| 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. © 2008 by The National Academy of Sciences of the USA. |
| Keywords: |
human tissue; clinical trial; cancer patient; comparative study; methodology; transcription factor foxp3; cd8+ t lymphocyte; ovarian neoplasms; metabolism; cytotoxic t lymphocyte antigen 4 antibody; ipilimumab; melanoma; metastasis; ovary cancer; cohort studies; granulocyte macrophage colony stimulating factor; inflammation; cohort analysis; tumor biopsy; enzyme linked immunosorbent assay; monoclonal antibody; regulatory t lymphocyte; immunology; antibodies, monoclonal; immunotherapy; t-lymphocytes, regulatory; ovary tumor; cancer immunization; tumor cell; carcinoma; tumor immunity; ctla-4; antigens, cd; enzyme-linked immunosorbent assay; toxicity; cytotoxic t lymphocyte antigen 4; granulocyte macrophage colony stimulating factor vaccine; leukocyte antigen; vaccine; antigens, differentiation; differentiation antigen; gm-csf; tumor necrosis; cytotoxic t-lymphocyte antigen 4; granulocyte-macrophage colony-stimulating factor; passive immunization; regulatory t cells (tregs); immunization, passive
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