The Gelfoam gelatin preparation is available either as a cross -linked sponge or as non-cross linked beads. It is able to absorb and hold within its interstices approximately 45 times its weight of blood and other fluids ( 26). The absorptive capacity of Gelfoam is a function of its physical size, increasing with increasing gelatin volume (27). Lubaroff Ad/PSA Phase II, protocol #2, page 6 The mechanism of action of surface-mediated hemostatic devices is supportive and mechanical ( 27). Surface -acting devices, when applied directly to bleeding surfaces, arrest bleeding by the formation of an artificial clot and by producing a mechanical matrix that facilitates clotting (28). Jenkins et al have theorized that the clotting effect of Gelfoam may be due to release of thromboplastin from platelets, occurring when platelets entering the Gelfoam become damaged by contact with its myriad of interstices ( 29). Thromboplastin interacts with prothrombin and calcium to produce thrombin, and this sequence of events initiates the clotting reaction. The authors suggest that the physiologic formation of thrombin in Gelfoam is sufficient to produce formation of a clot, by its action on the fibrinogen in blood ( 29). The spongy physical properties of Gelfoam hasten clot formation and provide structural support for the forming clot (28,30). Gelfoam has been used experimentally for the delivery of soluble proteins and drugs, including insulin, antibiotics, and growth factors (31-33). Gelfoam was used for sustained release of insulin in an ocular implant device (31). Delivery of insulin in solution had no effect on blood glucose levels. In contrast, the use of Gelfoam as a sustained release delivery agent provided measurable insulin activity for up to 10 hours after implantation. Glucose levels in the blood stabilized at 60% of the original value, whereas administration of insulin in eye drops had no effect. MacDonald and Mathews (34) studied Gelfoam implants in canine kidneys and reported that it assisted in healing, with no marked inflammatory or foreign- body reactions. Jenkins and Janda (35) studied the use of Gelfoam in canine liver resections and noted that Gelfoam appeared to offer a protective cover and provide structural support for the repar ative process. Correll et al (36) studied the histology of Gelfoam when implanted in rat muscle and reported no significant tissue reaction. Gelfoam has been used as a hemostatic agent in dog prostate ( 37). In these studies no gross histological evidence of tissue damage or calcification was induced. In addition, these investigators demonstrated that placement of Gelfoam into the lumen of the bladder resulted in liquefaction of the Gelfoam without any evidence of calculogenesis. Fi nally, Bischoff and Goerttler (38) used Gelfoam in human prostate therapeutic embolization with success. Our laboratory, in collaboration with Dr. Timothy Ratliff, has demonstrated that administration of the Ad/PSA vaccine in Gelfoam induces a stronger anti -PSA immune response (F igure 1). In our pre-clinical studies, immunization with the vaccine in an aqueous suspension induces strong immunity with 10 9 pfu with weaker immunity induced with 108 and 107 pfu. Use of Gelfoam permits the induction of strong responses at the lower dose of 108 pfu. In addition, strong anti -PSA T cell responses could be induced by immunization with the Ad/PSA vaccine in Gelfoam even in mice pre-immunized to adenovirus (Figure 2). In the Phase I clinical trial (section 1.4), the addition of Gelfoam to the vaccine immunization did not result in excess serious adverse events. 1.26 3.125 6.25 12.5 25020406080100 Ad5-PSA 109 Ad5-PSA 108 Ad5-PSA 107 Ad5-lacZFluid Phase Effector Cells x 104/104 Target Cells%51Cr Release 1.56 3.125 6.25 12.5 25020406080100 Ad5-PSA 109 Ad5-PSA 108 Ad5-PSA 107 Ad5-lacZGelfoam Effector Cells x 104/104 Target Cells%51Cr ReleaseFigure 1 – Anti- PSA cytotoxic activity of spleen cells obtained from mice immunized with Ad/PSA in aqueous (fluid phase) versus Gelfo am. Lubaroff Ad/PSA Phase II, protocol #2, page 7 1.4 Phase I study A Phase I clinical trial of the Ad/PSA vaccine has been completed in men with measurable metastatic prostate cancer, with the pr imary objective s of determining the toxicity profile and maximal tolerated dose (MTD) . The ability of the vaccine to induce anti -PSA immune responses and any clinical responses was also evaluated. Funding for the Phase I trial was provided by multiple sources that include the Holden Comprehensive Cancer Center, the Department of Urology, and the Carver College of Medicine at the University of Iowa. Eligible patients consisted of men with prostate cancer that had measurable metastatic disease, 90% of whom were stage D3. Prior therapies had included androgen depletion, ketaconazole, prednisone, Casodex, Taxotere, and external beam radiation, but the initiation of vacci ne therapy was equal to, or greater than , 30 days after the most recent therapy. Patients were treated in successive dose levels and aqueous vs.