Compositions and methods for prevention and treatment of primary and metastatic neoplastic diseases and infectious diseases with compositions comprising unfractionated cellular proteins

#The present invention relates to methods and compositions for the prevention and treatment of infectious diseases, and primary and metastatic neoplastic diseases, including, but not limited to human sarcomas and carcinomas. In the practice of the prevention and treatment of infectious diseases and cancer, compositions comprising unfractionated cellular proteins are used to augment the immune response to genotoxic and nongenotoxic factors, tumors and infectious agents.

#The era of tumor immunology began with experiments by Prehn and Main, who showed that antigens on the methylcholanthrene (MCA)-induced sarcomas were tumor specific in that transplantation assays could not detect these antigens in normal tissue of the mice (Prehn, R. T., et al., 1957, J. Natl. Cancer Inst. 18:769-778). This notion was confirmed by further experiments demonstrating that tumor specific resistance against MCA-induced tumors can be elicited in the autochthonous host, that is, the mouse in which the tumor originated (Klein, G., et al., 1960, Cancer Res. 20:1561-1572).

#In subsequent studies, tumor specific antigens were also found on tumors induced with other chemical or physical carcinogens or on spontaneous tumors (Kripke, M. L., 1974, J. Natl. Cancer Inst. 53:1333-1336; Vaage, J., 1968, Cancer Res. 28:2477-2483; Carswell, E. A., et al., 1970, J. Natl. Cancer Inst. 44:1281-1288). Since these studies used protective immunity against the growth of transplanted tumors as the criterion for tumor specific antigens, these antigens are also commonly referred to as “tumor specific transplantation antigens” or “tumor specific rejection antigens.” Several factors can greatly influence the immunogenicity of the tumor induced, including, for example, the specific type of carcinogen involved, immunocompetence of the host and latency period (Old, L. J., et al., 1962, Ann. N.Y. Acad. Sci. 101:80-106; Bartlett, G. L., 1972, J. Natl. Cancer Inst. 49:493-504).

#5.1. Measuring Generation of MHC Class I Restricted CD8+ CTLs Provides An Assay For In Vivo Tumor Rejection

#The effect of vaccination with compositions comprising unfractionated cellular proteins, can be measured by tumor rejection assays in vivo. While this assay is clearly the most demanding and rigorous evidence for immunogenicity, it is impractical for the purpose of monitoring immune response in humans. The ability of tumor-derived compositions comprising unfractionated cellular proteins, to elicit a CD8+ T cell response is evaluated in order to define an in vitro correlate for in vivo tumor rejection.

#Mice are immunized twice with a composition comprising 102 to 106 cell equivalents of unfractionated cellular proteins derived from 6138 or 6139SJ cells (Ward et al., 1989, J. Exp. Med. 170:217). Mixed lymphocyte-tumor cultures (MLTCs) are generated from immunized mice and tested in a 51Chromium release assay to assay for tumor-specific cytotoxicity for the tumor used as the source of the composition comprising unfractionated cellular proteins. This cytotoxic activity is blocked by anti-MHC class I antibody K44 (Ozato, K., et al., 1985, Proc. Natl. Acad. Sci. USA 82:2427) and by anti-CD8 antibody YTS169.4 (Cobbold, S. P., et al., 1984, Nature 312:548). No corresponding activity is expected in MLTCs generated from spleens of naive mice. Such results demonstrate that vaccination with a composition comprising 102 to 106 cell equivalents of unfractionated cellular proteins, elicits an effective tumor-specific CTL response, which may be measured in vitro.