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Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients
- Source :
- Proceedings of the National Academy of Sciences. 105:3005-3010
- Publication Year :
- 2008
- Publisher :
- Proceedings of the National Academy of Sciences, 2008.
-
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.
- Subjects :
- medicine.medical_treatment
Enzyme-Linked Immunosorbent Assay
chemical and pharmacologic phenomena
Ipilimumab
T-Lymphocytes, Regulatory
Cohort Studies
Antigen
Antigens, CD
medicine
Humans
Cytotoxic T cell
CTLA-4 Antigen
Melanoma
Ovarian Neoplasms
Multidisciplinary
business.industry
Carcinoma
Immunization, Passive
Antibodies, Monoclonal
Granulocyte-Macrophage Colony-Stimulating Factor
FOXP3
Immunotherapy
Biological Sciences
Antigens, Differentiation
GVAX
CTLA-4
Immunology
Female
business
CD8
medicine.drug
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 105
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....02bb913645b5c063097f41e3727a69a3