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

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.

No description available.

No description available.

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.

No description available.

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.

Hintergrund und Fragestellung: Seit Einführung der Immuncheckpointinhibitortherapie beim malignen Melanom konnte das Überleben der Patienten deutlich verbessert werden. Ein weiteres wichtiges Qualitätsmerkmal in der Onkologie neben dem Überleben ist die Lebensqualität, da diese für Therapie und Behandlung eine entscheidende Rolle spielt. Die Erfassung der HRQoL beim malignen Melanom unter ICI-Therapie ist unter Routinebedingungen sowie im Survivorship bisher unzureichend. Die vorliegenden Daten zur HRQoL aus klinischen Studien zeigen zudem eine Diskrepanz, da trotz hoher Toxizität keine Reduktion der Lebensqualität sichtbar war. In dieser Arbeit sollten Daten zu Symptomlast und HRQoL von Patienten während ICI-Therapie (Treatmentgruppe) sowie Patienten im Survivorship (Survivorgruppe, mindestens ein Jahr Therapie- und Rezidivfreiheit) generiert und miteinander verglichen werden. Es sollte überprüft werden, ob sich die Diskrepanz der HRQoL durch Erfassung dieser unter Routinebedingungen und den Einsatz krankheits-/therapiespezifischer Instrumente auflösen lässt und ob die Lebensqualitätsabfrage durch ein spezifisches Instrument besser differenziert werden kann. Material und Methoden: Es wurde eine Querschnittsstudie mit einmaliger Lebensqualitätsbefragung an einer Studienpopulation mit 73 Patienten unter aktiver ICI-Therapie und einer Survivorgruppe bestehend aus 26 Patienten durchgeführt. Dabei verwendete Instrumente waren der EORTC QLQ-C30 für die Gruppe unter aktiver Therapie bzw. der SURV100 für die Survivorgruppe und für beide Gruppen ein nach Expertenmeinung zusammengestellter Fragebogen aus Items des PRO-CTACE-Katalogs. Die Fragebogenauswertung erfolgte mittels Itemanalyse, deskriptiven Analysen, Spearman-Korrelation und explorativen Faktorenanalysen mit Maximum-Likelihoodschätzung. In der Gruppe unter aktiver Therapie erfolgte zusätzlich eine Subgruppenanalyse beider Fragebögen. Ergebnisse: In der Treatmentgruppe erhielten 78% eine PD1-Monotherapie und 22% Nivolumab/Ipilimumab. Bei den Survivors erhielten 96% eine PD1-Monotherapie und 4% die Kombinationstherapie. Die HRQoL der Treatmentgruppe (61,0 [±21,6]) lag gering unter der der Survivorgruppe (67,0 [±19,4]) und war somit gegenüber Normalbevölkerung und den Ergebnissen der klinischen Studien ebenfalls reduziert. Häufig berichtete Symptome waren in beiden Gruppen Xerosis cutis (67% Treatmentgruppe vs. 69% Survivorgruppe) und sexuelle Probleme (47% vs. 50%). Die Treatmentgruppe zeigte häufig Pruritus (51%) und Xerostomie (49%), die Survivors Gelenkschmerzen (77%) und Gedächtnisprobleme (54%). Die Symptome waren selten stark, insbesondere bei den Survivors und entsprachen weitgehend den Literaturangaben. Es zeigte sich im PRO-CTCAE ein nicht linearer Zusammenhang zwischen Frequenz, Stärke und Interferenz der Symptome. Haupteinflussfaktoren auf die HRQoL waren Fatigue und physische Funktion. Der therapiespezifische PRO-CTCAE konnte gegenüber dem QLQ-C30 weitere relevante Symptome wie Xerostomie, Hyp-/Dysästhesien oder sexuelle Probleme erfassen. In der Itemanalyse konnten für die jeweilige Gruppe ungeeignete Items der Fragebögen identifiziert werden. In der Subgruppenanalyse zeigten sich statistische auffällige Differenzen der HRQoL und Symptomlast hinsichtlich Geschlechts, eingesetztem ICI, Alters, ECOG, Vortherapie, Hirnmetastasierung und stattgehabter Nebenwirkung unter Therapie. Schlussfolgerungen: Bei einer ähnlichen HRQoL konnten Unterschiede in der Symptomlast zwischen Treatment- und Survivorgruppe festgestellt werden. Die HRQoL der Treatmentgruppe zeigte sich gegenüber den Ergebnissen klinischer Studien reduziert, was ein Hinweis darauf sein kann, dass sich unter Routinebedingungen im Vergleich zu klinischen Studien andere Outcomes zeigen. Ein krankheits-/therapiespezifisches Instrument bringt einen Zugewinn in der Symptomabfrage und kann eine bessere Differenzierung erlauben. Es werden weitere Daten zu spezifischen Aspekten der ICI-Therapie wie geschlechterspezifische Unterschiede oder Auswirkungen auf die Neurokognition oder Fertilität benötigt. / Background and objective: Since the introduction of immune checkpoint inhibitor therapy for malignant melanoma, there was a noticeable improvement of survival. In addition to survival, quality of life is another important quality criterion in oncology, as it plays a decisive role in therapy and treatment. Data on HRQoL of patients with melanoma undergoing an immune checkpoint inhibitor therapy under routine conditions, as well as data on melanoma survivors, have been insufficient so far. The available data on patients with melanoma and immune checkpoint inhibitor therapy show a gap, as no reduction in quality of life was visible despite high toxicity. The aim of this study was to generate and compare data on symptom burden and HRQoL of patients undergoing ICI therapy (treatment group) with patients in survivorship (survivor group, at least one year free of therapy and recurrence). It should be examined whether the gap of the HRQoL could be solved with measuring HRQoL on routine conditions and using a disease- and therapy-specific instrument and whether the quality-of-life survey can be better differentiated by a specific instrument. Methods: There was a one-time survey about HRQoL to a group of 73 patients receiving immune checkpoint inhibitor therapy and a group of survivors containing 26 patients. The used questionnaires were the EORTC QLQ-C30 for the group with ongoing therapy, the SURV100 for the survivor group and for both groups a questionnaire including items of PRO-CTCAE catalogue. The analysis of the questionnaires was based on item analysis, descriptive analysis, spearman correlation and exploratory factor analysis. Additionally, for the group receiving therapy, a subgroup analysis was done. Results: In the treatment group, 78% of the patients received PD-1-monotherapy and 22% Nivolumb/Ipilimumab. In the survivor group, 96% were undergoing PD1-monotherapy and 4% combined therapy. The HRQoL of the treatment (61,0 [±21,6]) group was slightly lower than the HRQoL of the survivor group (67,0 [±19,4]) and was lower than general population norm data and the outcomes of clinical trials. Common symptoms in both groups were xerosis cutis (67% treatment group vs. 69% survivor group) and sexual problems (47% vs. 50%). The treatment group frequently reported pruritus (51%) and xerostomia (49%), the survivor group aching joints (77%) and memory loss (54%). The symptoms were often mild to moderate, especially in the survivor group and had already been partially reported in literature. There was no linear correlation between frequency, strength and interference of symptoms in the PRO-CTCAE. Main impact factors on quality of life were fatigue and physical function. The therapy-specific PRO-CTCAE could identify new relevant symptoms like xerostomia or dysesthesia in comparison to the QLQ-C30. The item analysis showed not suitable items in each questionnaire for the corresponding group. Subgroup analysis showed statistical conspicuity for sex, immune checkpoint inhibitor, age, performance status, brain metastasis, adverse events and previous therapy. Conclusions: With similar HRQoL, differences in symptom burden were found between the treatment and the survivor group. Patients with immune checkpoint inhibitor therapy reported lower HRQoL than patients in clinical trials, which could show that real world experience could lead to different outcomes than clinical trials. It was shown that a disease and therapy specific questionnaire could measure more symptoms and better distinguish quality of life. Further data is needed on specific aspects of ICI therapy such as gender-specific differences or effects on neurocognition or fertility.

<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>