Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.
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.
Hodi
F Stephen
FS
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
Butler
Marcus
M
Oble
Darryl A
DA
Seiden
Michael V
MV
Haluska
Frank G
FG
Kruse
Andrea
A
Macrae
Suzanne
S
Nelson
Marybeth
M
Canning
Christine
C
Lowy
Israel
I
Korman
Alan
A
Lautz
David
D
Russell
Sara
S
Jaklitsch
Michael T
MT
Ramaiya
Nikhil
N
Chen
Teresa C
TC
Neuberg
Donna
D
Allison
James P
JP
Mihm
Martin C
MC
Dranoff
Glenn
G
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
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