S193. EX VIVO SIGNATURE OF PSYCHOSIS AND TREATMENT RESPONSE IN PATIENT-DERIVED NEURONS

Abstract Background Multiple sclerosis is one of the most prevalent neurological diseases in young adults affecting over 2 million people worldwide. Alemtuzumab is a highly effective therapy in relapsing remitting MS. Alemtuzumab is a monoclonal CD52 antibody that proved its efficacy against an active comparator (interferon [IFN]-β1a) in a phase II trial and two phase III trials regarding clinical and MRI outcomes. Nevertheless, the exact mode of action is still unknown. Alemtuzumab is commonly associated with secondary autoimmune disorders significantly affecting the risk-benefit ratio. Therefore, new biomarkers predicting treatment response and adverse events are urgently needed. This study aims to further elucidate the mechanism of action of the neuroprotective potential of alemtuzumab in relapsing-remitting multiple sclerosis (RRMS). Methods/Design This is a 3-year multicentre, explorative study including overall 150 patients comprising three different groups: (i) de novo patients prior and after alemtuzumab treatment initiation, (ii) patients under alemtuzumab treatment and (iii) patients requiring more than two alemtuzumab infusions. Peripheral blood and serum samples will be collected semi-annually for several in vitro/ex vivo assays to detect and characterize immune cells including their functional activity. Furthermore, data of MRI scans and disease-related impairment (using EDSS and MSFC), as well as the number and time of relapses, will be assessed. The clinical study is registered at clinicaltrials.gov (NCT04082260). Perspective Our study will provide deep insights into the underlying immunological changes in a longitudinal analysis of alemtuzumab treated RRMS patients. By combining clinical, radiological and functional immune-phenotype data, we will be able to identify biomarkers and/or immune signatures predicting treatment response and adverse events. Thereby, the understanding of the mechanisms of action of alemtuzumab will improve its efficacy and safety for present and future patients.

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S0447 Sex-Stratified Clinical Course and Treatment Response Patterns in an Adult Eosinophilic Esophagitis Cohort, and Protective Effects of Estradiol Ex Vivo

The American Journal of Gastroenterology ◽

10.14309/01.ajg.0000703836.14874.30 ◽

2020 ◽

Vol 115 (1) ◽

pp. S223-S224

Author(s):

Quan M. Nhu ◽

David J. Leung ◽

Claire P. Witmer ◽

Nguyen D. Nguyen ◽

Pooja Magavi ◽

...

Keyword(s):

Treatment Response ◽

Eosinophilic Esophagitis ◽

Clinical Course ◽

Ex Vivo ◽

Response Patterns ◽

Protective Effects

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CD44, γ-H2AX, and p-ATM Expressions in Short-Term Ex Vivo Culture of Tumour Slices Predict the Treatment Response in Patients with Oral Squamous Cell Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms23020877 ◽

2022 ◽

Vol 23 (2) ◽

pp. 877

Author(s):

Pierre Philouze ◽

Arnaud Gauthier ◽

Alexandra Lauret ◽

Céline Malesys ◽

Giovanna Muggiolu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Treatment Response ◽

Squamous Cell ◽

Ex Vivo ◽

Disease Free Survival ◽

Poor Response ◽

Response To Treatment ◽

Slice Culture ◽

Short Term

Squamous cell carcinoma is the most common type of head and neck cancer (HNSCC) with a disease-free survival at 3 years that does not exceed 30%. Biomarkers able to predict clinical outcomes are clearly needed. The purpose of this study was to investigate whether a short-term culture of tumour fragments irradiated ex vivo could anticipate patient responses to chemo- and/or radiotherapies. Biopsies were collected prior to treatment from a cohort of 28 patients with non-operable tumours of the oral cavity or oropharynx, and then cultured ex vivo. Short-term biopsy slice culture is a robust method that keeps cells viable for 7 days. Different biomarkers involved in the stemness status (CD44) or the DNA damage response (pATM and γ-H2AX) were investigated for their potential to predict the treatment response. A higher expression of all these markers was predictive of a poor response to treatment. This allowed the stratification of responder or non-responder patients to treatment. Moreover, the ratio for the expression of the three markers 24 h after 4 Gy irradiation versus 0 Gy was higher in responder than in non-responder patients. Finally, combining these biomarkers greatly improved their predictive potential, especially when the γ-H2AX ratio was associated with the CD44 ratio or the pATM ratio. These results encourage further evaluation of these biomarkers in a larger cohort of patients.

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Correlation Between Drug Sensitivity Profiles of Ex Vivo Expanded Circulating Tumor Cells and Clinical Treatment Response in Pancreatic Ductal Adenocarcinoma Patients

10.21203/rs.3.rs-845754/v1 ◽

2021 ◽

Author(s):

Yuan-Hung Wu ◽

Yi-Ping Hung ◽

Nai-Chi Chiu ◽

Rheun-Chuan Lee ◽

Chung-Pin Li ◽

...

Keyword(s):

Clinical Response ◽

Treatment Response ◽

Tumor Cells ◽

Drug Sensitivity ◽

Ex Vivo ◽

Clinical Treatment ◽

Ductal Adenocarcinoma ◽

Liquid Biopsies ◽

Sensitivity Testing ◽

Organoid Cultures

Abstract BackgroundPancreatic ductal adenocarcinoma (PDAC) is highly aggressive and has poor prognosis. There are few biomarkers to inform treatment decisions, and collecting tumor samples for genomic or drug sensitivity testing is challenging.MethodsCirculating tumor cells (CTCs) were prepared from the liquid biopsies of PDAC patients. These cells were subsequently expanded ex vivo to form CTC-derived organoid cultures, using a laboratory-developed biomimetic cell culture system. The CTC-derived organoids were tested for sensitivity to a PDAC panel of nine drugs, with tests conducted in triplicate, and a weighted cytotoxicity score (CTS) was calculated from the results. Clinical response to treatment in patients was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria at the time of blood sampling and 3 months later. CTS was then correlated with clinical response, and analyzed using 2 × 2 contingency tables.ResultsA total of 41 liquid biopsies were collected from 31 patients, with 87.8% of liquid biopsies from patients with Stage 4 disease. CTC-derived organoid expansion was achieved in 3 weeks, with 87.8% culture efficiency. CTC-derived organoid cultures were positive for EpCAM staining and negative for CD45 staining in surface marker analysis. All patients had received a median of two lines of treatment prior to enrollment, and prospective utility analysis indicated significant correlation of CTS with clinical treatment response. Two representative case studies are also presented to illustrate the relevant clinical contexts.ConclusionsIn this study, CTCs were expanded from the liquid biopsies of PDAC patients with a high success rate. Drug sensitivity profiles from CTC-derived organoid cultures correlated meaningfully with treatment response. Further studies are warranted to validate the predictive potential for this approach.Trial RegistrationTaipei Medical University Hospital Protocol Record N201803020, registered on July 10, 2018; ClinicalTrials.gov Identifier: NCT04972461, retrospectively registered on July 22, 2021.

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Tumoricidal stem cell therapy enables killing in novel hybrid models of heterogeneous glioblastoma

Neuro-Oncology ◽

10.1093/neuonc/noz138 ◽

2019 ◽

Vol 21 (12) ◽

pp. 1552-1564 ◽

Cited By ~ 1

Author(s):

Andrew B Satterlee ◽

Denise E Dunn ◽

Donald C Lo ◽

Simon Khagi ◽

Shawn Hingtgen

Keyword(s):

Stem Cell ◽

Combination Therapy ◽

Treatment Response ◽

Ex Vivo ◽

Hybrid Models ◽

Human Patient ◽

In Vivo Models ◽

Key Aspects ◽

The Impact

Abstract Background Tumor-homing tumoricidal neural stem cell (tNSC) therapy is a promising new strategy that recently entered human patient testing for glioblastoma (GBM). Developing strategies for tNSC therapy to overcome intratumoral heterogeneity, variable cancer cell invasiveness, and differential drug response of GBM will be essential for efficacious treatment response in the clinical setting. The aim of this study was to create novel hybrid tumor models and investigate the impact of GBM heterogeneity on tNSC therapies. Methods We used organotypic brain slice explants and distinct human GBM cell types to generate heterogeneous models ex vivo and in vivo. We then tested the efficacy of mono- and combination therapy with primary NSCs and fibroblast-derived human induced neural stem cells (iNSCs) engineered with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) or enzyme-prodrug therapy. Results Optical imaging, molecular assays, and immunohistochemistry revealed that the hybrid models recapitulated key aspects of patient GBM, including heterogeneity in TRAIL sensitivity, proliferation, migration patterns, hypoxia, blood vessel structure, cancer stem cell populations, and immune infiltration. To explore the impact of heterogeneity on tNSC therapy, testing in multiple in vivo models showed that tNSC-TRAIL therapy potently inhibited tumor growth and significantly increased survival across all paradigms. Patterns of tumor recurrence varied with therapeutic (tNSC-TRAIL and/or tNSC–thymidine kinase), dose, and route of administration. Conclusions These studies report new hybrid models that accurately capture key aspects of GBM heterogeneity which markedly impact treatment response while demonstrating the ability of tNSC mono- and combination therapy to overcome certain aspects of heterogeneity for robust tumor kill.

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Interleukin-36 family dysregulation drives joint inflammation and therapy response in psoriatic arthritis

Rheumatology ◽

10.1093/rheumatology/kez358 ◽

2019 ◽

Vol 59 (4) ◽

pp. 828-838 ◽

Cited By ~ 3

Author(s):

Marie-Astrid Boutet ◽

Alessandra Nerviani ◽

Gloria Lliso-Ribera ◽

Davide Lucchesi ◽

Edoardo Prediletto ◽

...

Keyword(s):

Treatment Response ◽

Early Treatment ◽

Ex Vivo ◽

Therapy Response ◽

Joint Inflammation ◽

Promising Therapeutic Target ◽

Treatment Naïve ◽

Synovial Tissues ◽

First Time

Abstract Objectives IL-36 agonists are pro-inflammatory cytokines involved in the pathogenesis of psoriasis. However, their role in the pathogenesis of arthritis and treatment response to DMARDs in PsA remains uncertain. Therefore, we investigated the IL-36 axis in the synovium of early, treatment-naïve PsA, and for comparison RA patients, pre- and post-DMARDs therapy. Methods Synovial tissues were collected by US-guided biopsy from patients with early, treatment-naïve PsA and RA at baseline and 6 months after DMARDs therapy. IL-36 family members were investigated in synovium by RNA sequencing and immunohistochemistry, and expression levels correlated with DMARDs treatment response ex vivo. Additionally, DMARDs effects on IL-36 were investigated in vitro in fibroblast-like synoviocytes. Results PsA synovium displayed a reduced expression of IL-36 antagonists, while IL-36 agonists were comparable between PsA and RA. Additionally, neutrophil-related molecules, which drive a higher activation of the IL-36 pathway, were upregulated in PsA compared with RA. At baseline, the synovial expression of IL-36α was significantly higher in PsA non-responders to DMARDs treatment, with the differential expression being sustained at 6 months post-treatment. In vitro, primary PsA-derived fibroblasts were more responsive to IL-36 stimulation compared with RA and, importantly, DMARDs treatment increased IL-36 expression in PsA fibroblasts. Conclusion The impaired balance between IL-36 agonists–antagonists described herein for the first time in PsA synovium and the decreased sensitivity to DMARDs in vitro may explain the apparent lower efficacy of DMARDs in PsA compared with RA. Exogenous replacement of IL-36 antagonists may be a novel promising therapeutic target for PsA patients.

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MRI based radiomic signature to predict treatment response to intraventricular natural killer (NK) cell infusion therapy for recurrent/refractory pediatric brain tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e21511 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e21511-e21511

Author(s):

Soumen Khatua ◽

Tagwa Idris ◽

Aikaterini Kotrotsou ◽

Sumit Gupta ◽

Wafik Tharwat Zaky ◽

...

Keyword(s):

Brain Tumors ◽

Cell Therapy ◽

Treatment Response ◽

Nk Cell ◽

Ex Vivo ◽

Statistical Significance ◽

Phase 1 ◽

Infusion Therapy ◽

Predict Treatment Response ◽

Nk Cell Therapy

e21511 Background: NK cell therapy is a novel immunotherapeutic strategy used in cancer therapy. We conducted first-in-human, loco-regional infusion of autologous ex-vivo expanded NK cell directly into the brain in children with recurrent medulloblastoma (MB) and ependymoma (EP). Radiomics is considered an emerging method to predict treatment response as well as evaluate prognosis and tumor milieu. This is the first study evaluating the ability of radiomics to predict response to intraventricular infusions of NK cell in children with recurrent/refractory posterior fossa malignant brain tumors. Methods: We evaluated 7 patients (5 males: 2 females; mean age 11.8 years) with refractory/recurrent MB or EP (MBs = 3, EPs = 4), who were enrolled on a Phase-1 trial (NCT02271711) and received 3 cycles of intraventricular NK cell infusions. Patients were categorized based on their clinical response into responders (N = 2) and non-responders (N = 5). After semiautomatic segmentation of the tumor, 3,660 radiomic features were extracted from the baseline (before treatment) MRI scan. The least absolute shrinkage and selection operator regression was used for feature selection, and the radiomics signature was built using the unsupervised anomaly detection algorithm. The performance of the radiomics model was assessed using leave-one-out cross-validation. Results: The radiomic signature/model was comprised of 6 radiomic features and demonstrated high discriminatory performance in predicting response to NK cell therapy with an area under the curve, sensitivity, and specificity of 100% ( P = 0.09486). In addition, patients clustered into responders and non-responders using unsupervised hierarchical clustering. Conclusions: To our knowledge, this is the first study to identify the ability of radiomics to predict those who will likely benefit from NK cell therapy. Though this small study did not attain statistical significance, the robust discriminatory results warrant larger prospective studies, evaluating radiomics as a potential tool to identify responders to NK cell therapy at diagnosis.

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