Sensitivity to cisplatin determined by the histoculture drug response assay and clinical response of endometrial cancer

Despite cytoreductive surgery and chemotherapy, the prognosis of advanced ovarian cancer is still poor. Predicting the chemosensitivity of tumors might improve the outcome. Therefore, we investigated the clinical value of the histoculture drug response assay for ovarian cancer. Tumor specimens were cultured for 7 days on collagen gel sponge in medium containing cisplatin, and the 50% inhibitory concentration was determined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay. Then the in vitro sensitivity to cisplatin was compared with the clinical response and survival. Apoptosis of tumor cells was also investigated. Among 173 ovarian cancer patients, 164 were evaluable by the assay, and 29 patients had measurable lesions for which the clinical response could be determined. The 5-year survival rate was significantly higher in patients with chemosensitive tumors than in those with chemoresistant tumors when the cutoff value was set at a 50% inhibitory concentration of 25 μg/mL and the accuracy of the assay was 82.8% (24/29). As chemosensitivity to cisplatin became greater, the number of apoptotic cells also increased. This chemosensitivity assay may help predict the clinical response to cisplatin-based chemotherapy, thus improving the survival of ovarian cancer patients.

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SAT0006 SIMULTANEOUS ANALYSIS OF ANTI-CCP, RHEUMATOID FACTOR, ANTI-PAD4 AND ANTI-CARBAMYLATED PROTEIN ANTIBODIES REVEALS INTERACTION EFFECTS WITH RESPONSE TO ANTI-TNF THERAPY IN RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3801 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 933.2-934

Author(s):

A. Julià ◽

M. Lopez Lasanta ◽

F. Blanco ◽

A. Gómez ◽

I. Haro ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Rheumatoid Factor ◽

Clinical Response ◽

Therapeutic Approach ◽

Drug Response ◽

Single Marker Analysis ◽

Das28 Score ◽

Positive Interaction ◽

Single Marker ◽

Necrosis Factor

Background:Blocking of the Tumor Necrosis Factor (TNF) activity is a successful therapeutic approach for 2 out of 3 Rheumatoid Arthritis patients. Identifying the patients that will not respond to this therapeutic approach is a major translational goal in RA. Association of seropositivity to rheumatoid factor (RF) or anti-cyclic-citrullinated antibodies (anti-CCP) with anti-TNF response has proven inconclusive, suggesting that other yet unexplored biomarkers could be more informative for this goal.Objectives:We tested the association of two recently introduced biomarkers in RA: anti-carbamylated protein antibodies (anti-CarP) and anti-peptidylarginine deiminase type 4 (anti-PAD4).Methods:A prospective cohort of n=80 RA patients starting anti-TNF therapy was recruited and levels for all four autoantibodies -RF, anti-CCP, anti-CarP and anti-PAD4- were measured at baseline. The change in DAS28 score between baseline and week 12 of therapy was used as the clinical endpoint.Results:Single marker-analysis showed no significant association with drug response. However, when testing for interactions between autoantibodies, we found highly significant associations with drug response. Anti-CCP and RF showed a positive interaction with the response to anti-TNF therapy (P=0.00068), and anti-PAD4 and antiCarP titers showed a negative interaction with the clinical response at week 12 (P=0.0062). Using an independent retrospective sample (n=199 patients), we validated the interaction between anti-CCP and RF with the clinical response to anti-TNF agents. (P=0.044).Conclusion:The results of this study show that interactions between antibodies are important in the response to anti-TNF therapy and suggest potential pathogenic relationships.Acknowledgments :We would like to thank the clinical researchers and patients participating in the IMID Consortium for their collaborationDisclosure of Interests:Antonio Julià: None declared, Maria Lopez Lasanta: None declared, Francisco Blanco: None declared, Antonio Gómez: None declared, Isabel Haro: None declared, Antonio Juan Mas: None declared, Alba Erra: None declared, Mª Luz García Vivar: None declared, Jordi Monfort: None declared, Simon Sánchez Fernandez: None declared, Isidoro González-Álvaro Grant/research support from: Roche Laboratories, Consultant of: Lilly, Sanofi, Paid instructor for: Lilly, Speakers bureau: Abbvie, MSD, Roche, Lilly, Mercedes Alperi-López: None declared, Raúl Castellanos: None declared, Antonio Fernandez-Nebro: None declared, Cesar Diaz Torne: None declared, Núria Palau: None declared, Raquel M Lastra: None declared, Jordi Lladós: None declared, Raimon Sanmarti: None declared, Sara Marsal: None declared

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186 Distinct immune signatures predicting clinical response to PD-1 blockade therapy in gynecological cancers revealed by high-dimensional immune profiling

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0186 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A200-A200

Author(s):

Yuki Muroyama ◽

Sasikanth Manne ◽

Alexandar Huang ◽

Divij Mathew ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

Endometrial Cancer ◽

T Cell ◽

Clinical Response ◽

Cancer Patients ◽

T Cell Response ◽

High Dimensional ◽

Uterine Endometrial Cancer ◽

Immune Profiling

BackgroundAlthough immune checkpoint blockade revolutionized cancer therapy, response rates have been mixed in gynecological malignancies. While uterine endometrial cancer with high microsatellite instability (MSIHI) and high tumor mutational burden (TMB) respond robustly to checkpoint blockade, high-grade serous ovarian cancer (HGSOC) with low TMB respond modestly. Currently, there has been no known immune signature or T cell phenotype that predicts clinical response in gynecological tumors.MethodsTo dissect the immune landscape and T cell phenotypes in gynecological cancer patients receiving PD-1 blockade, we used high-dimensional cytometry (flow cytometry and mass cytometry (CyTOF)). We performed longitudinal deep immune profiling of PBMC from patients with recurrent uterine endometrial cancer receiving single-arm nivolumab, and HSGOC patients receiving neoadjuvant nivolumab plus platinum-based chemotherapy prior to debulking surgery.ResultsChemotherapy-resistant MSI-H uterine cancer patients treated with nivolumab had a proliferative T cell response 2–4 weeks post PD-1 blockade, consistent with responses seen in high TMB melanoma and lung cancer. The responding Ki67+ CD8 T cell population was largely CD45RAloCD27hi or CD45RAloCD27lo and highly expressed PD1, CTLA-4, and CD39, consistent with the phenotype of exhausted T cells (TEX). These exhausted-like cells are enriched in responders, whereas early expansion Tregs are enriched in non-responders. Unlike patients with uterine endometrial cancer, patients with TMBlo ovarian cancer did not have a clear proliferative CD8 T cell response after neoadjuvant nivolumab plus chemotherapy treatment, suggesting systemic immune suppression. At baseline, ovarian cancer without recurrence have more terminally differentiated effector-like CD8 T cells, and patients with recurrence have more naive-like cells. Thus, both high and low TMB gynecological tumors have distinct immune landscapes associated with clinical response. Additionally, in MSI-H uterine endometrial cancer patients, the length of time between the prior chemotherapy and the initiation of immunotherapy was negatively correlated with T cell reinvigoration post immunotherapy and clinical response. This suggests the importance of optimize therapeutic timing to maximize the therapeutic efficacy when combining immunotherapy and chemotherapy.ConclusionsCollectively, our immune profiling revealed the distinct immune signatures associated with clinical response to PD-1 blockade in gynecological cancers. Our results also suggest that TMBhi inflamed versus TMBlo cold tumor microenvironment, and timing of chemo/immunotherapy could impact differentiation and functions of T cells.Ethics ApprovalThe study was approved by MSKCC Ethics Board, approval number 17–180 and 17–182.

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