Active Specific Immunotherapy with Autologous Tumor Cell Vaccines Modified by Newcastle Disease Virus: Experimental and Clinical Studies

Abstract

Active specific immunotherapy (ASI) procedures usually involve active vaccination with intact, but inactivated tumor cells or with tumor-derived subcellular membrane fractions. Such material is modified in various ways to make it more immunogenic. Modified tumor cell vaccines which have been applied in cancer patients were prepared for instance by polymerization of autologous tumor tissue (Tallberg 1974; Tykkä et al. 1974; Tallberg et al. 1986; Tallberg and Tykkä 1986; Tallberg et al. 1987; Kurth et al. 1987; Fowler 1986), by neurami-nidase treatment (Wunderlich et al. 1985), by chemical modification (Skornick et al. 1984), by the admixture of viruses (Cassel et al. 1977, 1983, 1986; Murray et al. 1977; Hersey et al. 1986, 1987; Wallack et al. 1986; Freedman et al. 1983; Sinkovics 1977), bacteria, in particular C. parvum (McCune et al. 1979, 1984), and bacillus Calmette-Guerin (BCG; Mathe et al. 1986; Hoover et al. 1984, 1985), fungi (Schärfe et al. 1986; Fowler 1986), Freun’s adjuvant (Hollinshead 1987), carrier proteins such as Keyhole Limpet hemocyanine (KLH; Klippel et al. 1981) or of biological response modifiers (Cortesina et al. 1988; Forni et al. 1984) as adjuvants. Some concepts of ASI procedures have been developed over years in well-defined animal models. Major contributions to the understanding of the principles of active-specific immunotherapy were made in the line 10 hepatocarcinoma guinea-pig tumor model (Hanna et al. 1979, 1980; Hanna and Key 1982), and in the well-characterized, highly metastatic ESb mouse lymphoma model (Schirrmacher et al. 1979, 1982, 1986; Bosslet et al. 1979; Heicappell et al. 1986). In the guinea-pig model a series of studies demonstrated that BCG, admixed with tumor cells, could induce a degree of systemic tumor immunity that would eliminate a small, disseminated tumor burden when the vaccine was carefully controlled for such variables as the number of viable, but nontumorigenic tumor cells (10⁷ optimal), the ratio of viable BCG organisms to tumor cells (1:1) and the vaccination regimen (3 vaccines, 1 week apart; Hanna et al. 1980). We reported previously on the prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells in the ESb tumor model (Heicappell et al. 1986; Schirrmacher et al. 1986). A nonlytic, avirulent strain of the paramyxovirus Newcastle disease virus (NDV) was used to infect the tumor cells at a low virus to tumor cell ratio. Such NDV-modified tumor cells were found to have increased tumor immunogenicity and to be effective as tumor vaccines for antimetastatic therapy in combination with surgical removal of the primary tumor. Postoperative immunization with ESb-NDV led to the establishment of long-lasting systemic antitumor immunity (Schirrmacher and Heicappell 1987). Important parameters for optimal therapeutic effects were the time of operation of the primary tumor, the remaining residual disseminated tumor burden, and the dose of virus admixed with a standard dose of 10⁷ irradiated tumor cells.