Development of novel substrates for tumor immunotherapy.
Acid-terminated polyglycolide microparticles (PG-MP) were prepared as a versatile substrate that could be surface-modified for either immobilization of anti-cd3 and anti-cd28 mAb to activate T cells or sustained release of granulocyte-macrophage colony stimulating factor (GM-CSF) for dendritic cell (DC) recruitment and maturation. PG-MP were prepared with a volume-weighted mean diameter of 56 or 57 microm. Accessible carboxylic acid group concentration was determined by potentiometric titration to be 0.3 mmole/g and corresponded to a zeta potential of -21.87 mV. PG-MP immobilized with either anti-human CD3/CD28 or anti-mouse cd3/cd28 induced significant proliferation of T cells. Intracellular flow cytometry in activated mouse T cells was significant for IFN-gamma, but not IL-4. Microparticles surface-modified for GM-CSF release were prepared from either PG-MP or PG pre-treated with poly-L-lysine (PG-Lys) to manipulate surface charge. GM-CSF released from PG-Lys-MP was observed for up to 26 days. The biologic activity of released GM-CSF was confirmed by using a h-GM-CSF-dependent cell line. The efficacy of the alpha-cd3/cd28-MP and GMCSF-MP was studied in a syngeneic mouse tumor prevention and regression model. Co-injection of Meth A fibrosarcoma cells with alpha-cd3/cd28-MP and GMCSF-MP completely prevented tumor implantation (0/24). The regression model showed complete tumor regression in four of seven animals and stable disease in three of seven. In the latter study, a dramatic level of DC infiltration was observed compared to controls.
Shalaby
Waleed S W
WS
Division of Gynecologic Oncology, University of Pennsylvania Medical Center, 3400 Spruce Street, First Floor Dulles, Suite 1000 Courtyard, Philadelphia, PA 19104, USA. wsalaby@mail.obgyn.upenn.edu
Yeh
Heidi
H
Woo
Edward
E
Hendren
Samantha
S
Corbett
Joel T
JT
Gray
Heidi
H
June
Carl H
CH
Shalaby
Shalaby W
SW
D000818:Animals; D018106:CD28 Antigens / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D016207:Cytokines / Q000737:chemistry; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D008863:Microspheres; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D011100:Polyglycolic Acid / Q000737:chemistry; D013601:T-Lymphocytes / Q000276:immunology
D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D011100:Polyglycolic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor