title: Mucin 1-specific active cancer immunotherapy with tecemotide (L-BLP25) in patients with multiple myeloma: an exploratory study.
abstract: Patients (n = 34) with previously untreated, slowly progressive asymptomatic stage I/II multiple myeloma or with stage II/III multiple myeloma in stable response/plateau phase following conventional anti-tumor therapy were immunized repeatedly with the antigen-specific cancer immunotherapeutic agent tecemotide (L-BLP25). Additionally, patients were randomly allocated to either single or multiple low doses of cyclophosphamide to inhibit regulatory T cells (Treg). Immunization with tecemotide resulted in the induction/augmentation of a mucin 1-specific immune response in 47% of patients. The immune responses appeared to involve a Th1-like cellular immune response involving CD4 and CD8 T cells. The rate of immune responses was similar with single versus multiple dosing of cyclophosphamide and in patients with vs. without pre-existing mucin 1 immunity. On-treatment reductions in the slope of M-protein concentration over time (but not fulfilling clinical criteria for responses with conventional anti-tumor agents) were observed in 45% of evaluable patients, predominantly in those without versus with pre-existing mucin 1 immunity and in patients with early stage disease. No differences were seen in patients receiving single or multiple cyclophosphamide dosing. Treatment with tecemotide was generally well tolerated. Repeated vs. single dosing of cyclophosphamide had no impact on Treg numbers and was stopped after a case of fatal encephalitis that was assessed as possibly study-related. Tecemotide immunotherapy induces mucin 1-specific cellular immune responses in a substantial proportion of patients, with preliminary evidence of changes in the M-protein concentration time curve in a subset of patients.
authors.affiliation: a Karolinska Institute and Karolinska University Hospital ; Stockholm , Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Rossmann
authors.forename: Anders
authors.initials: A
authors.lastname: Österborg
authors.forename: Eva
authors.initials: E
authors.lastname: Löfvenberg
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Choudhury
authors.forename: Ulf
authors.initials: U
authors.lastname: Forssmann
authors.forename: Anja
authors.initials: A
authors.lastname: von Heydebreck
authors.forename: Andreas
authors.initials: A
authors.lastname: Schröder
authors.forename: Håkan
authors.initials: H
authors.lastname: Mellstedt
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008562:Membrane Glycoproteins / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D018396:Mucin-1 / Q000276:immunology*; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D011897:Random Allocation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014611:Vaccination
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C518273:L-BLP25; C060192:MUC1 protein, human; D008562:Membrane Glycoproteins; D018396:Mucin-1; D003520:Cyclophosphamide
keywords: ASCI, antigen-specific cancer immunotherapy; AUC, area under the curve; Cy, cyclophosphamide; ELISpot, enzyme-linked immunosorbent spot; GM-CSF, granulocyte-macrophage colony-stimulating factor; HR, hazard ratio; IDA, Immunologic Diagnostic Analysis; IFN-g, interferon-g; IL-17, interleukin-17; IQR, interquartile range; L-BLP25; MM, multiple myeloma; MUC1; MUC1, mucin 1; NSCLC, non-small cell lung cancer; PBMC, peripheral blood mononuclear cell; TNF-α, tumor necrosis factor-α; Treg, regulatory T cell; URR, upper reference range; immunotherapy; mucin 1; multiple myeloma; tecemotide