Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients

F. Stephen Hodi, Marcus Butler, Darryl A. Oble, Michael V. Seiden, Frank G. Haluska, Andrea Kruse, Suzanne MacRae, Marybeth Nelson, Christine Canning, Israel Lowy, Alan Korman, David Lautz, Sara Russell, Michael T. Jaklitsch, Nikhil Ramaiya, Teresa C. Chen, Donna Neuberg, James P. Allison, Martin C. Mihm, Glenn Dranoff

Research output: Contribution to journalArticlepeer-review

538 Scopus citations

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.

Original languageEnglish
Pages (from-to)3005-3010
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number8
DOIs
StatePublished - 26 Feb 2008
Externally publishedYes

Keywords

  • CTLA-4
  • GM-CSF
  • Regulatory T cells (Tregs)
  • Vaccine

Fingerprint

Dive into the research topics of 'Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients'. Together they form a unique fingerprint.

Cite this