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Gemcitabine (gem) can enhance immunotherapy (IT) of pancreatic cancer – importance of schedule
Author(s) -
Schultes Birgit Corinna,
Daley Graham Elisabeth,
Nicodemus Christopher Farley
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1077.8
Subject(s) - gemcitabine , immunotherapy , cancer research , pancreatic cancer , immune system , in vivo , cd28 , medicine , tumor antigen , spleen , cancer immunotherapy , antigen , pancreatic tumor , cancer , t cell , immunology , chemistry , biology , microbiology and biotechnology
With a 5‐year survival rate of only 4%, non‐resectable pancreatic cancer is in urgent need of novel approaches to supplement current therapies. This study assessed parameters for combining gem and IT with the anti‐MUC1 antibody, AR20.5. Upon injection, AR20.5 forms immune complexes with circulating MUC1, leading to enhanced T cell immunity. To examine the effects of gem on immune cells and antigen processing, three parallel approaches were conducted: a) an in vitro co‐culture system of immature DC, tumor and T cells; b) a time course study of gem (60 mg/kg) in Panc02 tumor bearing mice; and c) a combination chemo‐IT study in MUC1‐transgenic mice with established Panc02.MUC1 tumors. In vitro , gem did not affect T cell or DC survival at concentrations ≤5 μg/mL. Interestingly, gem enhanced maturation of DC and T cell proliferation to non‐specific stimuli (anti‐CD3/CD28) as well as to the co‐cultured tumor cells. The in vivo time course study confirmed minor effects of gem on T and B cell survival with rapid recovery. Gem increased DC maturation in the spleen and tumor as well as DC migration to the tumor by Day 5. Further, gem significantly reduced T regs in the draining LN (Day 7) and tumor (Day 10). Reduction in myeloid derived suppressor cells was transient (Day 5–7) in spleen and tumor. Tumor control studies showed synergistic effects for combination gem‐IT over single agents when IT was given 1 week delayed relative to gem.