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1.
JCI Insight ; 5(11)2020 06 04.
Article in English | MEDLINE | ID: mdl-32369447

ABSTRACT

BACKGROUNDThe reshaping of the immune landscape by nivolumab (NIVO) and ipilimumab (IPI) and its relation to patient outcomes is not well described.METHODSWe used high-parameter flow cytometry and a computational platform, CytoBrute, to define immunophenotypes of up to 15 markers to assess peripheral blood samples from metastatic melanoma patients receiving sequential NIVO > IPI or IPI > NIVO (Checkmate-064).RESULTSThe 2 treatments were associated with distinct immunophenotypic changes and had differing profiles associated with response. Only 2 immunophenotypes were shared but had opposing relationships to response/survival. To understand the impact of sequential treatment on response/survival, phenotypes that changed after the initial treatment and differentiated response in the other cohort were identified. Immunophenotypic changes occurring after NIVO were predominately associated with response to IPI > NIVO, but changes occurring after IPI were predominately associated with progression after NIVO > IPI. Among these changes, CD4+CD38+CD39+CD127-GARP- T cell subsets were increased after IPI treatment and were negatively associated with response/survival for the NIVO > IPI cohort.CONCLUSIONCollectively, these data suggest that the impact of IPI and NIVO on the immunophenotypic landscape of patients is distinct and that the impact of IPI may be associated with resistance to subsequent NIVO therapy, consistent with poor outcomes in the IPI > NIVO cohort of Checkmate-064.


Subject(s)
Antigens, Differentiation/immunology , Immunophenotyping , Ipilimumab/administration & dosage , Melanoma , Nivolumab/administration & dosage , T-Lymphocytes/immunology , Female , Flow Cytometry , Humans , Male , Melanoma/drug therapy , Melanoma/immunology , Melanoma/pathology , Neoplasm Metastasis , T-Lymphocytes/pathology
2.
Clin Cancer Res ; 17(24): 7765-75, 2011 Dec 15.
Article in English | MEDLINE | ID: mdl-21994418

ABSTRACT

PURPOSE: ALT-801 is a bifunctional fusion protein comprising interleukin-2 (IL-2) linked to a soluble, single-chain T-cell receptor domain that recognizes a peptide epitope (aa264-272) of the human p53 antigen displayed on cancer cells in the context of HLA-A*0201 (p53+/HLA-A*0201). We evaluated the safety, pharmacokinetics, and pharmacodynamics of ALT-801 in p53+/HLA-A*0201 patients with metastatic malignancies. EXPERIMENTAL DESIGN: p53+/HLA-A*0201 patients were treated with ALT-801 on a schedule of four daily 15-minute intravenous infusions, then 10 days rest and four more daily infusions. Cohorts of patients were treated at 0.015, 0.040, and 0.080 mg/kg/dose. RESULTS: Four, 16, and 6 patients were treated at the 0.015, 0.04, and 0.08 mg/kg cohorts, respectively. Two dose-limiting toxicities (a grade 4 transient thrombocytopenia and a myocardial infarction) in the 0.08 mg/kg cohort established the maximum tolerated dose (MTD) at 0.04 mg/kg. Patients treated at the MTD experienced toxicities similar to those associated with high-dose IL-2 but of lesser severity. The serum half-life of ALT-801 was 4 hours and ALT-801 serum recovery was as expected based on the dose administered. ALT-801 treatment induced an increase of serum IFN-γ but not TNF-α. Response assessment showed 10 subjects with stable disease at at least 11 weeks, and in one who had melanoma metastasis, there is an ongoing complete absence of identifiable disease after resection of radiographically identified lesions. CONCLUSION: This first-in-man study defines an ALT-801 regimen that can be administered safely and is associated with immunologic changes of potential antitumor relevance.


Subject(s)
Interleukin-2/immunology , Neoplasms/drug therapy , Receptors, Antigen, T-Cell/immunology , Recombinant Fusion Proteins/therapeutic use , Adult , Aged , Dose-Response Relationship, Drug , Drug Administration Schedule , Epitopes/immunology , Female , Fever/chemically induced , HLA-A2 Antigen/immunology , Humans , Infusions, Intravenous , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-2/adverse effects , Interleukin-2/genetics , Interleukin-2/pharmacokinetics , Interleukin-2/therapeutic use , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lymphocyte Count , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/metabolism , Male , Metabolic Clearance Rate , Middle Aged , Neoplasms/immunology , Neoplasms/metabolism , Prospective Studies , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/therapeutic use , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/immunology , Recombinant Fusion Proteins/pharmacokinetics , Thrombocytopenia/chemically induced , Treatment Outcome , Tumor Suppressor Protein p53/immunology
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