonstrated robust clinical activity in UBC 1. Elevated PD-L1 expression on tumor-infiltrating immune cells (IC) is associated with increased clinical ...efficacy; however, the contribution of other immune biomarkers is unknown. In this study, we explored tumor-based and circulating biomarkers and their correlation with clinical benefit in atezolizumab-treated patients with UBC.MethodsPatients from the UBC cohort (n = 92) of the Phase Ia atezolizumab trial PCD4989g (NCT01375842) served as source population for tumor specimens, plasma and PBMC. Baseline tumor PD-L1 expression was assessed by immunohistochemistry using the SP142 antibody assay optimized to detect PD-L1 on both tumor cells (TC) and IC. RNA gene expression on tumor and PBMC samples was interrogated with a NanoString panel of 800 immune and cancer genes. Sequential blood draws assessed dynamic changes in circulating immune biomarkers in plasma (RBM, Multi-Analyte Platform). Correlation between biomarker expression and 6-month progression-free survival (PFS; as a measure of clinical benefit) was assessed.ResultsBaseline gene expression in tumors revealed an effector T cell signature (including CD8A, GZMA, IFNG) and NK gene signature (NKG2 family members) associated with clinical benefit. In contrast, disease progression was associated with either a concomitant presence of the immune signature and an opposing stromal signature (PDPN, COL5A1, etc) or the absence of both signatures. Expression of T cell effector and immune checkpoint genes (CTLA4, PD-1, TIGIT, LAG3) correlated with PD-L1 expression on IC but not TC. Increased expression of myeloid-derived cytokines (IL-6 and IL-8) in the plasma was associated with lack of clinical benefit. Moreover, on-treatment sampling revealed an increased plasma HCG, CA15-3 and TIMP-1 to be correlated with disease progression. Immune biomarkers associated with PBMC, as well as tumor biomarkers associated with various tumor subtypes, will also be discussed.ConclusionsOur findings indicate that clinical benefit (as defined by 6-month PFS) from atezolizumab is influenced by a pre-existing CD8+ effector T cell and NK cytolytic gene signature in the tumor, which correlated with IC PD-L1 expression. Increased stromal and myeloid-derived cytokine expression in tumor and plasma, respectively, were associated with lack of clinical benefit, underscoring the complex interplay among immunological components in UBC. These components may be conceivable targets to overcome potential resistance and promote response to atezolizumab.ClinicalTrials.gov Identifier: NCT01375842
Treatment options for metastatic urothelial bladder cancer (UBC) are limited. Mutational complexity is known to be high in UBC and may correlate with increased immunogenicity. MPDL3280A, a human ...PD-L1 monoclonal antibody containing an engineered Fc-domain designed to promote a Th1-driven response, has demonstrated a RECIST response rate of 43% in diagnostically selected, pretreated patients with UBC. A total of 68 patients (67 with efficacy evaluable) were enrolled in the UBC cohort of the Phase I study; 45% were PD-L1 IHC diagnostic positive as defined by expression of PD-L1 on ≥ 5% of tumor-infiltrating immune cells. In the prescreened UBC population, the prevalence of PD-L1-positive patients was 27%.Comprehensive gene expression analyses of UBC tumors were conducted to interrogate the tumor immune microenvironment in PD-L1-positive tumors and to identify potential mechanisms associated with response or resistance to MPDL3280A. In this study, PD-L1-positive tumors exhibited a high prevalence of gene expression markers associated with T-effector cells (Teff), including perforin, IFNγ, CD8A, granzyme B, granzyme A and EOMES. Additionally, a low baseline signature of genes associated with myeloid cell markers, including IL1B and IL8, appeared to be statistically significantly associated (P<0.01) with MPDL3280A response, suggesting a potential role for myeloid biology in resistance to MPDL3280A treatment in UBC.Tumor burden markers, including CA-125, CA19-9 and human chorionic gonadotropin (HCG), have been associated with chemotherapy response markers in UBC. A marked decrease in these markers, including CEA, CA19-9, CA-125 and HCG, was observed with MPDL3280A response after 1 treatment cycle, potentially enabling an on-treatment monitoring alternative for response to therapy. Similarly, evaluation of cytokines on treatment identified markers, including IL-6 and IL-10, elevated as early as Cycle 2 only in patients without response to MPDL3280A. These circulating cytokines and tumor-associated gene signatures suggest potential mechanisms associated with resistance and response to MPDL3280A in UBC and provide a rationale for informed combination strategies to further improve treatment benefit in this indication.
PD-L1 expressed in the tumor microenvironment regulates Th1 immune responses and mediates cancer immune evasion through interactions with PD-1 or B7.1 receptors on activated T cells. MPDL3280A, an ...engineered human monoclonal antibody, targets PD-L1 and inhibits its function. To identify immunologic predictive and pharmacodynamic biomarkers of MPDL3280A treatment, we performed a comprehensive analysis of tumors and blood samples collected at baseline and/or on treatment from ≈280 patients with locally advanced or metastatic solid tumors, including NSCLC, RCC, melanoma and bladder cancer. Regardless of tumor type, clinical responses were characterized by PD-L1 expression, the presence of markers of T cell activation (Th1 gene signature and CTLA4), and the absence of fractalkine at baseline in the tumor microenvironment. Elevated baseline expression of IFN-γ and IFN-γ-inducible genes (e.g., IDO1 and CXCL9) was associated with MPDL3280A response in melanoma but not NSCLC or RCC. On treatment, responding tumors showed increased infiltration of Th1-dominant immune infiltrate and evidence of adaptive PD-L1 up-regulation. In contrast, progressing tumors displayed the following patterns of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression: (1) few/no TILs and absent PD-L1 expression (immunologic ignorance), (2) TILs present with minimal/no PD-L1 expression (non-functional immune responses), or (3) TILs residing solely around the tumor cell mass outer edge (excluded infiltrate), suggesting that resistance to MPDL3280A may be associated with impaired T cell trafficking and/or function.Profiling of ≈180 circulating biomarkers revealed that plasma concentrations of IL-18 and interferon-inducible T cell alpha chemoattractant (ITAC) increased in all patients following MPDL3280A treatment, representing a pharmacodynamic measurement of PD-L1 inhibition. In addition, analysis of PBMC showed an increase in T cell activation, as measured by IFN-γ and granzymes A and B gene expression in responders following MPDL3280A treatment, consistent with the observations in responding tumors. Baseline soluble PD-L1 was not associated with response. Some indication-specific biomarkers, such as plasma VEGF, decreased in responders with RCC but not with other indications. In NSCLC, a decrease in tumor burden markers, CA-125 and CEA, was associated with response. Similarly, IL-6 and IL-8 were differentially expressed on treatment in responders vs non-responders. Additionally, responders exhibited a decrease in circulating tumor DNA (ctDNA) in plasma, suggesting that ctDNA may be used to monitor MPDL3280A clinical activity in NSCLC.In conclusion, these data provide general and indication-specific mechanistic insights into immune checkpoint inhibition, potential mechanisms of response and resistance, as well as identification of potential predictive and pharmacodynamic biomarkers of anti-PD-L1/PD-1 clinical activity across multiple tumor types.
Pyogenic osteomyelitis is a serious illness and up to 7% of all osteomyelitis cases involve vertebral structures. Major risk factors for pyogenic vertebral osteomyelitis (PVO) include infections at ...distant sites, which can seed the spine through hematogenous spread, and medically compromised status. The most commonly reported complications associated with PVO include pain, kyphotic deformity and neurological sequelae. While PVO remains rare, the epidemiology is changing with an evolving population risk profile. The most frequently isolated microbe associated with PVO in the general population is
S. aureus and post-spinal surgery osteomyelitis is frequently polymicrobial, however the ability to obtain definitive blood cultures is highly variable. Diagnosis of PVO includes laboratory findings consistent with escalating markers for inflammatory response. While MRI remains the imaging method of choice for PVO, plain radiographic changes associated with vertebral body or disk space infection are usually apparent 2–4 weeks following clinical symptoms. Initial medical management for uncomplicated PVO includes antibiotic therapy and immobilization. Approximately 25% of cases fail conservative therapies. Among the most consistently cited factors impacting surgical results regardless of approach are the number of significant co-morbidity factors and the impact of effective medical management. An analysis of the literature suggests that decompression and anterior grafting alone in patients who can tolerate prolonged immobilization is adequate. The use of instrumentation is more strongly indicated in circumferential decompression for anterior/posterior abscess, gross instability after debridement, medical compromise precluding prolonged bed rest or bracing, and in those patients with progressive spinal deformity.
The syntheses and spectroscopic properties of Cr(0) and Mo(0) carbonyl complexes involving the novel cyclotriphosphazane (C
6
H
4
N
2
)(PPh)
3
C
6
H
4
(NH)
2
(1) are reported. The cyclotriphosphazane ...1 is an interesting cyclic ligand that contains two unique types of phosphorus coordination environments as well as potential N-H reactivity. Reactions of 1 with one, two and excess molar equivalents of M(CO)
5
(THF) (M=Cr, Mo and W) were studied, leading to two new cyclophosphazane metal complexes (C
6
H
4
N
2
)(PPh)
3
C
6
H
4
(NH)
2
·2M(CO)
5
(M=Cr, Mo), where metal coordination is observed only to the phosphorus atoms that have their lone pair of electrons oriented exodentate to the phosphazane ring. The structures for the two new metal complexes are supported by
1
H,
13
C{
1
H} and
31
P{
1
H} NMR spectroscopy. The reaction of 1 with W(CO)
5
(THF) yields a mixture of ring opened and decomposition phosphazane products.
We thank the Camille and Henry Dreyfus foundation, Research Corporation (DS0332) and Fort Lewis College for funding that supported this research.
Aim: To compare the efficacy and safety of sitagliptin vs. glipizide in patients with type 2 diabetes and inadequate glycaemic control haemoglobin A1c (HbA1c) ≥ 6.5 and ≤10% on metformin ...monotherapy.
Methods: After a metformin dose titration/stabilization period (≥1500 mg/day), 1172 patients were randomized to the addition of sitagliptin 100 mg q.d. (N = 588) or glipizide 5 mg/day (uptitrated to a potential maximum 20 mg/day) (N = 584) for 52 weeks. The primary analysis assessed whether sitagliptin was non‐inferior to glipizide regarding HbA1c changes from baseline at Week 52 using a per‐protocol approach.
Results: From a mean baseline of 7.5%, HbA1c changes from baseline were −0.67% at Week 52 in both groups, confirming non‐inferiority. The proportions achieving an HbA1c < 7% were 63% (sitagliptin) and 59% (glipizide). Fasting plasma glucose changes from baseline were −0.56 mmol/l (−10.0 mg/dl) and −0.42 mmol/l (−7.5 mg/dl) for sitagliptin and glipizide, respectively. The proportion of patients experiencing hypoglycaemia episodes was significantly (p < 0.001) higher with glipizide (32%) than with sitagliptin (5%), with 657 events in glipizide‐treated patients compared with 50 events in sitagliptin‐treated patients. Sitagliptin led to weight loss (change from baseline =−1.5 kg) compared with weight gain (+1.1 kg) with glipizide between‐treatment difference (95% confidence interval) =−2.5 kg (−3.1, −2.0); p < 0.001.
Conclusions: In this study, the addition of sitagliptin compared with glipizide provided similar HbA1c‐lowering efficacy over 52 weeks in patients on ongoing metformin therapy. Sitagliptin was generally well tolerated, with a lower risk of hypoglycaemia relative to glipizide and with weight loss compared with weight gain with glipizide.
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