title: Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.
abstract: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as a negative regulator of endogenous and vaccine-induced antitumor immunity. The administration of fully human anti-CTLA-4 blocking monoclonal antibodies to advanced-cancer patients increases immune-mediated tumor destruction in some subjects. Nonetheless, patients that respond also frequently manifest serious inflammatory pathologies, raising the possibility that the therapeutic and toxic effects of CTLA-4 blockade might be linked. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. The application of this sequential immunotherapy to advanced ovarian carcinoma patients also revealed that tumor destruction and severe inflammatory pathology could be dissociated, although further refinements are required to increase clinical responses and to minimize toxicity in this population. The extent of therapy-induced tumor necrosis was linearly related to the natural logarithm of the ratio of intratumoral CD8(+) effector T cells to FoxP3(+) regulatory T cells (Tregs) in posttreatment biopsies. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy.
authors.affiliation: Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. stephen_hodi@dfci.harvard.edu
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.forename: Marcus
authors.initials: M
authors.lastname: Butler
authors.forename: Darryl A
authors.initials: DA
authors.lastname: Oble
authors.forename: Michael V
authors.initials: MV
authors.lastname: Seiden
authors.forename: Frank G
authors.initials: FG
authors.lastname: Haluska
authors.forename: Andrea
authors.initials: A
authors.lastname: Kruse
authors.forename: Suzanne
authors.initials: S
authors.lastname: Macrae
authors.forename: Marybeth
authors.initials: M
authors.lastname: Nelson
authors.forename: Christine
authors.initials: C
authors.lastname: Canning
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.forename: Alan
authors.initials: A
authors.lastname: Korman
authors.forename: David
authors.initials: D
authors.lastname: Lautz
authors.forename: Sara
authors.initials: S
authors.lastname: Russell
authors.forename: Michael T
authors.initials: MT
authors.lastname: Jaklitsch
authors.forename: Nikhil
authors.initials: N
authors.lastname: Ramaiya
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Chen
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology*; D060908:CTLA-4 Antigen; D002277:Carcinoma / Q000276:immunology / Q000628:therapy*; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D000074324:Ipilimumab; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor