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  • 1
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    378 Efficacy, safety and ancillary analyses of pembrolizumab in combination with nintedanib for the treatment of patients with relapsed advanced mesothelioma
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. Suppl 2 ( 2021-11), p. A409-A409
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. Suppl 2 ( 2021-11), p. A409-A409
    Abstract: We report the results from the advanced malignant mesothelioma (aMM) expansion cohort of the PEMBIB Phase Ib trial ( NCT02856425 ) evaluating the safety, efficacy & biomarkers of an antiangiogenic tyrosine kinase inhibitor (nintedanib) with an anti-PD1 immunotherapy (pembrolizumab). Methods Patients with aMM relapsing after at least one line of platinum doublet chemotherapy and not previously pre-exposed to IO were treated with a combination of oral nintedanib (150mg BID) & IV pembrolizumab (200mg Q3W) with a 7 days nintedanib lead-in preceding pembrolizumab initiation. Baseline and on-treatment (cycle D2, day 1 [C2D1]) fresh tumor & blood samples were prospectively phenotyped by flow cytometry (FC). RNAseq was run on tumor samples. Immune factors were titrated on tumor secretome and plasma. Results 30 aMM patients were treated and 29 evaluable for response. Median age was 68 years old (38–85) and 86% of aMM were epithelioid. The most frequent adverse events (AE) (grades 1–3) related to the combination were liver enzymes increase, fatigue, nausea, and diarrhea. 4 (13.3%) patients developed grade 3–5 immune- related AE. Patients died of cancer progression (n=14, 46.7%), myocarditis with thrombo-embolic event (n=1, 3.3%) and COVID-19 (n=1, 3.3%). Median follow-up was 14.8 months (95%CI [9.70–18.2]). Best Overall Response Rates (BORR) per RECISTv1.1 were Partial Response (PR, n=7/29; 24.1%), Stable Disease (SD, n=17/29; 58.6%) and Progressive Disease (n=5/29; 17.2%). Disease Control Rate (DCR) (defined as PR + SD) was 46.6% at 6 months. Patients with DCR at 6 months had significantly higher percentage of PDL1 expression on tumor cells (by Immuno-Histo-Chemistry, antibody clone SP263) and higher CD8+ T cells infiltrate in tumor biopsies (by FC) at screening. Upon treatment, soluble plasma rate of CXCL9 and CXCL13 increased in all patients, as well as tumor immune infiltrates estimated by deconvolution of tumor biopsies RNA-seq. But deconvoluted estimates of NK cells, T cells and myeloid dendritic cells infiltrates on baseline tumors and C2D1 biopsies were higher in patients with DCR at 6 months. Pre & on-treatment IL6 and IL8 rates in tumor secretome & plasma were higher in patients without DCR. Gene Set Enrichment Analyses on RNA-seq from screening biopsies highlighted an enrichment in E2F, MYC and KRAS gene pathways and lower expression of type 1 interferon signature in patients without DCR than those with DCR at 6 months. Conclusions With a BORR of 24% and a DCR of 47% at 6 months, pembrolizumab and nintedanib combination provided valuable therapeutic benefits for patients with aMM. Trial Registration ClinicalTrials gov, NCT02856425 . Registered August 4, 2016 — Prospectively registered,https://clinicaltrials.gov/ct2/show/ NCT02856425 ?term=PEMBIB & draw=2 & rank=1. Ethics Approval The protocol was first approved by the Agence Nationale de Sécurité du Médicament (ANSM) on June 24th 2016 (Ref #160371A-12). The protocol was also approved by the Ethical Committee (Comité de Protection des Personnes Ile de France 1) on Jul 12th 2016 (Ref #2016-mai-14236ND).
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-SITC2021.378
    Language: English
    Publisher: BMJ
    Publication Date: 2021
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    Baseline circulating unswitched memory B cells and B-cell related soluble factors are associated with overall survival in patients with clear cell renal cell carcinoma treated with nivolumab within the NIVOREN GETUG-AFU 26 study
    BMJ ; 2022
    In:  Journal for ImmunoTherapy of Cancer Vol. 10, No. 5 ( 2022-05), p. e004885-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 10, No. 5 ( 2022-05), p. e004885-
    Abstract: The phase II NIVOREN GETUG-AFU 26 study reported safety and efficacy of nivolumab in patients with metastatic clear cell renal cell carcinoma (m-ccRCC) in a ‘real-world setting’. We conducted a translational-research program to determine whether specific circulating immune-cell populations and/or soluble factors at baseline were predictive of clinical outcomes in patients with m-ccRCC treated with nivolumab within the NIVOREN study. Methods Absolute numbers of 106 circulating immune-cell populations were prospectively analyzed in patients treated at a single institution within the NIVOREN trial with available fresh-whole-blood, using dry formulation panels for multicolor flow cytometry. In addition, a panel of 14 predefined soluble factors was quantified for each baseline plasma sample using the Meso-Scale-Discovery immunoassay. The remaining patients with available plasma sample were used as a validation cohort for the soluble factor quantification analysis. Tumor immune microenvironment characterization of all patients included in the translational program of the study was available. The association of blood and tissue-based biomarkers, with overall survival (OS), progression-free survival (PFS) and response was analyzed. Results Among the 44 patients, baseline unswitched memory B cells (NSwM B cells) were enriched in responders (p=0.006) and associated with improved OS (HR=0.08, p=0.002) and PFS (HR=0.54, p=0.048). Responders were enriched in circulating T follicular helper (Tfh) (p=0.027) and tertiary lymphoid structures (TLS) (p=0.043). Circulating NSwM B cells positively correlated with Tfh (r=0.70, p 〈 0.001). Circulating NSwM B cells correlated positively with TLS and CD20 +B cells at the tumor center (r=0.59, p=0.044, and r=0.52, p=0.033) and inversely correlated with BCA-1/CXCL13 and BAFF (r=−0.55 and r=−0.42, p 〈 0.001). Tfh cells also inversely correlated with BCA-1/CXCL13 (r=−0.61, p 〈 0.001). IL-6, BCA-1/CXCL13 and BAFF significantly associated with worse OS in the discovery (n=40) and validation cohorts (n=313). Conclusion We report the first fresh blood immune-monitoring of patients with m-ccRCC treated with nivolumab. Baseline blood concentration of NSwM B cells was associated to response, PFS and OS in patients with m-ccRCC treated with nivolumab. BCA-1/CXCL13 and BAFF, inversely correlated to NSwM B cells, were both associated with worse OS in discovery and validation cohorts. Our data confirms a role for B cell subsets in the response to immune checkpoint blockade therapy in patients with m-ccRCC. Further studies are needed to confirm these findings.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2022-004885
    Language: English
    Publisher: BMJ
    Publication Date: 2022
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  • 3
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    Dose escalation phase 1 study of radiotherapy in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 monoclonal antibody ipilimumab in patients with metastatic melanoma
    BMJ ; 2020
    In:  Journal for ImmunoTherapy of Cancer Vol. 8, No. 2 ( 2020-08), p. e000627-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 8, No. 2 ( 2020-08), p. e000627-
    Abstract: A synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma. Patients and methods A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics. Results 19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5–2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2–1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS. Conclusion When combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation. Trial registration number NCT01557114 .
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2020-000627
    Language: English
    Publisher: BMJ
    Publication Date: 2020
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    Abstract C068: Factors associated with primary resistance to immune checkpoint blockade in early phase clinical trials
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics Vol. 22, No. 12_Supplement ( 2023-12-01), p. C068-C068
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 12_Supplement ( 2023-12-01), p. C068-C068
    Abstract: Introduction: Immune checkpoint blockade (ICB) therapies, particularly anti-PD1/PD-L1 monoclonal antibodies, have transformed the field of medical oncology. However, many patients with advanced cancer demonstrate primary resistance to ICB strategies. The identification of objective clinical and biological characteristics associated with treatment resistance is crucial for identifying patients who are most likely not to benefit from conventional or current ICB combinations strategies. Studies and trials dedicated to these patients are essential to overcome such resistance. Methods: We prospectively enrolled patients treated with ICB at Gustave Roussy between 2018 and 2022 in the PREMIS study (NCT03984318). We examined a sub-cohort of patients treated at the early drug development department (DITEP). We identified pre-treatment (baseline) clinical and biological characteristics, including patients’ oncogenic alterations documented via circulating tumor DNA (ctDNA) sequencing in our STING study (NCT04932525), to find a significant difference between patients according to their best objective antitumor response (BOR; complete response [CR], partial response [PR] , stable disease [SD], or progressive disease [PD] ). Results: We analyzed a total of 227 patients, with paired ctDNA available for 96 patients.  Patients were 52% women and 48% men, averaging 59 years old, with 24 different solid tumor types and enrolled in 50 different early phase clinical trials. Eleven percent of patients had received prior ICB treatment. BOR were PD (61%), SD (20%), PR (15%), and CR (4%).  We identified clinical characteristics significantly different between patients according to their BOR: performance status (PS), number of previous lines of therapy, number of metastases, presence of liver metastases, absolute neutrophils count (ANC), absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio, CRP, GGT and LDH plasma concentrations, and MLH1 mutations. Acording these results, a score from 0 to 5 was calculated according to the presence of the following characteristics (yes=+1): presence of liver metastases, ALC below the lower limit of the normal (LLN), ANC above the upper limit of the normal (ULN), CRP & gt; ULN, LDH & gt; ULN. Patients with a score ≥ 4 did not develop a response during ICB treatments (n=27, 12%). Among them, 25 (92.6%) had a PS of 0-1 and 9 (33.3%) had a  Royal Marsden Hospital (RMH) score of 1. Additionally, both progression-free survival (PFS) and overall survival (OS) decreased significantly with the addition of each point score. Conclusion: Patients with advanced cancer treated by ICB in early phase clinical trials with at least 4 detrimental characteristics (presence of liver metastases, ALC & lt; LLN, ANC, CRP and LDH & gt; ULN) had primary resistance to ICB regardless of tumor type, ICB regimen, PS or RMH. Identification of immunological and oncogenic alterations specific to these patients could support the development of targeted and personalized ICB combination trials to overcome tumor resistance. Citation Format: Stéphane Champiat, Paul Matte, Capucine Baldini, Damien Vasseur, Kaïssa Ouali, Anas Gazzah, Rastilav Bahleda, Arnaud Bayle, Sophie Postel-Vinay, Cristina Smolenschi, Madona Sakkal, Jean-Marie Michot, Antoine Hollebecque, Nathalie Chaput-Gras, Yohann Loriot, Santiago Ponce, Antoine Italiano, Aurélien Marabelle, François-Xavier Danlos. Factors associated with primary resistance to immune checkpoint blockade in early phase clinical trials [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C068.
    Type of Medium: Online Resource
    ISSN: 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-23-C068
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    284 Integrated molecular characterization of primary resistance mechanisms to immune checkpoint blockade in advanced non-small cell lung carcinoma (a-NSCLC)
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. Suppl 2 ( 2021-11), p. A308-A308
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. Suppl 2 ( 2021-11), p. A308-A308
    Abstract: Reinvigoration of anti-tumor immunity via immune checkpoint blockade (ICB) has transformed outcomes in a-NSCLC. However, a majority of patients are innately resistant to ICB, and a better understanding of the resistance mechanisms may guide the development of new treatment strategies and therapies for patients. Methods Biopsies performed immediately before treatment with single agent ICB in patients with a-NSCLC (MATCH-R trial [ NCT02517892 ]) were analyzed. The stromal microenvironment and immune context were characterized via an integrated analysis of whole transcriptome (RNA-seq), whole exome sequencing (WES), and immunohistochemistry (IHC) of CD3, CD8, FOXP3 and PDL1. Specifically, the immune context and the relative abundance of 10 immune and stromal cell types were assessed with integrated IHC and Cell Populations-counter (MCP-counter) [1] analysis of the RNA-seq. Somatic mutations and Tumor Mutation Burden (TMB) were evaluated. The transcriptional state of the tumor and its microenvironment were assessed by GSVA analysis [2] of the MSigDB collection [3] . Patient‘s outcome was associated to molecular data. Primary resistance to ICB was defined as PD (progressive disease) in the first radiological examination, or a median PFS inferior to 3 months. Results Fifty-two patients with NSCLC were enrolled (43 adeno, 6 squamous, and 3 other carcinoma): Median age was 61 (34–93), 18 were female, 46 were smokers, 22 were responders, and 30 were non-responders. Median tumor cellularity was 60% (30%–90%).Patients may be divided into two groups (HIGH and LOW) at baseline based on their degree of immune infiltration as assessed by RNAseq or IHC. A hallmark of the HIGH infiltration group is an increase in Interferon Gamma (IFN-γ) pathway signature [4]. In contrast, patients in the LOW infiltration group (relative to the HIGH infiltration group) exhibit a decrease in IFN-γ pathway signaling and concomitantly an increase in hypoxia and gluconeogenic pathway signatures. Response rates to ICB were not associated to immune infiltration groups at baseline, but an analysis within each infiltration group revealed that high TMB is only associated to response in the HIGH infiltration group. Furthermore, only in the LOW infiltration group was increased the transforming growth factor (TGF-β) pathway signature associated to ICB response. Conclusions This study suggests that the tumor and its microenvironment influence baseline immune infiltration. Tumors with LOW baseline infiltration show altered metabolism such as gluconeogenic activation and hypoxia activation. In contrast, factors such as TMB are not associated with baseline infiltration
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-SITC2021.284
    Language: English
    Publisher: BMJ
    Publication Date: 2021
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    Abstract 2195: Combined strategy based on pre-activated analogs of oxazaphosphorines for increased therapeutic index and immune modulation
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2195-2195
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2195-2195
    Abstract: Oxazaphosphorines (Oxaza) represented by cyclophosphamide (CPA) and ifosfamide (IFO) are still the corner stone of several polychemotherapy protocols as they are widely indicated in the treatment of numerous cancer from soft tissue sarcomas to lymphomas and immune-related diseases. However, Oxaza are prodrugs requiring cytochrome (CYP) P450 bioactivation responsible of limiting adverse effects. In the case of IFO, bioactivation leads to a low release of 4-OH-IFO (10%), which generates the active nitrogen mustard displaying DNA cross-links. Associated toxicities of IFO due to acrolein, (urotoxicity) and to chloroacetaldehyde (neuro and nephrotoxicity) have been described. Thus, increasing IFO therapeutic index could be of major interest. To circumvent these toxicities, our team has designed new pre-activated IFO analogs to avoid CYP bioactivation (Skarbek et al J Med Chem 2015). Among these analogues some have the ability to self-assemble as nanoassemblies (NAs), the others can be encapsulated within nano-lipid capsules (NLCs). These new drug delivery systems (DDS) can take advantage of passive targeting, as stealthiness of these DDS can be provided by PEGylation by using Cholesterol-polyethylene glycol or the use of surfactant. These DDS can also be functionalized by appropriate monoclonal antibodies leading to multi stage DDS with active targeting properties. Regarding CPA, it has been shown and described in literature that low doses of CPA enhance the immunity by promoting differentiation of CD4+ cell toward Th1. As IFO is isomeric form of CPA, it was assumed that IFO could also have such properties. Studies on immunocompetent MCA205 mouse model, an immunogenic fibrosarcoma mouse model, demonstrate a dose-dependent immunomodulation of IFO towards a modulation of the secretion of IFNy, IL-17A and IL-6 cytokines. The ongoing experiments on mouse model depleted in CD4+ T cells and CD8+ T cells show the antitumor efficacy of IFO 150mg/kg on these immune cells in tumor regression. Both strategies could lead to the design of nano-immuno-conjugates (NICs) which could benefit of the immunomodulatory effects of X-Oxaza combined to their antiproliferative properties targeted through immune checkpoint antibodies. These new functionalized DDS may provide a useful strategy to give specificity to active drugs used for many years in clinical practice. Both DDS could be grafted with mAbs which could lead to a new family of DDS aiming to combine antiproliferative and immunomodulatory properties for a dual antitumoral action Citation Format: Julia Delahousse, Charles Skarbek, Valentine Gauthier, M Desbois, Emilie Roger, C. Pioche-Durieu, M. Rivard, D. Desmaële, T. Martens, E. LeCam, Jean-Pierre Benoit, P. Couvreur, Nathalie Chaput-Gras, Angelo Paci. Combined strategy based on pre-activated analogs of oxazaphosphorines for increased therapeutic index and immune modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2195. doi:10.1158/1538-7445.AM2017-2195
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-2195
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    Abstract A51: Phase I, safety, tolerability and preliminary efficacy study of Tremelimumab (Trem) in combination with Gefitinib (Gef) in EGFR-mutant (EGFR-mut) NSCLC (GEFTREM)
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. A51-A51
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. A51-A51
    Abstract: Background: Robust advances in our understanding of NSCLC molecular biology and host immunity have expanded the field of cancer therapy with new immunotherapeutic approaches that unlock the immune response, such as blockade of the T-cell lymphocyte-4 (CTLA-4) obtained with Trem, and molecularly targeted agents, including EGFR tyrosine kinase inhibitors (TKI) such as Gef. A Phase I open-label multicenter study was initiated to evaluate the association of Trem with Gef in EGFR-mut NSCLC (NCT02040064). Methods: Key inclusion criteria included advanced/metastatic lung cancer with an activating mutation of EGFR (i.e., exon 19 deletion or exon 21 L858R point mutation), progression on any prior EGFR TKI (first line or beyond), measurable disease, adequate PS (0-1) and organ function. Patients (pts) may have received chemotherapy between EGFR TKI and inclusion. The primary objective was to determine the safety and tolerability of the combination of Gef (oral 250mg once-daily) with escalating doses of Trem (starting dose of 3mg/kg IV every 4 weeks for 6 cycles and beyond every 12 weeks) and to establish a recommended phase 2 dose (RP2D). A rolling 6 design and a dose limiting toxicity period of 42 days were applied. Three escalating doses of Trem were pre-planned (3, 6 and 10mg/kg). Data included here are preliminary and will be updated for presentation. Results: Between January, 2014 and March, 2015, 20 stage IV pts received at least one dose of Trem (median age of 66 years, female 70%, never smoker 65% and 60% had received ≥2 lines). Seventeen pts were evaluable for dose-limiting toxicities (DLT). DLTs occurred in 4 pts, 1 at 3mg/Kg (grade 3 colitis, cycle 1), 1 at 6mg/Kg (grade 3 colitis, cycle 1) and 2 at 10mg/Kg (one grade 3 diarrhea and one AST-ALT increase grade 3, cycle 2) of Trem. All toxicities were reversible with discontinuation of Trem. Consequently, Trem 10mg/Kg plus Gef 250mg daily exceeded the maximum tolerable dosage. Most common (≥20%) adverse events (AEs/grade 3-4 AEs) were diarrhea (90%/30%), asthenia (55%/5%), dry skin (55%/5%), nausea (25%/0%), decreased of appetite (25%/10%), dyspnea (25%/0%), colitis (25%/15%), and vomiting (20%/0%). No pneumonitis or increases in cutaneous toxicity related to treatments were observed. To date, 3 pts remain on therapy (past cycles 4, 6 and 9) and 5 patients experienced long-term benefit (≥4months). Longest duration of treatment is 12 months thus far. A translational research program on biomarkers and PK data is currently being performed. Conclusions: The recommended dose of Trem in phased combination with Gef in EGFR-mut pts with NSCLC was identified as 3mg/kg. The safety profile was consistent with the previously defined AE profile. An expansion cohort is enrolling pts at RP2D. Citation Format: David Planchard, Fabrice Barlesi, Carlos Gomez-Roca, Julien Mazieres, Andrea Varga, Laurent Greillier, Nathalie Chaput-Gras, Emilie Lanoy, Cedric Parlavecchio, Katty Malekzadeh, Maud Ngocamus, Sarah ZAHI, Benjamin Besse, Audrey Poterie, Jean-Charles Soria. Phase I, safety, tolerability and preliminary efficacy study of Tremelimumab (Trem) in combination with Gefitinib (Gef) in EGFR-mutant (EGFR-mut) NSCLC (GEFTREM). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A51.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-A51
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    Treatment of gastric peritoneal carcinomatosis by combining complete surgical resection of lesions and intraperitoneal immunotherapy using catumaxomab
    Springer Science and Business Media LLC ; 2014
    In:  BMC Cancer Vol. 14, No. 1 ( 2014-12)
    Details
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2014-12)
    Type of Medium: Online Resource
    ISSN: 1471-2407
    URL: Article
    DOI: 10.1186/1471-2407-14-148
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
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    Abstract 2194: New oxazaphosphorine prodrugs for immunotherapy and nanomedicine against cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2194-2194
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2194-2194
    Abstract: Oxazaphosphorines (Oxaza) are widely used in the treatment of numerous cancers, activity against various tumor types, from soft tissue sarcomas to genito-urinary cancers for ifosfamide (IFO), from lymphoma to breast cancer for cyclophosphamide (CPA) and are still the corner stone of several polychemotherapy protocols. Limiting their toxicity and increasing their efficacy and safety through a better specificity could be of major interest. By consequence, we have designed new pre-activated oxazaphosphorines (X-Oxaza, Skarbek et al J Med Chem. 2015 Jan 22;58(2):705-17) to improve antitumoral response with reduced toxicity or side effects, as metabolization is not needed to liberate the active metabolite. We also aimed to design new drug delivery systems (DDS) based on these X-Oxaza to take advantage of passive and active targeting in order to improve the response selectivity. Indeed, nanocarriers formulations take advantage of the so-called enhanced permeability and retention effect (EPR effect) and increase the circulation time in the bloodstream. Active targeting is planed by grafting targeting ligands on the surface of DDS such as monoclonal antibody-mAbs and amino acids… The different steps leading to the design of the X-Oxaza has been developed within our laboratory and the proof of concept has been validated by their in vitro evaluation on a panel of tumor cell lines (Skarbek et al J Med Chem. 2015 Jan 22;58(2):705-17; Paci et al Bioorg Med Chem Lett. 2001 May 21;11(10):1347-9). These pre-activated Oxaza have been formulated as DDS either using the physicochemical properties of the terpene derivatives, which can self-assembly into nano-assemblies (NAs), or by encapsulating the short-chain X-Oxaza into Lipid nanocapsules (LNCs). Both DDS were tested on rhabdomyosarcoma and Ewing sarcoma cell lines and showed an increased activity compared to the free form. Regarding the immunological field, CPA was shown to enhance the immune defenses particularly promoting differentiation of CD4+ cell toward Th1. The isomeric form of CPA, IFO, leads us to believe that IFO could have an influence on the immune system. Indeed, we have studied the immunomodulatory activity of IFO and the results show that IFO participates in the modulation of the secretion of cytokines from immune cells with a dose / effect relationship. In the meantime, we investigate the influence of IFO and these X-Oxaza on the immune system using immunocompetent and immunodepressed mouse models. With the link of immune checkpoint antibodies, this strategy will benefit of the immunomodulatory effects of X-Oxaza combined to the antiproliferative properties of these antibodies. These new functionalized DDS may provide a useful strategy to give specificity to active drugs used for many years in clinical practice. Both DDS could be grafted with mAbs which could lead to a new family of DDS aiming to combine antiproliferative and immunomodulatory properties for a dual antitumoral action Citation Format: Charles Skarbek, Henri Gonde, Mélanie Desbois, Julia Delahousse, Nathalie Chaput-Gras, Jean-Pierre Benoit, Emilie Roger, Angelo Paci. New oxazaphosphorine prodrugs for immunotherapy and nanomedicine against cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2194.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-2194
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    detail.hit.zdb_id: 410466-3
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    277 Safety and efficacy of intratumoral ipilimumab with IV nivolumab in metastatic melanoma. The NIVIPIT trial
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. Suppl 2 ( 2021-11), p. A300-A300
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. Suppl 2 ( 2021-11), p. A300-A300
    Abstract: Intratumoral (IT) administration of Ipilimumab (Ipi), could maximize its dose/efficacy ratio while preventing its on-target/off-tumor systemic adverse events. We report the results of a randomized multicenter Phase 1b study comparing IT vs IV Ipi with intravenous nivolumab (nivo) in patients with metastatic melanoma. Methods Previously untreated metastatic melanoma patients were randomly assigned 1:2, to receive IV Nivo (1mg/kg) in combination with either IV Ipi (3mg/kg) or 10x lower dose IT Ipi (0.3mg/kg) Q3W for 4 doses, followed by Nivo 3mg/kg Q2W for up to 2 years. The primary objective was to compare ≥grade 3 irAE rates at 6 months. Secondary objectives were to assess anti-tumor efficacy and related predictive immune biomarkers.Fresh tumor biopsies pre & on-treatment on both injected and non-injected tumors were analyzed by flow-cytometry, and soluble factors from their supernatant were titrated with Meso-Scale-Discovery® multiplex. Fresh sequential whole blood samples were collected for flow-cytometry phenotyping of immune cells, and for measuring systemic exposure to Ipi using ELISA Results 40 patients were treated in the IT-arm and 21 in the IV-arm. The study met its primary endpoint with lower toxicity rate at 6 months in the IT-arm, with 30% [18.1;45.4] vs 57.1% [36.5;75.5] of patients presenting ≥grade 3 treatment related AEs, and no procedure-related ≥grade 3 AEs in the IT-arm out of 162 IT injections performed (including deep seated lesions).ORR per RECIST 1.1 were observed in 50% [32.9;67.1] in the IT-arm vs 65.0% [0.41;0.85] in the IV-arm. In the IT-arm, 65.7% of the injected tumors showed a CR or PR.Serum Ipi concentrations were much lower in the IT arm (:10). At C2, patients in both arms had significant decreased circulating naïve Tregs independently from tumor responses. Presence of intratumoral CD25hi CD39hi activated Tregs that decreased significantly upon IT (but not IV) injection only in responders, was predictive of the overall tumor response in the IT-arm. Moreover, granzyme B concentrations in tumor secretome at baseline were higher in responders than non-responders in both arms. Conclusions 0.3mg/kg IT Ipi in combination with IV Nivo is not only safe but could reduce ≥grade 3 toxicity of the ICB combination. The high response rate in injected lesions was associated with the reduction of local Treg -not observed with systemic Ipi- and prompts a use in the oligometastatic and neoadjuvant setting. Direct assessment of cytolytic and regulatory pathways on fresh biopsies represents a novel, simple and rapid strategy to predict treatment efficacy. Acknowledgements Authors would like to thank the patients taking part to the Nivipit trial, and all the medical and paramedical staff that contributed to this trial. Trial Registration NCT02857569EudraCT 2015-005429-37 Ethics Approval This study was approved by the national ethics committee (CPP, ANSM). Written informed consent was obtained from all patients. Consent N/A
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-SITC2021.277
    Language: English
    Publisher: BMJ
    Publication Date: 2021
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