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  • American Association for Cancer Research (AACR)  (13)
  • 1
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    Abstract 981: A genetic-metabolic axis of metastatic liver organotropism
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 981-981
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 981-981
    Abstract: Genomic and adaptive determinants of organ-specific metastasis are poorly understood. A model of sequential acquisition of divergent somatic mutations is insufficient to explain metastasis. Liver metastasis (LM) occurs frequently and is associated with a poor prognosis and reduced therapy response in several cancers, including in patients with melanoma and lung cancer. To identify drivers of metastatic niches, we used a syngeneic mouse melanoma model which recapitulates genomic, metastatic and therapy response patterns seen in patients. We performed a large-scale in vivo CRISPR-Cas9 knockout screen and identified perturbations that promote LM, but not primary tumor growth or metastasis to other organs (e.g. lung). The “top hit” in this screen associated with LM was loss Pip4k2c. We generated Pip4k2cKO cells and show that in otherwise isogenic melanoma cell lines, loss of Pip4k2c led to increased baseline and insulin-induced activation of the PI3K/AKT pathway, and increased invasive capacity. Rescuing Pip4k2cKO with full-length (Pip4k2cRec) or allosteric domain deficient (Pip4k2cAD) Pip4k2c ORFs, we show that hyperactivation of the PI3K/AKT pathway in is mediated by loss of the allosteric domain function, and not loss of the kinase domain of Pip4k2c. Treatment with different PI3K inhibitors effectively abrogated the pathway, but was partly bypassed in the presence of insulin in Pip4k2cKO and Pip4k2cAD, but not parental or Pip4k2cRec cells. Upon tail vein injection, Pip4k2cKO cells produced a significantly increased LM burden compared to parental cells, and this effect was rescued in Pip4k2cRec but not Pip4k2cAD, further affirming that loss of allosteric domain was required for this phenotype. We reasoned that Pip4k2cKO cells preferentially colonized the liver by co-opting the insulin-rich milieu in this organ. To test this, we used shRNA targeted against the insulin receptor (Insr) generated Pip4k2cKO/InsrshIR and showed that Insr was required but not sufficient to enhance LM burden. Given the promising in vitro activity of PI3K inhibitors, we next tested whether these could abrogate LM in vivo. Surprisingly, we found a substantial increase in LM burden in mice with Pip4k2cKO-bearing LM treated with PI3K inhibition compared to vehicle treated animals. We show that this paradoxical observation was due to host-mediated increased in glucose and insulin in response to PI3K inhibitor, which promoted a forward loop of increased liver metastasis. Breaking this loop with either ketogenic diet or treatment with a SGLT2 inhibitor in turn rescued increased these host responses and resulted in reduced LM burden in combination with PI3K inhibition. In summary, we identify a novel mechanism of metastatic liver organotropism and pharmacological and dietary combinations to reduced liver metastatic burden. Given the expanding use of PI3K inhibitors, our findings may have important clinical implications. Citation Format: Meri Rogava, Johannes C. Melms, Stephanie Davis, Clemens Hug, Bryan Ngo, Michael J. Lee, Patricia Ho, Amit Dipak Amin, Yiping Wang, Sean Chen, William Ge, David Liu, Thomas Tüting, Martin Röcken, Thomas K. Eigentler, Samuel F. Bakhoum, Andrei Molotkov, Akiva Mintz, Lewis C. Cantley, Peter K. Sorger, Benjamin Izar. A genetic-metabolic axis of metastatic liver organotropism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 981.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-981
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    Abstract 3514: A genetic-metabolic circuit of liver-specific metastatic organotropism
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3514-3514
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3514-3514
    Abstract: Liver metastasis (LM) occurs frequently in patients with melanoma and is associated with a poor prognosis and reduced therapy response. To identify drivers of metastatic niches, we used a syngeneic mouse melanoma model which recapitulates genomic, metastatic and therapy response patterns seen in patients, and performed a large-scale in vivo CRISPR-Cas9 knockout screen, which identified perturbations that strongly promoted liver but not lung metastasis. The “top hit” in this screen associated with LM was loss Pip4k2c. Mechanistically, loss of Pip4k2c sensitized both mouse and human melanoma to insulin-mediated PI3K/AKT pathway activation. Interestingly, this observation was dependent on the allosteric but not kinase domain activity. Treatment with different PI3K inhibitors abrogated the pathway in vitro, but was partly bypassed in the presence of insulin. As expected, loss of Pip4k2c was associated with significant increase in LM but not lung-metastatic burden in both syngeneic and patient-derived xenograft models, and this phenotype was rescued by reconstitution of full-length, but not allosteric domain deficient Pip4k2c constructs. We reasoned that Pip4k2cKO cells preferentially colonized the liver by co-opting the insulin-rich milieu in this organ. To test this, we generated Pip4k2c-/-/InsrshIR-KD and showed that Insr was required but not sufficient to enhance LM burden. Surprisingly, treatment with PI3K inhibition in vivo resulted in increased and not decreased LM burden as we had expected. PET-CT imaging of animals treated with PI3K revealed increased glucose uptake in LM in the presence of PI3K inhibition. We therefore reasoned that paradoxical activation due to host-mediated increase in glucose and insulin in response to PI3K inhibitor, may results in increased homing and metastasis to the liver. In further in vivo experiments, we showed that breaking this loop with either SGLT2 inhibitor or ketogenic diet circumvented host responses and resulted in reduced LM burden, while having no effect on lung metastasis burden. To further substantiate these findings, we performed single cell RNA-seq of concurrent liver and lung metastasis bearing mice which revealed strong tumor-intrinsic enrichment of central carbon metabolism. Lastly, analysis of 243 human liver vs extra-hepatic metastases across 75 cancers and addition of newly generated RNA-seq data of additional melanoma LM, revealed concordant pathways enrichment of glycolysis and oxidative phosphorylation LM. Together, we identify an axis of liver-metastatic organotropism that can be abrogated with a combination of PI3K inhibition and SGLT2-inhibition or concurrent ketogenic diet. Citation Format: Meri Rogava, Tyler Joseph Aprati, Wei-Yu Chen, Johannes Melms, Clemens Hug, Amit Dipak Amin, Bryan Ngo, Michae l Lee, Patricia Ho, Yiping Wang, Stephen Tang, Ethan Earlie, Sean Chen, Thomas Tüting, Martin Röcken, Thomas K. Eigentler, Samuel F. Bakhoum, Andrei Molotkov, Akiva Mintz, Dirk Schadendorf, Lewis C. Cantley, Peter K. Sorger, Ashley Laughney, David Liu, Benjamin Izar. A genetic-metabolic circuit of liver-specific metastatic organotropism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3514.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-3514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
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    A Dose-Escalation and Signal-Generating Study of the Immunocytokine L19-IL2 in Combination with Dacarbazine for the Therapy of Patients with Metastatic Melanoma
    American Association for Cancer Research (AACR) ; 2011
    In:  Clinical Cancer Research Vol. 17, No. 24 ( 2011-12-15), p. 7732-7742
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 24 ( 2011-12-15), p. 7732-7742
    Abstract: Purpose: L19-IL2 is an immunocytokine composed of an antibody fragment specific to the EDB domain of fibronectin, a tumor angiogenesis marker, and of human interleukin-2 (IL2). L19-IL2 delivers IL2 to the tumor site exploiting the selective expression of EDB on newly formed blood vessels. Previously, the recommended dose of L19-IL2 monotherapy was defined as 22.5 million international units (Mio IU) IL2 equivalents. In this study, safety and clinical activity of L19-IL2 in combination with dacarbazine were assessed in patients with metastatic melanoma. Experimental Design: The first 10 studied patients received escalating doses of L19-IL2 on days 1, 3, and 5 in combination with 1 g/m2 of dacarbazine on day 1 of a 3-weekly therapy cycle. Subsequently, 22 patients received L19-IL2 at recommended dose plus dacarbazine. Up to six treatment cycles were given, followed by a maintenance regimen with biweekly L19-IL2. Results: The recommended dose of L19-IL2 in combination with dacarbazine was defined as 22.5 Mio IU. Toxicity was manageable and reversible, with no treatment-related deaths. Twenty-nine patients were evaluable for efficacy according to Response Evaluation Criteria in Solid Tumors (RECIST). In a centralized radiology analysis, eight of 29 (28%) patients achieved a RECIST-confirmed objective response, including a complete response still ongoing 21 months after treatment beginning. The 12-month survival rate and median overall survival of the recommended dose–treated patients (n = 26) were 61.5% and 14.1 months, respectively. Conclusions: The repeated administration of L19-IL2 in combination with dacarbazine is safe and shows encouraging signs of clinical activity in patients with metastatic melanoma. This combination therapy is currently evaluated in a randomized phase II trial with patients with metastatic melanoma. Clin Cancer Res; 17(24); 7732–42. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-11-1203
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 4
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    Abstract 3034: 18F-FDG-positron emission tomography (PET)/CT enables the identification of checkpoint inhibitor immunotherapy (CIT) responders by determination of CIT-induced metabolic changes in secondary lymphatic organs
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3034-3034
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3034-3034
    Abstract: Although the majority of patients with metastatic melanoma achieve a prolongation of overall survival by using checkpoint inhibitor based immunotherapy (CIT), there is still a larger number of patients who do not benefit from this therapy. As a CIT-induced systemic immune response is required to promote the anti-tumor effect we analyzed the glucose metabolism in secondary lymphoid organs such as the spleen by 18F-FDG-Positron Emission Tomography (PET). In preclinical studies, we were able to distinguish responders from non responders by focusing on the spleen 18F-FDG-uptake of mice with CIT in experimental tumor models. Thus, we aimed to gain deeper insights into impact of CIT on the metabolism in secondary lymphatic organs to identify responders and to stratify patients for differential treatment strategies. We retrospectively analyzed 18F-FDG-PET/CT scans (baseline and post-therapy) of 38 patients with metastatic melanoma with CTLA-4 or PD-1 Ab treatment as third line therapy (21 responder: 5x nivolumab; 7x pembrolizumab; 9x ipilimumab; 17 non-responder: 2x nivolumab; 11x pembrolizumab; 4x ipilimumab). Spleen regions of interest (ROI) were defined in the CT data, copied to the coregistered PET and analyzed semiquantitatively. Total lesion glycolysis (TLG) was calculated by multiplication of the spleen volume and the SUVmean. We determined in the baseline 18F-FDG-PET/CT-scans (prior to CIT), no significant differences in spleen volume (221±18 cm3 vs. 209 ±22 cm3) and in the spleen 18F-FDG-uptake (SUVmean: 1,74±0,06vs.1,72±0,05; TLG: 384±37 vs. 359±36) between responders and non-responders. In the follow up 18F-FDG-PET/CT-scans 110±68 days after onset of CIT we measured a similar increase in spleen volume in responders (+8±6%) and non-responders (+7±5%). 15 out of 21 responders revealed an enhanced spleen 18F-FDG uptake when compared to the baseline 18F-FDG-PET/CT-scans. The mean standard uptake values in the spleen of responders increased by +10±9% SUVmean. In sharp contrast, we determined hardly any change in the spleen 18F-FDG uptake of non-responders (SUVmean -1,3±2,6%). Additionally, the total lesion glycolysis (TLG) in the CIT-responders increased stronger (+25±22%) than in non-responders (+6±6%). Our results suggest that CIT-induced metabolic changes in secondary lymphatic organs are associated with therapy responds. Thus, non invasive 18F-FDG-PET/CT investigations might represent a powerful tool to monitor CIT-induced systemic immune responses in patients. Consequently, preclinical research is prerequisite to uncover the exact mode of action of CIT-induced systemic immune response in secondary lymphatic organs. Moreover, prospective clinical studies are essential to evaluate the prognostic value of our method. Citation Format: Johannes Schwenck, Barbara Schörg, Francesco Fiz, Kilian Wistuba-Hamprecht, Andrea Forschner, Thomas Eigentler, Benjamin Weide, Claus Garbe, Martin Röcken, Christina Pfannenberg, Bernd J. Pichler, Christian la Fougere, Manfred Kneilling. 18F-FDG-positron emission tomography (PET)/CT enables the identification of checkpoint inhibitor immunotherapy (CIT) responders by determination of CIT-induced metabolic changes in secondary lymphatic organs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3034.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3034
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 5
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    Abstract LB-021: Intratumoral RNA-based TLR-7/-8 and RIG-I agonist CV8102 alone and in combination with anti-PD-1 in a Phase I dose-escalation and expansion trial in patients with advanced solid tumors
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. LB-021-LB-021
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. LB-021-LB-021
    Abstract: CV8102 comprises a single-stranded non-coding RNA complexed with a cationic peptide. It acts as an agonist to TLR-7/-8 and RIG-I (Ziegler 2018) to stimulate the innate and adaptive immune system. CV8102 was shown to induce an upregulation of inflammatory cytokines, chemokines and IFN-γ related genes at the injection site along with an activation of T, NK, NKT and migratory dendritic cells in the draining lymph nodes (Heidenreich 2015). Intratumoral (IT) CV8102 demonstrated dose-dependent anti-tumor activity and synergized with systemic PD-1 inhibition in preclinical models. Methods This Phase I study investigates IT CV8102 as single agent and in combination with systemic anti-PD-1 antibodies (as per product label). Patients (pts) with advanced inoperable melanoma (MEL), cutaneous/head and neck squamous cell or adenoid cystic carcinoma (cSCC, SCCHN, ACC) are eligible for single agent CV8102, pts with MEL and SCCHN who did not respond or slowly progressed on anti-PD-1 therapy are eligible for the combination. CV8102 is administered for up to 8 IT injections into a single accessible tumor lesion over a 12-week period. A Bayesian logistic regression model with overdose control is used for the dose escalation parts. Response is assessed by RECIST 1.1/irRECIST (injected and non-injected target lesions). Pre- and on-treatment samples are collected for biomarker analyses. Results A total of 20 pts have been treated with either CV8102 alone (N=15: 6 MEL, 2 SCCHN, 5 ACC, 2 cSCC) or CV8102 in combination with anti-PD-1 (N=5: 4 MEL, 1 SCCHN). Dose cohorts with doses up to 150 µg (CV8102 alone) and 100µg (CV8102+anti-PD-1) have been completed. Most common AEs were mild to moderate flu-like symptoms and injection site reactions. No dose limiting toxicities (DLT) were observed during the DLT period of the first two weeks of treatment. 12 pts treated with CV8102 alone were evaluable for response assessment. 1 MEL pt treated at 150µg experienced a complete regression of injected and non-injected lesions. This patient also experienced a marked increase of IL-6 and CRP at 6 and 24 hours after the first injection, respectively. 7 pts achieved stable disease, with two pts treated at 100 µg (SCCHN pt) and 200µg (MEL pt who had developed acquired resistance to previous anti-PD-1 therapy) showing regression of non-injected lymph node lesions. Dose escalation parts are continuing, updated safety and efficacy results will be presented. Conclusion Intratumoral single agent CV8102 appears well tolerated and showed preliminary evidence of clinical efficacy with shrinkage of injected and non-injected lesions. Citation Format: Thomas Eigentler, Juergen Krauss, Jutta Schreiber, Carsten Weishaupt, Patrick Terheyden, Lucie Heinzerling, Peter Mohr, Benjamin Weide, Ralf Gutzmer, Juergen C. Becker, Felix Kiecker, Angelika Daehling, Fatma Funkner, Regina Heidenreich, Sarah-Katharina Kays, Ute Klinkhardt, Birgit Scheel, Oliver Schoenborn-Kellenberger, Tobias Seibel, Claudia Stosnach, Tanja Strack, Ulrike Gnad-Vogt. Intratumoral RNA-based TLR-7/-8 and RIG-I agonist CV8102 alone and in combination with anti-PD-1 in a Phase I dose-escalation and expansion trial in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-021.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-LB-021
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 6
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    Abstract CT004: Adjuvant therapy with nivolumab (NIVO) combined with ipilimumab (IPI) vs NIVO alone in patients (pts) with resected stage IIIB-D/IV melanoma (CheckMate 915)
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT004-CT004
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT004-CT004
    Abstract: Background: NIVO has demonstrated significant benefit over IPI as adjuvant treatment in pts with resected stage IIIB–C or stage IV melanoma (AJCC v7). Combination NIVO + IPI has shown numerically longer survival than NIVO alone in pts with metastatic melanoma. CheckMate 915 evaluated adjuvant NIVO + IPI 1 mg/kg Q6W vs NIVO. Methods: Pts aged ≥ 12 y with completely resected stage IIIB–D or stage IV melanoma (AJCC v8) were stratified by tumor PD-L1 expression and stage and treated with NIVO 240 mg Q2W + IPI 1 mg/kg Q6W (NIVO + IPI1) or placebo-controlled NIVO 480 mg Q4W alone for ≤ 1 y (NIVO + IPI were to be discontinued together). Dual endpoints were recurrence-free survival (RFS) in the PD-L1 & lt; 1% and intent-to-treat populations. Distant metastasis-free survival (DMFS) in pts with stage III disease was an exploratory endpoint. Results: Of 920 pts randomized to NIVO + IPI1 and 924 to NIVO alone, most had stage IIIB (31% vs 31%) or IIIC (53% vs 52%) disease and had undergone complete lymph node dissection (64% vs 64%). Pts treated with NIVO + IPI1 vs NIVO alone had a shorter median duration of therapy (7.6 vs 11.1 mo) and therefore, a lower median cumulative NIVO dose (3840 vs 6240 mg). At a minimum follow-up of 24 mo, RFS and DMFS did not differ between treatment groups (table). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 33% of pts treated with NIVO+IPI1 and 13% with NIVO alone; any-grade TRAEs led to discontinuation of therapy in 32% vs 10% of pts, respectively. There were 4 treatment-related deaths (all with NIVO + IPI1). Conclusions: The NIVO + IPI1 regimen did not result in RFS or DMFS improvement vs NIVO in stage IIIB–D/IV resectable melanoma; safety profiles were consistent with previous studies. NIVO 480 mg Q4W outcomes in CheckMate 915 were similar to previous NIVO results and reinforce NIVO as an adjuvant standard of care in a study population that included pts with and without complete lymphadenectomy. NIVO 240 mg Q2W + IPI 1 mg/kg Q6W (ITT)NIVO 480 mg Q4W (ITT)NIVO 240 mg Q2W + IPI 1 mg/kg Q6W (tumor PD-L1 & lt; 1%)NIVO 480 mg Q4W (tumor PD-L1 & lt; 1%)RFS24-mo rate64.6% (95% CI, 61.3-67.7)63.2% (95% CI, 59.9-66.4)53.6% (95% CI, 48.0-58.8)52.4% (95% CI, 46.8-57.7)Median, mo (events/pts)Not reached (327/920)Not reached (347/924)33.2 (159/349)25.3 (166/351)HR, NIVO + IPI1 vs NIVO0.92 (97.295% CI, 0.77-1.09); P = 0.2690.91 (95% CI, 0.73-1.14)DMFS in pts with stage III disease24-mo rate75.4% (95% CI, 72.1-78.4)77.4% (95% CI, 74.1-80.3)67.9% (95% CI, 61.9-73.1)68.4% (95% CI, 62.5-73.7)Median, mo (events/pts)Not reached (195/797)Not reached (194/798)Not reached (92/305)Not reached (96/307)HR, NIVO + IPI1 vs NIVO1.01 (95% CI, 0.83-1.23)0.94 (95% CI, 0.70-1.25) Citation Format: Georgina V. Long, Dirk Schadendorf, Michele Del Vecchio, James Larkin, Victoria Atkinson, Michael Schenker, Jacopo Pigozzo, Helen J. Gogas, Stéphane Dalle, Nicolas Meyer, Paolo A. Ascierto, Shahneen Sandhu, Thomas Eigentler, Ralf Gutzmer, Jessica C. Hassel, Caroline Robert, Matteo Carlino, Anna Maria Di Giacomo, Marcus O. Butler, Eva Muñoz-Couselo, Michael P. Brown, Piotr Rutkowski, Andrew Haydon, Jean-Jacques Grob, Jacob Schachter, Paola Queirolo, Alexander Menzies, Sandra Re, Tuba O. Bas, Veerle de Pril, Daniel Tenney, Hao Tang, Jeffrey S. Weber. Adjuvant therapy with nivolumab (NIVO) combined with ipilimumab (IPI) vs NIVO alone in patients (pts) with resected stage IIIB-D/IV melanoma (CheckMate 915) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT004.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-CT004
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 12 ( 2016-06-15), p. 2908-2918
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 12 ( 2016-06-15), p. 2908-2918
    Abstract: Purpose: To identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients. Experimental Design: Frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan–Meier and Cox regression analysis, including calibration and discrimination by C-statistics. Results: Low baseline LDH, absolute monocyte counts (AMC), Lin−CD14+HLA-DR−/low-MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4+CD25+FoxP3+-Treg frequencies were significantly associated with better survival, and were considered in a combination model. Patients (43.5%) presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2–0) was also associated with OS (P & lt; 0.001 for all pairwise comparisons) in the main study and additionally in an independent validation cohort. Conclusions: A baseline signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12); 2908–18. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-2412
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 8
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    Abstract PO-009: Phase 3 KEYNOTE-630 study of adjuvant pembrolizumab in high-risk locally advanced cutaneous squamous cell carcinoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 18_Supplement ( 2023-09-15), p. PO-009-PO-009
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 18_Supplement ( 2023-09-15), p. PO-009-PO-009
    Abstract: Introduction: Among patients with high-risk locally advanced (LA) cutaneous squamous cell carcinoma (cSCC), approximately 20% experience local disease recurrence within 5 years after standard-of-care surgical resection and adjuvant radiotherapy. Better treatment options are needed for patients who experience recurrence after surgery. The PD-1 inhibitors pembrolizumab (pembro) and cemiplimab have shown durable antitumor activity in advanced metastatic cSCC. The randomized, double-blind, placebo-controlled, phase 3 KEYNOTE-630 (NCT03833167) trial will be conducted to evaluate adjuvant pembro in patients with resectable, high-risk, LA cSCC. Materials and Methods: Eligible patients will have histologically confirmed LA cSCC as the primary site of malignancy and have undergone complete macroscopic resection of all disease with ≥1 high-risk feature: histologically involved nodal disease with extracapsular extension, with ≥1 lymph node & gt;2 cm in diameter or ≥2 lymph nodes involved; any gross cortical bone, skull base, and/or skull base foramen invasion; any index tumor with ≥2 of the following: tumor ≥4 cm with & gt;6-mm depth or invasion beyond subcutaneous fat, multifocal perineural invasion for nerves & lt;0.1 mm in diameter (≥3 foci) or any involved nerve ≥0.1 mm in diameter, poor differentiation and/or sarcomatoid and/or spindle cell histology, recurrent disease (recurrence within 3 years in the previously treated area), or satellite lesions and/or in-transit metastases, lymphatic or vascular involvement. Patients must have received adequate postoperative dose of hypofractionated or conventional radiotherapy, including a BED EQD2 & gt;48 Gy, have ECOG PS of 0 or 1, and completed adjuvant radiotherapy ≥4 and ≤16 weeks from randomization. Patients are required to provide tumor tissue for PD-L1 testing and have an ECOG PS of 0 or 1. Approximately 570 patients will be randomly assigned 1:1 to pembro 400 mg IV every 6 weeks or placebo for approximately 1 year (≤9 cycles). Stratification factors are extracapsular extension, cortical bone invasion, and prior systemic therapy (all, yes vs no). Patients receiving placebo may be eligible to cross over to receive pembro (≤18 cycles) if first biopsy-proven recurrence occurs within 5 years. In the pembro arm, eligible patients may receive pembro retreatment for up to 18 cycles. The primary end point is recurrence-free survival per investigator assessment with biopsy confirmation and secondary end points include overall survival, health-related quality of life, and safety. Computed tomography/magnetic resonance imaging of disease-involved areas and associated lymph nodes will be performed at screening and every 12 weeks until the end of year 2, then every 6 months until the end of 5 years. Adverse events will be monitored throughout the study and for 30 days after treatment end and graded per NCI CTCAE v4.0. Results: Recruitment is underway at sites in Asia, Australia, Europe, and North and South America. Conclusions: Results of KEYNOTE-630 will elucidate the role of adjuvant pembro in patients with high-risk, LA cSCC. Citation Format: Michael Schenker, Mikhail Klochikhin, Dmitry Kirtbaya, Laurent Mortier, Martin Gschnell, Caroline Robert, Nicolas Meyer, Lukas Flatz, Stephane Dalle, Marie Beylot-Barry, Thomas Eigentler, Rachel Kloss Silverman, Burak Gumuscu, Jianda Yuan, Aase Bratland. Phase 3 KEYNOTE-630 study of adjuvant pembrolizumab in high-risk locally advanced cutaneous squamous cell carcinoma [abstract] . In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-009.
    Type of Medium: Online Resource
    ISSN: 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.AACRAHNS23-PO-009
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    detail.hit.zdb_id: 2036787-9
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    Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Immunology Research Vol. 2, No. 7 ( 2014-07-01), p. 668-678
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 2, No. 7 ( 2014-07-01), p. 668-678
    Abstract: L19–IL2 is a recombinant protein comprising the cytokine IL2 fused to the single-chain monoclonal antibody L19. In previous studies, intralesional injection with IL2 has shown efficacy for the locoregional treatment of cutaneous/subcutaneous metastases in patients with advanced melanoma. The objectives of this study were to investigate whether (i) intralesional delivery of a targeted form of IL2 would yield similar results, with reduction of injection frequency and treatment duration; and (ii) systemic immune responses were induced by the local treatment. Patients with stage IIIB/IIIC melanoma and cutaneous/subcutaneous injectable metastases received weekly intratumoral injections of L19–IL2 at a maximum dose of 10 MIU/week for 4 consecutive weeks. Tumor response was evaluated 12 weeks after the first treatment. Twenty-four of 25 patients were evaluable for therapy-induced responses. A complete response (CR) by modified immune-related response criteria (irRC) of all treated metastases was achieved in 6 patients (25%), with long-lasting responses in most cases (5 patients for ≥24 months). Objective responses were documented in 53.9% of all index lesions [44.4% CR and 9.5% partial responses (by irRC)], and 36.5% of these remained stable, while 9.5% progressed. Toxicity was comparable with that of free IL2, and no serious adverse events were recorded. A significant temporary increase of peripheral regulatory T cells and natural killer cells, sustained increase of absolute CD4+ lymphocytes, and decrease of myeloid-derived suppressor cells were observed upon treatment. Finally, we recorded encouraging data about the progression time to distant metastases and overall survival. Cancer Immunol Res; 2(7); 668–78. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-13-0206
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2732517-9
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  • 10
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    PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 23 ( 2016-12-01), p. 5818-5828
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 23 ( 2016-12-01), p. 5818-5828
    Abstract: Purpose: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for “brain-specific” therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro. We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases. Experimental Design and Results: Buparlisib inhibited AKT activity, decreased proliferation, and induced apoptosis in metastatic melanoma cell lines and short-term brain melanoma cells, irrespective of their BRAF and NRAS mutation status. In addition, buparlisib inhibited hyperactivated AKT and induced apoptosis in melanoma cells that were stimulated with astrocyte-conditioned medium. The growth of tumors induced by injecting human BRAF- and NRAS-mutant metastatic melanoma cells into the brain of mice was significantly inhibited by buparlisib. Conclusions: These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases. Clin Cancer Res; 22(23); 5818–28. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-0064
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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