title: Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients.
abstract: A large number of cancer-associated gene products evoke immune recognition, but host reactions rarely impede disease progression. The weak immunogenicity of nascent tumors contributes to this failure in host defense. Therapeutic vaccines that enhance dendritic cell presentation of cancer antigens increase specific cellular and humoral responses, thereby effectuating tumor destruction in some cases. The attenuation of T cell activation by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) further limits the potency of tumor immunity. In murine systems, the administration of antibodies that block CTLA-4 function inhibits the growth of moderately immunogenic tumors and, in combination with cancer vaccines, increases the rejection of poorly immunogenic tumors, albeit with a loss of tolerance to normal differentiation antigens. To gain a preliminary assessment of the biologic activity of antagonizing CTLA-4 function in humans, we infused a CTLA-4 blocking antibody (MDX-CTLA4) into nine previously immunized advanced cancer patients. MDX-CTLA4 stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in three of three metastatic melanoma patients and the reduction or stabilization of CA-125 levels in two of two metastatic ovarian carcinoma patients previously vaccinated with irradiated, autologous granulocyte-macrophage colony-stimulating factor-secreting tumor cells. MDX-CTLA4 did not elicit tumor necrosis in four of four metastatic melanoma patients previously immunized with defined melanosomal antigens. No serious toxicities directly attributable to the antibody were observed, although five of seven melanoma patients developed T cell reactivity to normal melanocytes. These findings suggest that CTLA-4 antibody blockade increases tumor immunity in some previously vaccinated cancer patients.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Frank G
authors.initials: FG
authors.lastname: Haluska
authors.forename: Marcus
authors.initials: M
authors.lastname: Butler
authors.forename: Michael V
authors.initials: MV
authors.lastname: Seiden
authors.forename: Thomas
authors.initials: T
authors.lastname: Davis
authors.forename: Rochele
authors.initials: R
authors.lastname: Henry-Spires
authors.forename: Suzanne
authors.initials: S
authors.lastname: MacRae
authors.forename: Ann
authors.initials: A
authors.lastname: Willman
authors.forename: Robert
authors.initials: R
authors.lastname: Padera
authors.forename: Michael T
authors.initials: MT
authors.lastname: Jaklitsch
authors.forename: Sridhar
authors.initials: S
authors.lastname: Shankar
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Chen
authors.forename: Alan
authors.initials: A
authors.lastname: Korman
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
mesh_terms: D000069594:Abatacept; D000328:Adult; D000368:Aged; D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D017951:Antigen Presentation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008875:Middle Aged; D009336:Necrosis; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept