A5073399228- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Cancer Genomics and Diagnostics
- Computational Drug Discovery Methods
- Monoclonal and Polyclonal Antibodies Research
- Immune cells in cancer
- Bladder and Urothelial Cancer Treatments
- interferon and immune responses
- Nanoplatforms for cancer theranostics
- vaccines and immunoinformatics approaches
- Cancer, Stress, Anesthesia, and Immune Response
- Adenosine and Purinergic Signaling
- Single-cell and spatial transcriptomics
- Advanced Biosensing Techniques and Applications
- Lung Cancer Diagnosis and Treatment
- Epigenetics and DNA Methylation
- Immune Response and Inflammation
- Cytokine Signaling Pathways and Interactions
- Ferroptosis and cancer prognosis
- Hepatocellular Carcinoma Treatment and Prognosis
- Esophageal Cancer Research and Treatment
- CRISPR and Genetic Engineering
AstraZeneca (United Kingdom)
2012-2025
University College London
2024
AstraZeneca (United States)
2024
AstraZeneca (Brazil)
2009-2024
AstraZeneca (Singapore)
2021
PredictImmune
2019
University of Manchester
2010-2017
Manchester Academic Health Science Centre
2012-2017
Cancer Research UK Manchester Institute
2010-2016
Cancer Research Center
2015
Abstract Radiotherapy is a major part in the treatment of most common cancers, but many patients experience local recurrence with metastatic disease. In evaluating response biomarkers, we found that low doses fractionated radiotherapy led to PD-L1 upregulation on tumor cells variety syngeneic mouse models cancer. Notably, delivered combination αPD-1 or αPD-L1 mAbs generated efficacious CD8+ T-cell responses improved control, long-term survival, and protection against rechallenge. These...
Murine syngeneic tumor models are critical to novel immuno-based therapy development, but the molecular and immunologic features of these still not clearly defined. The translational relevance differences between is fully understood, impeding appropriate preclinical model selection for target validation, ultimately hindering drug development. Across a panel commonly used murine models, we showed variable responsiveness immunotherapies. We array comparative genomic hybridization, whole-exome...
Abstract Purpose: Radiotherapy is a highly effective anticancer treatment forming part of the standard care for majority patients, but local and distal disease recurrence remains major cause mortality. known to enhance tumor immunogenicity; however, contribution mechanisms radiotherapy-induced immune responses are unknown. Experimental Design: The impact low-dose fractionated radiotherapy (5 × 2 Gy) alone in combination with αPD-1 mAb on microenvironment was evaluated by flow cytometry...
<h3>Background</h3> Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, patients with immunologically “cold” tumors, tumor-resident innate immune cell activation may be required to prime an response so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically successfully treat superficial skin systemic TLR not well-tolerated. <h3>Methods</h3> The human cells TLR7 8 agonism was measured...
The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate significant immune-related adverse events suboptimally limiting the doses anti-CTLA4 mAb that used. MEDI5752 a monovalent bispecific antibody designed to suppress pathway and provide modulated favoring enhanced on PD-1+ activated T cells. We show preferentially saturates cells versus PD-1- cells, reducing dose required elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, leads...
Improving the efficacy of immune checkpoint therapies will require a better understanding how cells are recruited and sustained in tumors. Here, we used photoconversion tumor cell compartment to identify newly entering lymphocytes, determine they change over time, investigate their egress from tumor. Combining single-cell transcriptomics flow cytometry, found that while diverse mix CD8 T subsets enter tumor, all retained within this environment for more than 72 h developed an exhausted...
Immune cell dysfunction within the tumor microenvironment (TME) undermines control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, temporal dynamics, mechanistic underpinning and functional significance NK compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic cellular analyses, to interrogate fate intratumoral cells. We reveal that cells rapidly lose...
Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a better prognosis than those HPV-negative tumours. There is interest in de-escalating their treatment but strategies are needed for risk stratification to identify subsets poor prognosis. This study investigated tumour-infiltrating lymphocytes (TILs) relation HPV tumour status and patient survival.
<h3>Background</h3> Numerous oncology combination therapies involving modulators of the cancer immune cycle are being developed, yet quantitative simulation models predictive outcome lacking. We here present a model-based analysis tumor size dynamics and markers, which integrates experimental data from multiple studies provides validated framework biomarkers anti-tumor response rates, for untested dosing sequences schedules combined radiation (RT) anti PD-(L)1 therapies. <h3>Methods</h3> A...
Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled an activation programme enriched in regulatory molecule expression, including PD-L1. However, the spatio-temporal dynamics of
Fractionated radiation therapy (RT) leads to adaptive changes in the tumor microenvironment that may limit generation of an antitumor immune response. We demonstrated fractionated RT led increased cell expression programmed death ligand 1 (PD-L1) response CD8+ T production interferon gamma. Our data reveal efficacy can be significantly improved through durable systemic responses when combined with concurrent, but not sequential, blockade PD-1/PD-L1 pathway.
// Kenneth Oguejiofor 1 , Henry Galletta-Williams Simon J. Dovedi 2 Darren L. Roberts Peter Stern 3 and Catharine M.L. West Translational Radiobiology Group, Division of Molecular & Clinical Cancer Sciences, School Medical Faculty Biology, Medicine Health, University Manchester, Manchester Academic Health Science Centre, Christie Hospital NHS Trust, UK Targeted Therapy Immunology/Children’s Correspondence to: Stern, email: Keywords : checkpoint inhibitor, PD-L1, human...
<h3>Background</h3> T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of inhibitors as standalone therapies, impact inhibition on activity remains incompletely understood. Here we sought to characterize combined anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining both T-cells tumor microenvironment (TME). <h3>Methods</h3> In mice, inhibition, via selumetinib, immune responses keyhole limpet...
Abstract CTLA‐4 and PD‐1 are key immune checkpoint receptors that targeted in the treatment of cancer. A recently identified physical interaction between respective ligands, CD80 PD‐L1, has been shown to block PD‐L1/PD‐1 binding prevent PD‐L1 inhibitory functions. Since is known capture degrade its ligands via transendocytosis, we investigated interplay transendocytosis CD80/PD‐L1 interaction. We find results a time‐dependent recovery availability correlates with removal. Moreover, highly...
Abstract T cells gene-modified to express chimeric Ag receptors (CARs) have shown potent antitumor activity in vivo and are clinical trials at locations worldwide. However, CAR has been investigated mouse models which expression is restricted the tumor. To explore impact of normal tissue target Ag, we developed a CD19-specific investigate efficacy against syngeneic B cell lymphoma line within background CD19+ host cells. Mouse engrafted with amCD19CD3ζ specifically lysed A20 targets vitro....
Abstract Tumor cells dying after cytotoxic therapy are a potential source of antigen for T-cell priming. Antigen-presenting (APC) can cross-present MHC I–restricted peptides the uptake cells. Depending on nature surrounding environmental signals, APCs then orchestrate spectrum responses ranging from immune activation to inhibition. Previously, we had demonstrated that combining radiation with either agonistic monoclonal antibody (mAb) CD40 or systemically administered TLR7 agonist could...
Combining radiotherapy (RT) with DNA damage response inhibitors may lead to increased tumor cell death through radiosensitization. DNA-dependent protein kinase (DNA-PK) plays an important role in double-strand break repair via the nonhomologous end joining (NHEJ) pathway. We hypothesized that addition a radiosensitizing effect from combination of RT AZD7648, potent and specific inhibitor DNA-PK, therapy also modulation anticancer immune response.
The concept of exploiting tumor intrinsic deficiencies in DNA damage repair mechanisms by inhibiting compensatory pathways is well established. For example, ATM-deficient cells show increased sensitivity to the ATR inhibitor ceralasertib. response (DDR)-deficient are also more sensitive damaging agents like crosslinker pyrrolobenzodiazepine (PBD) SG-3199. However, additional antitumor benefits from targeting DDR pathways, which could operate through activation innate immune system less...
Although topical TLR7 therapies such as imiquimod have proved successful in the treatment of dermatological malignancy, systemic delivery may be required for optimal immunotherapy nondermatological tumors. We report that intravenous novel small molecule agonist, DSR‐6434, leads to induction type 1 interferon and activation T B lymphocytes, NK NKT cells. Our data demonstrate administration DSR‐6434 enhances efficacy ionizing radiation (IR) improved survival mice bearing either CT26 or KHT Of...
Abstract Anti-CD20 monoclonal antibodies (mAb) such as rituximab have been proven to be highly effective at improving outcome in B-cell malignancies. However, many patients ultimately relapse and become refractory treatment. The glycoengineered anti-CD20 mAb obinutuzumab was developed induce enhanced antibody-dependent cellular cytotoxicity, phagocytosis direct cell death shown lead improved outcomes a randomized study B-CLL. We hypothesized that immune stimulation through Toll-like receptor...