title: Phase I trial of large multivalent immunogen derived from melanoma lysates in patients with disseminated melanoma.
abstract: OBJECTIVE
  The purpose of this research was to determine the toxicity and immunological activity of large multivalent immunogen (LMI), a preparation of tumor cell membranes affixed to amorphous silica microbeads, in patients with melanoma.
  
  
  METHODS
  Nineteen patients with metastatic (stage IV) melanoma were entered into the study, of whom 15 received the full 3 months of treatment with LMI. LMI was administered without adjuvant, one-half intradermally (i.d.) and the other half s.c. Because we expected little toxicity, we first treated 2 patients at each dose level, 10-, 30-, or 100-million tumor cell equivalents on weeks 0, 4, and 8, and subsequently randomized the remaining 13 patients to receive treatment with one of those dosage schedules, for a total of 19 patients. Two patients who were registered were found to be ineligible because of brain metastases, and 2 others did not complete the course of treatment for reasons other than toxicity. Thus, 15 patients were fully evaluable. Patients with evidence of a clinical response (at least stable disease at the 12-week checkpoint) had the option of continuing treatment at 4-week intervals. Frequencies of cytolytic T cell precursors against HLA-A2 matched melanoma cells, and delayed-type hypersensitivity to a melanoma cell membrane preparation from a component melanoma cell line were performed to measure immunological efficacy, and serum chemistries and complete blood counts were performed every 2 weeks throughout the study to measure possible toxicity. Computed tomography scans were performed pretreatment and at week 12 to measure possible beneficial effects on known lesions.
  
  
  RESULTS
  Eight of the 15 evaluable patients had an increase in cytolytic T-cell precursors during the course of therapy, usually by day 42. No patient had demonstrable delayed-type hypersensitivity to a melanoma membrane preparation before or after treatment. No toxicity of any kind was observed. A degree of clinical effectiveness of LMI was suggested by the elicitation of stable disease in 5 patients at 12 weeks. One patient had >50% regression of a lung nodule but progression of disease to the brain, whereas a second patient had a bona fide partial remission of a 3-cm diameter solitary lung nodule.
  
  
  CONCLUSIONS
  LMI was nontoxic, improved immunological reactivity to melanoma cells, and showed evidence of clinical effectiveness (shrinkage of tumor) in 1 patient. Additional studies with LMI with added adjuvant materials, in melanoma and other cancers, appear warranted.
authors.affiliation: Center for Biological Therapy and Melanoma Research, University of California, San Diego, La Jolla, California, USA. NMitchell995@netscape.net
authors.forename: Malcolm S
authors.initials: MS
authors.lastname: Mitchell
authors.forename: June
authors.initials: J
authors.lastname: Kan-Mitchell
authors.forename: Philip R
authors.initials: PR
authors.lastname: Morrow
authors.forename: Denise
authors.initials: D
authors.lastname: Darrah
authors.forename: Vicky E
authors.initials: VE
authors.lastname: Jones
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Mescher
mesh_terms: D000276:Adjuvants, Immunologic; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002462:Cell Membrane / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005260:Female; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D006968:Hypersensitivity, Delayed; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D012074:Remission Induction; D012822:Silicon Dioxide / Q000737:chemistry; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D012822:Silicon Dioxide