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Re: Maud Rijnders, Ronald de Wit, Joost L. Boormans, Martijn P.J. Lolkema, Astrid A.M. van der Veldt. Systematic Review of Immune Checkpoint Inhibition in Urological Cancers. Eur Urol. 2017;72:411–23Martinez Merizalde Balarezo, Nelson, Monroe Rivera, Mark, Tejada, Romina A. 03 1900 (has links)
El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / “Cartas al editor” / Revisión por pares
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Immune checkpoint inhibitor-induced inflammatory arthritis: a single center reviewSarazin, Jeffrey 24 November 2020 (has links)
INTRODUCTION: Immune checkpoint inhibitors are a new form of immunotherapy that has transformed the treatment landscape for an ever-increasing number of malignancies. While these medications utilize and enhance the immune system to treat malignancies, they can also have significant side effects, termed immune related adverse events, that in many ways resemble autoimmune disease states. One such example is inflammatory arthritis, which has been found to resemble a number of different presentations, including rheumatoid arthritis and seronegative spondyloarthropathies. In addition to these traditional inflammatory arthritis phenotypes, worsening of pre-existing arthritis is another subgroup of inflammatory arthritis that has previously not been considered in this population. Furthermore, while the effects of these autoimmune arthropathies on functionality is well-documented, it is not known whether there is a significant effect on functionality in patients that experience immune checkpoint inhibitor-induced arthritis. Given that patient reported outcomes are a validated and routinely utilized measure of functionality and quality of life, the Health Assessment Questionnaire, pain visual analogue scale and Patient Global Assessment were used to measure these outcomes following diagnosis. Our aim here is to explore the subtypes of inflammatory arthritis that result from this type of treatment and its overall effect on functionality and quality of life.
METHODS: This study was a retrospective review of patients at one academic center who experienced an inflammatory arthritis resulting from immune checkpoint inhibition and required a referral to a rheumatologist for further work-up. Patients were evaluated in clinic at which time they also completed a Health Assessment Questionnaire as part of standard of care. Once patients were evaluated, their inflammatory arthritis was classified based on which clinical arthritis that it matched most closely, including polymyalgia rheumatica, rheumatoid arthritis, seronegative spondyloarthritis, or an exacerbation or osteoarthritis. Other demographic information such as gender, age, and race were also collected. Patient questionnaires were scored and compared to the type of inflammatory arthritis to assess for any correlations.
RESULTS: We found 30 patients that had an inflammatory arthritis resulting from immune checkpoint inhibition, with 12 having a polyarthritis similar to rheumatoid arthritis, 11 patients having osteoarthritis exacerbation, 4 patients with a polymyalgia rheumatica arthritis phenotype and 3 patients with a spondyloarthopathy. In terms of the patient reported outcomes, the overall score was 0.57 ± 0.47, indicating that there was little effect of these arthropathies on overall functionality. The pain visual analogue scale had an average score of 41.8 ± 31.4 mm and the Patient Global Assessment had an overall score of 25.6 ± 26.7 mm.
DISCUSSION: The overall results suggest that the inflammatory arthritis phenotypes do not significantly impact the functionality or quality of life of most patients who experience this side effect. Given that the use of immune checkpoint inhibitors will continue to grow, the overall need to better understand the resulting arthritis presentations is key. This is perhaps most true for those with pre-existing osteoarthritis, given the widespread nature of the disease in the general population and the prominence of the exacerbation as seen in our cohort.
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Evaluating Immune Modulatory Therapeutic Strategies for Diffuse Intrinsic Pontine GliomaFurnish, Robin January 2020 (has links)
No description available.
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Evaluating Immune Modulatory Therapeutic Strategies for Diffuse Intrinsic Pontine GliomaFurnish, Robin 04 November 2020 (has links)
No description available.
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Modulating the gut microbiome to improve immune checkpoint inhibitor response to cancer: current therapies and emerging methodsWeatherly, Madison E. 15 March 2024 (has links)
Immunotherapy has emerged as one of the four “standard” cancer therapies, alongside surgery, chemotherapy, and radiotherapy. Immune checkpoint inhibitor (ICI) therapy is an immunotherapy that blocks inhibitory immune checkpoint interactions, allowing T cells and other immune cells to kill tumor cells. In the tumor microenvironment, there is often overexpression of immune checkpoint proteins, whose binding interaction with cytotoxic T cells and other immune cells results in the dampening of the antitumor response. Programmed cell death protein 1 (PD-1) and T-lymphocyte-associated protein 4 (CTLA-4) are the two most targeted immune checkpoint proteins. Antibodies against PD-1 and CTLA-4, as well as other checkpoint proteins, are approved for clinical use as well as in clinical trials. While ICIs have changed the treatment landscape for many cancers, particularly those with significant immunogenicity, only 20-40% of patients respond to ICI therapy. Many factors are behind the lack of response and resistance, and significant efforts are aimed at improving the response to ICI therapy. One major area is modulating the gut microbiome, as it is well-established that microbial dysbiosis is associated with various human diseases. The concept is that by modulating the microbiome, we might be able to return it to a composition more similar to that seen in healthy individuals or provide microorganisms beneficial to clinical response. In the case of ICI therapy, it is proposed that there is a connection between certain microbial species and the immune system via metabolites and other signaling effects. The microbiome can be manipulated through many methods, including fecal microbiota transplantation (FMT), transferring bacterial isolates or consortia, probiotics, antibiotics, and soluble dietary fiber. For clinical insights, it is important to consider how the pre-treatment microbiome of patients may affect their response to ICI therapy, as well as how their microbiomes can be manipulated to enhance their response. Initial clinical trials have been promising, but this is an emerging field with additional work to be done. Particularly, a better understanding of the microorganisms involved in the response to ICI therapy and the mechanism by which they communicate with the immune system is essential. Future studies will need to be much larger to reduce noise between studies and to allow for emerging computational techniques to be applied.
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Elevated Clearance of Immune Checkpoint Inhibitors in Animal Models of Cancer CachexiaVu, Trang Thu January 2022 (has links)
No description available.
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FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical RationaleAdam, Pia, Kircher, Stefan, Sbiera, Iuliu, Koehler, Viktoria Florentine, Berg, Elke, Knösel, Thomas, Sandner, Benjamin, Fenske, Wiebke Kristin, Bläker, Hendrik, Smaxwil, Constantin, Zielke, Andreas, Sipos, Bence, Allelein, Stephanie, Schott, Matthias, Dierks, Christine, Spitzweg, Christine, Fassnacht, Martin, Kroiss, Matthias 04 April 2023 (has links)
Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC)
thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a
multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is
approved for advanced radioiodine refractory thyroid carcinoma, but response to single
agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor
pembrolizumab (PEM) are promising.
Materials and Methods: Primary ATC (n=93) and PDTC (n=47) tissue samples
diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1
expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4
mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization.
Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls.
Disease specific survival (DSS) was the primary outcome variable.
Results: PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens.
Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%;
p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%.
FGFR mRNA expression was generally low in all samples but combined FGFR1-4
expression was significantly higher in PDTC and ATC compared to NT (each p<0.001).
No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.
Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a
subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR
expression is low thyroid tumor cells. The clinically observed synergism of PEM with
LEN may be caused by immune modulation.
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PHARMACOLOGICAL TARGETING OF FGFR IN METASTATIC BREAST CANCER IS AUGMENTED BY DNMT1 INHIBITIONMitchell G Ayers (18990533) 02 August 2024 (has links)
<p dir="ltr">Metastatic breast cancer (BC) remains a dauting therapeutic challenge due to the heterogeneity and cellular plasticity that exists. Because of these, BC resistance to targeted therapies and immune checkpoint blockade (ICB) present major challenges in the clinical setting. As a result, incomplete clearance of BC during a therapeutic regimen can lead to the persistence of minimal residual disease (MRD) which greatly contributes to tumor relapse. Here we develop a powerful in vivo model of lung metastasis in which we can achieve robust pulmonary tumor regression in response to the fibroblast growth factor receptor (FGFR) inhibitor, pemigatinib.</p><p dir="ltr">To enhance the efficacy of ICB, tumors must first be converted from an immune “cold” environment to an immune “hot” environment. Using our in vivo model of lung metastasis, we demonstrated that pemigatinib can significantly increase the presence of infiltrating T-cells into the lungs while suppressing the presence of MDSCs both locally in the lungs and systemically. Taken together, pemigatinib is an ideal candidate to prime these immune “cold” tumors for combination with ICB.</p><p dir="ltr">Upon establishment of MRD by pemigatinib in our in vivo model we observe upregulation of an alternate growth factor receptor, platelet-derived growth factor receptor (PDGFR). Functionally, upon FGFR inhibition, there is increased response to pulmonary fibroblast derived PDGF ligand, fueling survival of MRD. We demonstrated that knockdown of PDGFR significantly delayed tumor growth reinitiation in an in vitro 3D culture following pemigatinib as well as delayed tumor relapse in our pulmonary metastasis model.</p><p dir="ltr">To limit cellular plasticity and reduce survival of MRD, we propose a novel dual-targeted approach utilizing pemigatinib, in conjunction with inhibition of DNMT1 using the reversible inhibitor GSK3484862. We used our in vivo model of lung metastasis after treatment with pemigatinib as a model of cellular plasticity to targeted therapy. This combination therapy prevented growth factor plasticity and delayed tumor recurrence. Through prevention of PDGFR upregulation induced by pemigatinib.</p><p dir="ltr">In the present dissertation works, our study demonstrates pemigatinib’s robust ability to increase infiltrating T-cells in addition to its strong antitumor effects on pulmonary tumors. Despite the robust effects of pemigatinib, acquired mechanism of resistance through upregulation of PDGFR allows survival of MRD and are supported by PDGF secreting fibroblasts. Using an approach of limiting cellular plasticity through DNA methylation inhibition combined with pemigatinib, we achieved a more durable therapeutic response. Our findings underscore the significance of understanding adaptive responses to targeted therapies and provide a tangible therapeutic strategy to prolong treatment response in metastatic breast cancer.</p>
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