Publications by authors named "Paul J Neeson"

Background: Immunotherapy has demonstrated limited activity in prostate cancer to date. This likely reflects an immune suppressive tumor microenvironment (TME), with previous studies suggesting low PD-L1 expression and a sparse immune cell infiltrate. We aimed to further characterise the immune TME in primary prostate cancer and correlate immune subset densities with clinical outcomes.

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Background: Locally advanced oral cavity squamous cell carcinoma (OCSCC) presents a significant clinical challenge despite being partially responsive to standard treatment modalities. This study investigates the prognostic implications of programmed death-ligand 1 (PD-L1) expression in these tumors, focusing on its association with treatment outcomes and the immune microenvironment.

Methods: We assessed tumor-infiltrating lymphocytes (TILs) in 132 patients with OCSCC to evaluate their impact on survival.

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Article Synopsis
  • The study reveals a method to create human haemogenic DLL4+ arterial endothelial cells (AECs) from pluripotent stem cells, essential for forming blood cells during embryonic development.* -
  • Using single-cell RNA sequencing, researchers tracked the development of blood cell types in human embryos, identifying key pre-haematopoietic stem cell genes along the way.* -
  • The research shows that IL7 influences the decision between T cells and innate lymphoid cells and establishes a pathway for RAG1+ lymphoid precursors to develop into natural killer cells, offering insights into blood system development.*
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High-risk localized prostate cancer remains a lethal disease with high rates of recurrence, metastases and death, despite attempts at curative local treatment including surgery. Disease recurrence is thought to be a result of failure of local control and occult micrometastases. Neoadjuvant strategies before surgery have been effective in many cancers, but, to date, none has worked in this setting for prostate cancer.

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A multidisciplinary approach to the management of tongue cancer is vital for achieving optimal patient outcomes. Nursing and allied health professionals play essential roles within the team. We developed symposia comprising a series of online lectures offering a detailed perspective on the role each discipline and consumer perspective has in the management of patients with tongue cancer.

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  • CAR T cell therapy has been effective for treating blood cancers but struggles with solid tumors due to challenging tumor microenvironments.
  • Research indicates that CAR T cells with a 'stem-like' phenotype and greater mitochondrial mass have better treatment outcomes.
  • The study highlights that overexpressing the transcription factor FOXO1 in CAR T cells can enhance their fitness and effectiveness against solid tumors by promoting a more beneficial metabolic state.
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Background: High-risk localised prostate cancer (HRCaP) has high rates of biochemical recurrence; [Lu]Lu-PSMA-617 is effective in men with advanced prostate cancer.

Objective: To investigate the dosimetry, safety, and efficacy of upfront [Lu]Lu-PSMA-617 in men with HRCaP prior to robotic radical prostatectomy (RP).

Design, Setting, And Participants: In this single-arm, phase I/II trial, we recruited men with HRCaP (any of prostate-specific antigen [PSA] >20 ng/ml, International Society of Urological Pathology (ISUP) grade group [GG] 3-5, and ≥cT2c), with high tumour uptake on [Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PSMA PET/CT), and scheduled for RP.

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Spatial proteomics technologies have revealed an underappreciated link between the location of cells in tissue microenvironments and the underlying biology and clinical features, but there is significant lag in the development of downstream analysis methods and benchmarking tools. Here we present SPIAT (spatial image analysis of tissues), a spatial-platform agnostic toolkit with a suite of spatial analysis algorithms, and spaSim (spatial simulator), a simulator of tissue spatial data. SPIAT includes multiple colocalization, neighborhood and spatial heterogeneity metrics to characterize the spatial patterns of cells.

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Background: Surgery remains the standard of care for localised renal cell carcinoma (RCC). Nevertheless, nearly 50% of patients with high-risk disease experience relapse after surgery, with distant sites being common. Considering improved outcomes in terms of disease-free survival with adjuvant immunotherapy with pembrolizumab, we hypothesise that neoadjuvant SABR with or without the addition of pembrolizumab before nephrectomy will lead to improved disease outcomes by evoking better immune response in the presence of an extensive reserve of tumor-associated antigens.

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Background: Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy.

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Patients who receive chimeric antigen receptor (CAR)-T cells that are enriched in memory T cells exhibit better disease control as a result of increased expansion and persistence of the CAR-T cells. Human memory T cells include stem-like CD8 memory T cell progenitors that can become either functional stem-like T (T) cells or dysfunctional T progenitor exhausted (T) cells. To that end, we demonstrated that T cells were less abundant in infused CAR-T cell products in a phase 1 clinical trial testing Lewis Y-CAR-T cells (NCT03851146), and the infused CAR-T cells displayed poor persistence in patients.

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Background: Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers.

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Chemotherapy has long been a standard treatment for a wide range of malignancies, where patients typically undergo multiple rounds of chemotherapy regimens to control tumor growth. In the clinic, the chemotherapy drugs cyclophosphamide and fludarabine are commonly used prior to Chimeric Antigen Receptor T (CAR-T) cell therapy to lymphodeplete and improve CAR-T cell engraftment. In this review, we discuss the use of chemotherapy in combination with CAR-T cell therapy.

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CD8 tumor-infiltrating lymphocytes with a tissue-resident memory T (T) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the relative contribution of CD8 T cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8 T cells in murine mammary tumors transcriptionally resemble those from TNBC patients.

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Purpose: Tumor cells thrive by adapting to the signals in their microenvironment. To adapt, cancer cells activate signaling and transcriptional programs and migrate to establish micro-niches, in response to signals from neighboring cells and non-cellular stromal factors. Understanding how the tumor microenvironment evolves during disease progression is crucial to deciphering the mechanisms underlying the functional behavior of cancer cells.

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Brain tumours are the most common solid tumour in children and the leading cause of cancer related death in children. Current treatments include surgery, chemotherapy and radiotherapy. The need for aggressive treatment means many survivors are left with permanent severe disability, physical, intellectual and social.

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Background: In esophageal cancer (EC), there is a paucity of knowledge regarding the interplay between the tumor immune microenvironment and response to neoadjuvant treatment and, therefore, which factors may influence outcomes. Thus, our goal was to investigate the changes in the immune microenvironment with neoadjuvant treatment in EC by assessing the expression of immune related genes and their association with prognosis.

Methods: We examined the transcriptome of paired pre- and post-neoadjuvant treated EC specimens.

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Patients with refractory relapsed multiple myeloma respond to combination treatment with elotuzumab and lenalidomide. The mechanisms underlying this observation are not fully understood. Furthermore, biomarkers predictive of response have not been identified to date.

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Background: Vaginal melanoma (VM) is a rare cancer and has a poor response to immune checkpoint blockade (ICB). CD8Tissue Resident Memory (TRM) T cells proliferate in response to ICB and correlate with longer survival in metastatic cutaneous melanoma. However, their capacity to respond to VM and their neoantigens is not known.

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Article Synopsis
  • Treatment-naive melanoma patients with -mutant and wild-type (-wt) variants show different immune responses to immunotherapy, which remains unexplored.
  • Analysis using various techniques revealed -mutant melanoma has fewer CD8 T cells and macrophages but more B cells and CD4 T cells compared to -wt melanoma.
  • The unique immune composition in -mutant melanoma may contribute to its distinct response to treatment, indicating potential avenues for targeted immunotherapy strategies.
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Although the impressive clinical responses seen with modern cancer immunotherapy are currently limited to a subset of patients, the underlying paradigm shift has resulted in now hardly a segment in oncology that has not been touched by the immuno-oncology revolution. A growing body of data indicates that radiation therapy (RT) can modulate the tumour immune microenvironment and complement cancer immunotherapy via non-overlapping mechanisms to reinvigorate immunity against cancer. Thus, increasingly RT is viewed as a highly unique partner for immunotherapy across the spectrum of cancer settings, as radiobiology and cancer immunology foreseeably become more intertwined.

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Radiotherapy (RT) is the standard-of-care treatment for more than half of cancer patients with localized tumors and is also used as palliative care to facilitate symptom relief in metastatic cancers. In addition, RT can alter the immunosuppressive tumor microenvironment (TME) of solid tumors to augment the anti-tumor immune response of immune checkpoint blockade (ICB). The rationale of this combination therapy can also be extended to other forms of immunotherapy, such as chimeric antigen receptor T cell (CAR-T) therapy.

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Despite aggressive surgery, chemotherapy, and radiotherapy, survival of children and adolescents and young adults (AYAs) with sarcoma has not improved significantly in the past four decades. Immune checkpoint inhibitors (ICIs) are an exciting type of immunotherapy that offer new opportunities for the treatment of paediatric and AYA sarcomas. However, to date, most children do not derive a benefit from this type of treatment as a monotherapy.

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Background: Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib-trametinib and ipilimumab-nivolumab have similar intracranial response rates (50%-55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab-nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance.

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