Immune checkpoint blockade (ICB) has revolutionized cancer treatment, providing remarkable clinical responses in some patients. However, the majority of patients do not respond. It is therefore ...crucial both to identify predictive biomarkers of response and to increase the response rates to immune checkpoint therapy. In this review we explore the current literature about the predictive characteristics of the tumor microenvironment and discuss therapeutic approaches that aim to change this toward a milieu that is conducive to response. We propose a personalized biomarker-based adaptive approach to immunotherapy, whereby a sensitizing therapy is tailored to the patient's specific tumor microenvironment, followed by on-treatment verification of a change in the targeted biomarker, followed by immune checkpoint therapy. By incorporating detailed knowledge of the immunological tumor microenvironment, we may be able to sensitize currently non-responsive tumors to respond to immune checkpoint therapy.
Abstract
The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin ...therapeutic efficacy due to the inability to frequently sample tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNβ is targeted, not IFNα. We identify Ly6C
+
/CD11b
+
inflammatory monocytes as the primary source of IFNβ and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response.
Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple ...cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune checkpoint blockade (ICB). Although a variety of isolated immunostimulatory effects have been reported for several classes of chemotherapeutics, it is unclear which chemotherapeutics provide the most benefit when combined with ICB. We investigated 10 chemotherapies from the main canonical classes dosed at the clinically relevant maximum tolerated dose in combination with anti-CTLA-4/anti-PD-L1 ICB. We screened these chemo-immunotherapy combinations in two murine mesothelioma models from two different genetic backgrounds, and identified chemotherapies that produced additive, neutral or antagonistic effects when combined with ICB. Using flow cytometry and bulk RNAseq, we characterized the tumor immune milieu in additive chemo-immunotherapy combinations. 5-fluorouracil (5-FU) or cisplatin were additive when combined with ICB while vinorelbine and etoposide provided no additional benefit when combined with ICB. The combination of 5-FU with ICB augmented an inflammatory tumor microenvironment with markedly increased CD8
T cell activation and upregulation of IFNγ, TNFα and IL-1β signaling. The effective anti-tumor immune response of 5-FU chemo-immunotherapy was dependent on CD8
T cells but was unaffected when TNFα or IL-1β cytokine signaling pathways were blocked. Our study identified additive and non-additive chemotherapy/ICB combinations and suggests a possible role for increased inflammation in the tumor microenvironment as a basis for effective combination therapy.
•Patients with previously treated pleural mesothelioma were treated with AZD4547.•12 % of patients were progression free at 6 months.•There were no confirmed objective responses to treatment.•There ...was no association between tumour BAP1 protein expression and treatment outcome.•This study did not meet its primary endpoint.
Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1–3 inhibitor, as a second or third-line treatment.
We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon’s two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients.
3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes.
The FGFR 1–3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although immunotherapy has recently proven effective in some cancers, most patients with metastatic cancer do not benefit from this therapy. A lack of understanding of the mechanisms that underpin a ...successful immunotherapeutic response hamper the development of novel effective treatment combinations. In addition, defining a reliable predictive biomarker is a challenging feature selection problem given the complex and dynamic nature of an effective anti-tumour immune response. Functional genomics is an increasingly common approach to the field of biomarker discovery in cancer immunotherapy. A variety of sequencing technologies are available and data can be analysed on multiple platforms, making it accessible to scientists in many disciplines. This review explores computational strategies that can be leveraged to analyse large amounts of high-dimensional sequencing data to yield biological insight into the processes involved in the immunotherapeutic response and to identify candidate biomarkers and drug targets for laboratory-based validation.
A hitchhiker's guide to biomarker discovery in immune checkpoint blockade.
KMT2/Set1 is the catalytic subunit of the complex of proteins associated with Set1 (COMPASS) that is responsible for the methylation of lysine 4 of histone H3 (H3K4) in
Saccharomyces cerevisiae. ...Whereas monomethylated H3K4 (H3K4me1) is found throughout the genome, di- (H3K4me2) and tri- (H3K4me3) methylated H3K4 are enriched at specific loci, which correlates with the promoter and 5′-ends of actively transcribed genes in the case of H3K4me3. The COMPASS subunits contain a number of domains that are conserved in homologous complexes in higher eukaryotes and are reported to interact with modified histones. However, the exact organization of these subunits and their role within the complex have not been elucidated. In this study we showed that: (1) subunits Swd1 and Swd3 form a stable heterodimer that dissociates upon binding to a modified H3K4me2 tail peptide, suggesting a regulatory role in COMPASS; (2) the affinity of the subunit Spp1 for modified histone H3 substrates is much higher than that of Swd1 and Swd3; (3) Spp1 has a preference for H3K4me2/3 methylation state; and (4) Spp1 contains a high-affinity DNA-binding domain in the previously uncharacterised C-terminal region. These data allow us to suggest a mechanism for the regulation of COMPASS activity at an actively transcribed gene.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Precision medicine promises to transform healthcare for groups and individuals through early disease detection, refining diagnoses and tailoring treatments. Analysis of large-scale genomic-phenotypic ...databases is a critical enabler of precision medicine. Although Asia is home to 60% of the world's population, many Asian ancestries are under-represented in existing databases, leading to missed opportunities for new discoveries, particularly for diseases most relevant for these populations. The Singapore National Precision Medicine initiative is a whole-of-government 10-year initiative aiming to generate precision medicine data of up to one million individuals, integrating genomic, lifestyle, health, social and environmental data. Beyond technologies, routine adoption of precision medicine in clinical practice requires social, ethical, legal and regulatory barriers to be addressed. Identifying driver use cases in which precision medicine results in standardized changes to clinical workflows or improvements in population health, coupled with health economic analysis to demonstrate value-based healthcare, is a vital prerequisite for responsible health system adoption.
Full text
Available for:
GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The catalytic pyrolysis of Chlorella vulgaris, high-density polyethylene (Pure HDPE) and, their binary mixtures were conducted to analyse the kinetic and thermodynamic performances from 10 to ...100 K/min. The kinetic parameters were computed by substituting the experimental and ANN predicted data into these iso-conversional equations and plotting linear plots. Among all the iso-conversional models, Flynn-Wall-Ozawa (FWO) model gave the best prediction for kinetic parameters with the lowest deviation error (2.28–12.76%). The bifunctional HZSM-5/LS catalysts were found out to be the best catalysts among HZSM-5 zeolite, natural limestone (LS), and bifunctional HZSM-5/LS catalyst in co-pyrolysis of binary mixture of Chlorella vulgaris and HDPE, in which the Ea of the whole system was reduced from range 144.93–225.84 kJ/mol (without catalysts) to 75.37–76.90 kJ/mol. With the aid of artificial neuron network and genetic algorithm, an empirical model with a mean absolute percentage error (MAPE) of 51.59% was developed for tri-solid state degradation system. The developed empirical model is comparable to the thermogravimetry analysis (TGA) experimental values alongside the other empirical model proposed in literature
Display omitted
•Synergistic effect of catalytic co-pyrolysis of M/HDPE were evaluated.•ANN model was established to generate the weight loss data of samples.•FWO model gave the best prediction for kinetic parameters.•The Ea range of M/HDPE/ Bifunctional HZSM-5/LS was reduced to 75.37 – 76.90 kJ/mol.•Empirical model with a MAPE of 51.59% was developed.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Display omitted
•Characteristics and hazards of different types of PPCPs are summarized.•Advantages and limitations of the technologies for the removal of PPCPs from aqueous solutions are ...summarized.•PPCPs removal efficiencies of different removal processes are compared.•Hybrid treatment generally has greater potential to remove a wide range of PPCPs.•Challenges and future perspectives of the current advancement in the removal of PPCPs are described.
In recent years, the removal of pharmaceutical and personal care products (PPCPs) from aqueous solutions has been gaining a lot of attention from researchers throughout the world. This is particularly due to the concern about their potential hazards and toxicities, as they are classified as emerging contaminants. Thus, there is an increasing need to investigate removal technologies for PPCPs at a deeper and more holistic level. This review aims to provide the latest developments in removal technologies for PPCPs. It first succinctly describes the types, characteristics, and hazards of PPCPs on the environment and human health. It then comprehensively covers a wide range of technologies for removing PPCPs from aqueous solutions, comprising the adsorption process(using carbon-based adsorbents, plant biomasses, clay and clay minerals, silica-based adsorbents, zeolite-based adsorbents, polymers and resins, and hybrid adsorbents),advanced oxidation processes (AOPs) (photocatalysis, Fenton or photo-Fenton or electro-Fenton, ozonation, ultrasonication, electrochemical oxidation, persulfate oxidation), membrane separation processes (ultrafiltration, nanofiltration, reverse osmosis), biodegradation processes (bacteria, fungi, and algae), and hybrid treatment (adsorption-AOP, AOP-membrane, membrane-biodegradation, and others).According to the specific experimental conditions, the reported removal efficiencies for adsorption, AOPs, membrane processes, biodegradation processes and hybrid treatment were 40–100%, 40–100%, 3–100%, 14–100% and 5–100%, respectively. This review paper also highlights the challenges in this field of research, particularly incomplete removal of certain PPCPs, high costs of some treatment technologies and generally insufficient understanding on the removal kinetics and mechanisms of PPCPs. This review offers recommendations for future works to further advance the technical performances to eventually realize the wider application of these technologies at the industrial scale.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
