![]() ![]() ![]() Initial clinical experience raised the possibility of important therapeutic interactions between CTLA-4 blockade and GM-CSF secreting tumor cell vaccines 10- 12 with clinical benefits observed in melanoma, prostate cancer, and ovarian carcinoma. In multiple pre-clinical models, the combination of CTLA-4 antibody blockade and GM-CSF secreting tumor cell vaccines demonstrated therapeutic synergies 9. Ipilimumab, a fully human IgG1 monoclonal antibody that blocks CTLA-4, has demonstrated survival advantages in patients with pretreated metastatic melanoma when compared to a gp100 peptide vaccine 7 as well as in treatment naive patients when combined with dacarbazine chemotherapy as compared to dacarbazine alone 8. A concern for clinical development is evidence that GM-CSF may induce negative regulatory immune responses 6.ĬTLA-4 is an immune checkpoint molecule that inhibits T lymphocyte activity. Systemic administration of GM-CSF has activity in prostate and ovarian carcinoma and is being evaluated in Phase III adjuvant trials for melanoma and lymphoma 4, 5. GM-CSF is a cytokine that enhances activation of dendritic cells for antigen presentation and potentiates T and B lymphocyte anti-tumor functions 1- 3. Median progression free survival for ipilimumab+sargramostim was 3.1 months (95% CI 2.9, 4.6) and for ipilimumab was 3.1 months (95% CI 2.9, 4.0). There was no difference in progression-free survival. ![]() O'Brien-Fleming boundary was crossed for improvement in overall survival. A planned interim analysis was conducted at 69.8% (104 observed/ 149 planned deaths) information time. 64, one-sided 90% repeated CI (not applicable. One-year survival rate for sargramostim was 68.9% (95% CI 60.6%, 85.5%) compared to 52.9% (95% CI 43.6%, 62.2%) with ipilimumab (stratified logrank one-sided P=.01 mortality hazard ratio. Median overall survival for sargramostim plus ipilimumab was 17.5 months (95% CI 14.9, not reached) compared to 12.7 months (95% CI 10.0, not reached) for ipilimumab.
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