Phase I trial of immunological adjuvant SAFm in melanoma patients vaccinated with antiidiotype antibody MELIMMUNE-1 Journal Article

  


Authors: Livingston, P. O.; Adluri, S.; Raychaudhuri, S.; Hughes, M. H.; Calves, M. J.; Merritt, J. A.
Article Title: Phase I trial of immunological adjuvant SAFm in melanoma patients vaccinated with antiidiotype antibody MELIMMUNE-1
Abstract: We have screened a variety of immunological adjuvants in preclinical studies and selected SAFm (a vehicle emulsion of squalane, polysorbate 80, pluronic triblock copolymer L121, and threonyl-muramyl dipeptide [T-MDP]) for clinical evaluation. We report here the results of a phase I evaluation of SAFm administered intramuscularly to 34 patients in a sequential, escalating dose format using MELIMMUNE-1 as antigen. MELIMMUNE-1 is a murine antiidiotype antibody that mimicks an epitope on the high molecular weight chondroitin sulfate proteoglycan (MPG) expressed on melanoma cells. Four dose levels of T-MDP were evaluated, as well as two concentrations of the vehicle emulsion. SAFm produced mild to moderate local discomfort due largely to the vehicle emulsion and self-limited systemic effects that were dose related to T-MDP. At doses from 0.05 to 0.1 mg of T-MDP, SAFm was associated with mild headache, fever, or myalgias/arthralgias after 30% or fewer of doses administered. SAFm (0.25 mg of T-MDP) was associated with fever or arthralgias after 38 and 63% of doses. SAFm (1.0 mg of T-MDP) produced profound fatigue, severe myalgias, and arthralgias, lasting 2 to 4 days, in five of six patients. All side effects abated by day 6 at the 1-mg T-MDP dose as opposed to day 3 at doses of 0.25 mg or lower, and no long-term sequelae have occurred. No evidence of uveitis was found at any dose level. As expected and desired, anti-MELIMMUNE antibodies were induced in all patients, and were of higher titer and more durable with the use of the vehicle emulsion or SAFm than in patients receiving MELIMMUNE-1 in saline. Cross-reactivity of postimmunization sera with MPG could not be demonstrated by rosetting or direct binding immunofluorescence assays but was suggested by inhibition of binding of anti-MPG monoclonal antibody to MPG-positive cells. Delayed-type hypersensitivity reactions to MELIMMUNE-1 could not be demonstrated, despite the use of adjuvant. We have demonstrated that SAFm is a potent adjuvant in humans, and have identified 0.1 mg of T-MDP as a dose that is well tolerated in a multiple-dose regimen in the outpatient setting.
Keywords: clinical article; controlled study; clinical trial; fatigue; drug safety; melanoma; controlled clinical trial; pain; myalgia; arthralgia; fever; melanoma cell; outpatient; immunological adjuvant; headache; rosette formation; immunofluorescence test; phase 1 clinical trial; cross reaction; antigen binding; antibody production; antibody titer; uveitis; intramuscular drug administration; delayed hypersensitivity; idiotypic antibody; proteochondroitin sulfate; squalene; human; priority journal; article; polysorbate 80; poloxamer; muramyl dipeptide
Journal Title: Vaccine Research
Volume: 3
Issue: 2
ISSN: 1056-7909
Publisher: Mary Ann Liebert, Inc.  
Date Published: 1994-01-01
Start Page: 71
End Page: 81
Language: English
PROVIDER: scopus
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-0027980467&partnerID=40&md5=0abd32aa96da9dbe32bd72006c8ad354
Notes: VACCINE RES. -- Cited By :5 -- Export Date: 14 January 2019 -- Article -- CODEN: VAREE -- Source: Scopus