scholarly journals Combining CTLA-4 and angiopoietin-2 blockade in patients with advanced melanoma: a phase I trial

2021 ◽  
Vol 9 (11) ◽  
pp. e003318
Author(s):  
Patrick A Ott ◽  
Matthew Nazzaro ◽  
Kathleen L Pfaff ◽  
Evisa Gjini ◽  
Kristen D Felt ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Human Leukocyte ◽  
Interleukin 10 ◽  
Advanced Melanoma ◽  
Angiopoietin 2

BackgroundAngiogenic factors promote the growth of tumor vasculature, modulate lymphocyte trafficking into tumors, and inhibit maturation of dendritic cells. We hypothesized that MEDI3617, a human IgG1 kappa monoclonal antibody directed against human angiopoietin-2, in combination with tremelimumab (treme), an IgG2 monoclonal antibody blocking cytotoxic T-lymphocyte-associated protein- (CTLA-4), is safe in patients with advanced melanoma.MethodsIn a phase I, 3+3 dose escalation trial, patients with metastatic or unresectable melanoma received treme in combination with MEDI3617. The primary objectives of the study were safety and determination of recommended phase II dose (RP2D). The secondary objectives included determination of 6-month and 1-year overall survival and best overall response rate. Immune cell populations and soluble factors were assessed in peripheral blood and metastatic tumors using Fluorescence activated cell sorting (FACS), Luminex, and multiplexed immunofluorescence.ResultsFifteen patients (median age: 62) were enrolled in the study (3 patients in cohort 1: treme at 10 mg/kg and MEDI3617 at 200 mg; and 12 patients in cohort 2: treme at 10 mg/kg and MEDI3617 at 600 mg). The most common all-grade treatment-related adverse events were rash, pruritus, fatigue, and extremity edema. No dose-limiting toxicities were observed. Cohort 2 was determined to be the RP2D. There were no patients with confirmed immune-related complete response or immune-related partial response. Six of 15 patients had immune-related stable disease, resulting in a disease control rate of 0.40 (95% CI 0.16 to 0.68). An increase in frequencies of circulating inducible T-cell costimulator (ICOS)+ and human leukocyte antigen (HLA)-DR+ CD4+ and CD8+ T cells and production of Interleukin-2 and Interleukin-10 was observed post therapy.ConclusionsTremelimumab in combination with MEDI3617 is safe in patients with advanced melanoma. Angiopoietin-2 inhibition in combination with immune checkpoint inhibition warrants further exploration.Trial registration numberNCT02141542.

DOWN-REGULATION OF INTERLEUKIN-2 AND INTERFERON-?? AND MAINTENANCE OF INTERLEUKIN-4 AND INTERLEUKIN-10 PRODUCTION AFTER ADMINISTRATION OF AN ANTI-CD3 MONOCLONAL ANTIBODY IN MICE1

1999 ◽  
Vol 68 (5) ◽  
pp. 677-684 ◽  
Author(s):  
K. Martin Wissing ◽  
Fabrice Desalle ◽  
Daniel Abramowicz ◽  
Fabienne Willems ◽  
Oberdan Leo ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Interleukin 2 ◽  
Interleukin 10 ◽  
Interleukin 4 ◽  
Down Regulation

scholarly journals A phase I study of the WT2725 dosing emulsion in patients with advanced malignancies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Siqing Fu ◽  
David E. Piccioni ◽  
Hongtao Liu ◽  
Rimas V. Lukas ◽  
Santosh Kesari ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Cytotoxic T Lymphocyte ◽  
Wilms Tumor ◽  
Biological Marker ◽  
Human Leukocyte ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Advanced Malignancies

AbstractWT2725 is a Wilms’ tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1+ tumors in human leukocyte antigen (HLA)-A*0201+ and/or HLA-A*0206+ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, the WT2725 dosing emulsion was administered as a monotherapy to patients with advanced malignancies known to overexpress WT1, including glioblastoma. In part 1, 44 patients were sequentially allocated to four doses: 0.3 mg (n = 5), 0.9 mg (n = 5), 3 mg (n = 6), and 9 mg (n = 28). In part 2, 18 patients were allocated to two doses: 18 mg (n = 9) and 27 mg (n = 9). No dose-limiting toxicities were observed, so the maximum tolerated dose was not reached. Median progression-free survival was 58 (95% confidence interval [CI] 56–81) days (~ 2 months) across all patients with solid tumors; median overall survival was 394 days (13.0 months) (95% CI 309–648). Overall immune-related response rate in solid tumor patients was 7.5% (95% CI 2.6–19.9); response was most prominent in the glioblastoma subgroup. Overall, 62.3% of patients were considered cytotoxic T-lymphocyte responders; the proportion increased with increasing WT2725 dosing emulsion dose. WT2725 dosing emulsion was well tolerated. Preliminary tumor response and biological marker data suggest that WT2725 dosing emulsion may exert antitumor activity in malignancies known to overexpress the WT1 protein, particularly glioblastoma, and provide a rationale for future clinical development.Trial registration: NCT01621542.

A phase I/II study of multiple peptides cocktail vaccine for advanced/recurrent ovarian cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3116-TPS3116 ◽  
Author(s):  
Satoshi Takeuchi ◽  
Tadahiro Shoji ◽  
Masahiro Kagabu ◽  
Tatsuya Honda ◽  
Fumiharu Miura ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Leucine Zipper ◽  
Cytotoxic T Lymphocyte ◽  
Subcutaneous Administration ◽  
Immunological Response ◽  
Human Leukocyte ◽  
Complete Response ◽  
Recurrent Ovarian Cancer ◽  
Ctl Responses

TPS3116 Background: Despite improvement in chemotherapy including the molecular targeting agents, advanced or recurrent ovarian cancer (A/ROC) are still incurable. Some tumor associated proteins, hypoxia-inducible protein 2 (HIG2), and tumor related vascular endothelial growth factor receptor 1,2 (VEGFR1,VEGFR2) were found to be candidates as new targets, and their epitope peptides have been shown to have the ability to induce specific cytotoxic T lymphocyte ( CTL) responses. We conducted a phase I/II study of these peptides cocktail vaccine (PCV) in patients with A/ROC in order to evaluate toxicity, immunological response, and tumor response. Methods: 23 patients positive for human leukocyte antigen (HLA)-A2402 (A24) and 15 patients with HLA-A0201(A02) were enrolled in this study. Enrollment is still on going up to 30 evaluable patients in each group. PCV for A24 comprises FOXM1(Forkhead Box M1), MELK(maternal embryonic leucine zipper kinase), HJURP(Holliday junction recognition protein), VEGFR1 and VEGFR2. As for A02- PCV comprises HIG2, VEGFR1and VEGFR2. Cocktails were made at a dose of 1mg of each peptide with GMP grade-adjuvant, MONTANIDE ISA51. Vaccination schedule included weekly subcutaneous administration for first 12 weeks, then bi-weekly administration for next 16 weeks, then further vaccination was done monthly for 8 times and 3-6 months as a maintenance step according to patient’s need. Pre- and post-vaccination blood samples were obtained from the patients for toxicity assessment and immunological evaluation. Clinical responses were evaluated every three months by RECIST v 1.1. Results: PCV were generally well tolerated with no major adverse events, and most of the patients developed specific CTL responses. One patient showed complete response, two showed partial response and 10 showed stable disease in 22 evaluable patients. At the time of the analysis, median overall survival was 5 months (from 30 to 623 days) and 9 months(from 54 to 921 days),in A24 and A02, respectively. 11 patients remained alive with median follow up of 9 months. Conclusions: These findings suggest these peptides cocktail vaccines are safe and applicable for advanced/recurrent ovarian cancer. Clinical trial information: UMIN000003862, UMIN000003860.

scholarly journals Antiphospholipid Antibody Induced by Nivolumab

2018 ◽  
Vol 2018 ◽  
pp. 1-3 ◽  
Author(s):  
Ahmed Aburahma ◽  
Nour Aljariri Alhesan ◽  
Farah Elounais ◽  
Emad Abu Sitta
Keyword(s):  
Monoclonal Antibody ◽  
Adverse Events ◽  
Interleukin 2 ◽  
Advanced Melanoma ◽  
Antiphospholipid Antibody ◽  
Gi Tract ◽  
The Third ◽  
Programmed Death ◽  
Prolonged Aptt ◽  
Programmed Death Protein 1

Nivolumab is a monoclonal antibody against the programmed death protein 1 and is used for patients with advanced melanoma. It is associated with potentially immune-related adverse events, including disorders of the skin, GI tract, and the thyroid; these disorders were successfully treated with prednisone and infliximab. Other immunotherapeutic agents were observed to induce the formation of antiphospholipid antibody (APA) including α-interferon and interleukin-2. We present a case of APA development after the third dose of nivolumab in a 71-year-old male with advanced melanoma. The APA was detected after finding a prolonged aPTT; the lupus anticoagulant assay tested positive. The patient was treated with prednisone but, unfortunately, he expired a few days later.

scholarly journals The combination of anti-B7 monoclonal antibody and cyclosporin A induces alloantigen-specific anergy during a primary mixed lymphocyte reaction.

1994 ◽  
Vol 179 (2) ◽  
pp. 715-720 ◽  
Author(s):  
S W Van Gool ◽  
M de Boer ◽  
J L Ceuppens
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Cyclosporin A ◽  
Mixed Lymphocyte Reaction ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Third Party ◽  
Clonal Deletion ◽  
Antigen Presenting

Interaction of CD28/CTLA-4 on T cells with B7 on antigen-presenting cells constitutes an important costimulatory signal for T cells and is responsible for cyclosporin A-resistant interleukin 2 (IL-2) gene expression and potentially also for prevention of anergy induction after T cell receptor triggering. In this paper, we demonstrate that addition of a monoclonal antibody to B7, which blocks B7-CD28/CTLA-4 interaction, and of cyclosporin A together, but not separately, to a primary mixed lymphocyte reaction of freshly isolated human T cells towards a human B cell line, induces nonresponsiveness of alloantigen-specific cytotoxic T lymphocyte precursors, whereas reactivity to a third party stimulator is intact. Nonresponsiveness could be reversed by culture in IL-2, indicating that anergy, and not clonal deletion, is responsible for this phenomenon. Our finding opens important perspectives for the development of new therapeutic strategies in transplantation.

Phase I trial of sequential decitabine plus high-dose interleukin-2 (HD IL-2) in patients with advanced melanoma

2005 ◽  
Vol 23 (16_suppl) ◽  
pp. 7527-7527
Author(s):  
J. Gollob ◽  
M. Thoreson ◽  
T. Richmond ◽  
C. Sciambi ◽  
T. Bael
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Interleukin 2 ◽  
Advanced Melanoma ◽  
High Dose

A phase I study of lirilumab (BMS-986015), an anti-KIR monoclonal antibody, administered in combination with ipilimumab, an anti-CTLA4 monoclonal antibody, in patients (Pts) with select advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3106-TPS3106 ◽  
Author(s):  
Naiyer A. Rizvi ◽  
Jeffrey R. Infante ◽  
Geoffrey Thomas Gibney ◽  
Erin Marie Bertino ◽  
Sarah A. Cooley ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Adaptive Immunity ◽  
Phase I Study ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Innate And Adaptive Immunity

TPS3106 Background: Immune checkpoint blockade represents a novel form of cancer immunotherapy. Killer cell immunoglobulin-like receptors (KIR) and cytotoxic T lymphocyte antigen-4 (CTLA-4) are immune receptors that down-regulate NK and T cell activity, respectively. The anti-KIR antibody, lirilumab (BMSE986015), potentiates innate immunity by blocking signaling through inhibitory KIRs and has demonstrated modest side effects in a Phase I trial. The anti-CTLA-4 antibody, ipilimumab, potentiates adaptive immunity and has demonstrated improved overall survival in pts with advanced melanoma and preliminary evidence of clinical activity in Phase I and II trials. We hypothesized that coordinate modulation of innate and adaptive immunity by combining anti-KIR and anti-CTLA4 antibodies could achieve enhanced biologic and clinical activity compared to either agent alone. Here, we describe a Phase I study of lirilumab plus ipilimumab in pts with selected advanced solid tumors. Methods: This study will be performed in two parts and enroll approximately 150 pts. During dose escalation, pts with advanced melanoma, non-small cell lung cancer and castrate resistant prostate cancer, will be enrolled. During cohort expansion, 20 pts with each tumor type will be enrolled at the maximum tolerated dose (MTD), or the maximum administered dose, if no MTD is defined. The primary study objectives are to delineate the safety and tolerability, dose limiting toxicities, and MTD of this combination. Secondary objectives are to assess preliminary anti-tumor activity, pharmacokinetics, and immunogenicity of this combination in all pts, and the pharmacodynamic effects on tumor infiltrating lymphocytes in a cohort of melanoma pts. Exploratory objectives include a thorough assessment of the modulation of innate and adaptive immunity by this combination in peripheral blood and/or tumor specimens, and preliminary evaluation of the association of these changes with clinical outcome. Clinical trial registration number: NCT01750580 Clinical trial information: NCT01750580.

scholarly journals Immunostimulatory Oligodeoxynucleotides Containing CpG Motifs Enhance the Efficacy of Monoclonal Antibody Therapy of Lymphoma

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2994-2998 ◽  
Author(s):  
James E. Wooldridge ◽  
Zuhair Ballas ◽  
Arthur M. Krieg ◽  
George J. Weiner
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Immune Cell ◽  
Interleukin 2 ◽  
Antibody Therapy ◽  
Monoclonal Antibody Therapy ◽  
Cpg Odn ◽  
Antitumor Effects ◽  
Murine Splenocytes ◽  
Murine Lymphoma

Abstract Bacterial DNA and synthetic oligodeoxynucleotides containing the CpG motif (CpG ODN) can activate various immune cell subsets, including natural killer cells and macrophages. We evaluated whether the combination of CpG ODN and antitumor monoclonal antibody is effective at preventing tumor growth in an immunocompetent murine lymphoma model. CpG ODN–activated murine splenocytes induced lysis of tumor targets more effectively than unactivated splenocytes. These effector cells were also superior to unactivated splenocytes or cells activated with a control methylated ODN at inducing antibody-mediated lysis of 38C13 murine lymphoma cells. In vivo, CpG ODN alone had no effect on survival of mice inoculated with 38C13 cells. However, a single injection of CpG ODN enhanced the antitumor response to antitumor monoclonal antibody therapy. Ninety percent of mice treated with monoclonal antibody alone developed tumor compared with 20% of mice treated with antibody and CpG ODN. These antitumor effects were less pronounced when treatment consisted of an identical ODN containing methylated CpG dinucleotides. A single dose of CpG ODN appeared to be as effective as multiple doses of interleukin-2 at inhibiting tumor growth when combined with antitumor monoclonal antibody. We conclude that immunostimulatory CpG ODN can enhance antibody dependent cellular cytotoxicity and warrant further evaluation as potential immunotherapeutic reagents in cancer.

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