Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients
Published online on February 19, 2008
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0712237105
F. Stephen Hodia,b, Marcus Butlera, Darryl A. Oblec, Michael V. Seidend,e, Frank G. Haluskaf, Andrea Krusea, Suzanne MacRaea, Marybeth Nelsona, Christine Canninga, Israel Lowyg, Alan Kormang, David Lautzh, Sara Russellh, Michael T. Jaklitschh, Nikhil Ramaiyai, Teresa C. Chenj, Donna Neubergk, James P. Allisonb,l, Martin C. Mihmc, and Glenn Dranoffa
aDepartment of Medical Oncology and Cancer Vaccine Center, Dana–Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 44 Binney Street, Boston, MA 02115; Departments of cPathology and dMedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; fCancer Center and Division of Hematology/Oncology, Tufts–New England Medical Center, Boston, MA 02111; gMedarex, Inc., 67 Beaver Avenue, Annandale, NJ 08801; hDepartment of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; iDepartment of Radiology, Dana–Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115; jMassachusetts Eye and Ear Infirmary and Harvard Medical School, 243 Charles Street, Boston, MA 02114; kDepartment of Biostatistics and Computational Biology, Dana–Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115; and lHoward Hughes Medical Institute and Program in Immunology, Memorial Sloan–Kettering Cancer Institute, New York, NY 10021
Contributed by James P. Allison, December 27, 2007 (sent for review July 24, 2007)
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.
pnas.org |
