title: Low-dose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma.
abstract: Clinical outcomes from cancer vaccine trials in patients with advanced melanoma have so far been disappointing. This appears at least partially due to a state of immunosuppression in these patients induced by an expansion of regulatory cell populations including regulatory T cells (Tregs). We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine in patients with resected melanoma (study LUD99-08); however, the same vaccine induced only a few vaccine antigen-specific immune responses in patients with advanced disease (study LUD2002-013). Pre-clinical models suggest that the alkylating agent cyclophosphamide can enhance immune responses by depleting Tregs. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine. The combination treatment led to a significant increase in vaccine-induced NY-ESO-1-specific CD4(+) T cell responses compared with the first trial cohort treated with vaccine alone. We could not detect a significant decline in regulatory T cells in peripheral blood of patients 14 days after cyclophosphamide administration, although a decline at an earlier time point cannot be excluded. Our observations support the inclusion of cyclophosphamide in combination trials with vaccines and other immune-modulatory agents.
authors: Ludwig Institute for Cancer Research (Melbourne-Austin Branch), 147-163 Studley Road, Heidelberg, VIC, 3084, Australia, oliver.klein@ludwig.edu.au.
authors: Oliver
authors: O
authors: Klein
authors: Ian D
authors: ID
authors: Davis
authors: Grant A
authors: GA
authors: McArthur
authors: Li
authors: L
authors: Chen
authors: Andrew
authors: A
authors: Haydon
authors: Phillip
authors: P
authors: Parente
authors: Nektaria
authors: N
authors: Dimopoulos
authors: Heather
authors: H
authors: Jackson
authors: Kun
authors: K
authors: Xiao
authors: Eugene
authors: E
authors: Maraskovsky
authors: Wendie
authors: W
authors: Hopkins
authors: Rodica
authors: R
authors: Stan
authors: Weisan
authors: W
authors: Chen
authors: Jonathan
authors: J
authors: Cebon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000276:immunology*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D002784:Cholesterol / Q000276:immunology*; D015331:Cohort Studies; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008565:Membrane Proteins / Q000276:immunology*; D008875:Middle Aged; D009367:Neoplasm Staging; D010743:Phospholipids / Q000276:immunology*; D011379:Prognosis; D012503:Saponins / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D018906:Antineoplastic Agents, Alkylating; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D004338:Drug Combinations; C493786:ISCOMATRIX; D008565:Membrane Proteins; D010743:Phospholipids; D012503:Saponins; D003520:Cyclophosphamide; D002784:Cholesterol