Summary
A method of active immunization by direct Endolymphatic Instillation (ELI) of a mixture of BCG and Autologous Irradiated Tumor Cells (AITC) is described. ELI was performed in 36 patients with advanced breast cancer, melanoma and some other solid tumors. The procedure was well tolerated and was not associated with any untoward systemic side effects other than those often encountered in conventional BCG immunotherapy. Exposure of patients to AITC by the direct endolymphatic route proved to be superior to immunization by the intradermal route as judged by the subsequent induction of cutaneous Delayed Hypersensitivity Reaction (DHR) toward AITC. When employed as the first immunization attempt ELI was effective in 5 of 6 patients. It led to invigoration of preexisting weak DHR in 6 of 8 patients. In 15 of 22 patients conversion to a strongly positive cutaneous DHR to AITC was achieved by ELI, where previous attempts of immunization by the intradermal route had failed to elicit a positive response. Acquisition of positive cutaneous response to AITC following ELI was found to correlate with favourable prognosis in terms of longer median survival. The effect of ELI was particularly notable with respect to enhancement of in vitro lymphocyte stimulation by PPD antigen, but was not followed by increased reactivity of other in vitro parameters of cell-mediated immunity such as peripheral lymphocyte count, proportion of E-rosette forming cells, and PHA lymphocyte stimulation.
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Adler, A., Stein, J. A., Ben-Efraim, S.: Effective BCG stimulation in patients treated with melphalan after mastectomy. Isr. J. Med. Sci. 13, 837 (1977)
Adler, A., Stein, J. A., Ben-Efraim, S.: Implication of levels of immunocompetence at diagnosis on the subsequent course of breast cancer disease. In: Proc. Intr. Symposium on Tumor-Associated Antigens and Their Specific Immune Response. Milan, 1977. New York: Academic Press (in press) 1978a
Adler, A., Stein, J. A., Czernobilsky, B.: Induction of cutaneous DHR to irradiated autologous tumor cells in inoperable breast cancer. In: Proc. third Intr. DePCa Symposium. New York, 1976. Part I., Vol. I, pp. 573–587. New York: Marcel Dekker 1978b
Andersen, V., Bjerrum, O., Bedixen, G., Schiødt, T., Dissing, I.: Effect of autologous mammary tumor extracts on human leucocyte migration inhibition in vitro. Int. J. Cancer 5, 357 (1970)
Bartlett, G. L., Katsilas, D. C., Kreider, J. W., Purnell, D. M.: Immunogenicity of “viable” tumor cells after storage in liquid nitrogen. Cancer Immunol. Immunother. 2, 127 (1977)
Bekesi, J. G., Holland, J. F. Roboz, J. P.: Specific immunotherapy with neuraminidase-modified leukemic cells. Experimental and clinical trials. Med. Clin. North Am. 61, 1083–1100 (1977)
Black, M. M., Leis, H. P., Shore, B., Zachrau, E.: Cellular hypersensitivity to breast cancer. Assessment by a leukocyte migration procedure. Cancer 33, 952 (1974)
Boyer, P. J. J., Juillard, G. J. F., Yamashiro, C. H., McCarthy, T.: Characterization of immune responses to tumor cells following intralymphatic immunization (abstract 27b). Proc. Amer. Ass. Cancer Res. 17, 69 (1976)
Burger, D. R., Vendenbark, A. A., Fiuke, P., Malley, A., Frikke, M., Black, J., Acott, K., Begley, D., Vetto, M.: Assessment of reactivity to tumor extraxts by leucocyte adherance inhibition and dermal testing. J. Natl. Cancer Inst. 59, 317 (1977)
Cascinelli, N., Balzarini, G. P., Fontana, V., Orefice, S., Veronesi, U.: Intralymphatic administration of BCG in melanoma patients. Cancer Immunol. Immunother. 2, 157 (1977)
Char, D. H., Hollingshead, A. C., Cogan, D. G., Ballintine, E. J., Hogan, M. J., Herberman, R. B.: Cutaneous delayed hypersensitivity reactions to soluble melanoma antigen in patients with ocular malignant melanoma. New Engl. J. Med. 291, 274 (1974)
Cunningham, T. J., Antemann, R., Paonessa, D., Sponzo, R. W., Steiner, D.: Adjuvant immuno-and/or chemotherapy with neuraminidase-treated autogenous tumor vaccine and BCG for head and neck cancer. Ann. N.Y. Acad. Sci. 277, 339 (1976)
Currie, G. A., McElwain, T. J.: Active immunotherapy as an adjunct to chemotherapy in the treatment of disseminated malignant melanoma: a pilot study. Br. J. Cancer 31, 143 (1975)
Felsburg, P. J., Edelman, R.: The active E-rosette test: a sensitive in vitro correlate for human delayed-type hypersensitivity. J. Immunol. 118, 62 (1977)
Flores, M., Marti, J. H., Grossor, N., McFarlane, J. K., Thomson, D. M. P.: An overview: antitumor immunity in breast cancer assayed by tube leukocyte adherence inhibition. Cancer 39, 494 (1977)
Green, A. A., Pratt, C., Webster, R. G., Smith, K.: Immunotherapy of osteosarcoma patients with virus-modified tumor cells. Ann. N.Y. Acad. Sci. 277, 396 (1976)
Hanna, M. G., Peters, L. C.: Immunotherapy of established micrometastases with Bacillus Calmette-Guérin tumor cell vaccine. Cancer Res. 38, 204 (1978)
Herberman, R. B.: In vivo and in vitro assays of cellular immunity in human tumor antigens. Fed. Proc. 32, 160 (1973)
Ikonopisov, R. L., Lewis, M. G., Hunter-Craig, I. D., Bodenham, D. C., Phillips, Y. R., Cooling, I. C., Proctor, J. W., Hamilton-Fairley, G., Alexander, P.: Autoimmunization with irradiated tumor cells in malignant melanomas. Brit. med. J. 1970 II, 725
Jondal, M., Holm, G., Wigzell, H.: Surface markers on human T and B lymphocytes. A large population of lymphocytes forming nonimmune rosettes with sheep red blood cells. J. Exp. Med. 136, 207 (1972)
Juillard, J. G. F., Boyer, P. J., Snow, H. D.: Intralymphatic infusion of autochthonous tumor cells in canine lymphoma. Int. J. Radiat. Oncol. Biol. Phys. 1, 497 (1976)
Juillard, G. J., Boyer, P. J. J., Yamashiro, C. H., Snow, H. D., Weisenburger, T. H., McCarthy, T., Miller, R. J.: Regional intralymphatic infusion (ILI) of irradiated tumor cells with evidence of distant effects. Cancer 39, 126 (1977)
Leibo, S. P.: Comment on the loss of immunogenicity of tumor cells caused by freezing. Cancer Immunol. Immunother. 3, 211 (1978)
Mangan, C. E., Jeglum, K. A., Sedlacek, T. V., Wheeler, J. E., Mikuta, J. J.: Intralymphatic injection of BCG into Rhesus monkeys. J. Natl. Cancer Inst. 55, 699 (1975)
Mathé, G., Schwarzenberg, O., Halle-Pannenko, O., Simmler, M. C.: Experimental and clinical immunopharmacological data applicable to cancer immunotherapy. Discussion paper. Ann. N.Y. Acad. Sci. 277, 467 (1976a)
Mathé, G., DeVassal, F., Delgado, M., Pouillart, P., Belpomme, D., Joseph, R., Schwarzenberg, L., Amiel, J. L., Shneider, M., Cattan, A., Musset, M., Misset, J. L., Jasmin, C.: 1975 current results of the first 100 cytologically typed acute lymphoid leukemia submitted to BCG active immunotherapy. Cancer Immunol. Immunother. 1, 77 (1976b)
Shibata, H. R., Jerry, L. M., Lewis, M. G., Mansell, P. W. A., Capek, A., Marquis, G.: Immunotherapy of human malignant melanoma with irradiated tumor cells, oral BCG and levamisol. Ann. N.Y. Acad. Sci. 277, 355 (1976)
Sokal, J. E.: Immunotherapy for chronic granulocytic leukemia. Clin. Haematol. 6, 129 (1977)
Sokal, J. E., Aungst, C. W., Snyderman, M., Gomez, G.: Immunotherapy of chronic myelocytic leukemia: effect of different vaccination schedules. Ann. N.Y. Acad. Sci. 277, 367 (1976)
Stein, J. A., Adler, A., Ben-Efraim, S., Maor, M.: Immunocompetence, immunosuppression and human breast cancer. I. An analysis of their relationship by known parameters of cell-mediated immunity in well defined stages of disease. Cancer 38, 1171 (1976)
Stein, J. A., Adler, A., Czernobilsky, B., Goldfarb, A. J., Rozin, R. R., Teva, Z., Stavorovsky, M.: Cutaneous response toward autochthonous tumor cells in breast cancer and melanoma patients by active immunization. In: Proc. Int. Symposium on Tumor-Associated Antigens and Their Specific Immune Response, Milan, 1977. New York: Academic Press (in press) 1978
Steward, T. H. M., Hollingshead, A. C., Harris, J. E., Belanger, R., Crepeau, A., Hooper, G. D., Sachs, H. J., Klaasen, D. J., Hirte, W., Rapp, E., Crook, A. F., Orizaga, M., Sengar, D. P. S., Ramen, S.: Immunochemotherapy of lung cancer. Ann. N.Y. Acad. Sci. 277, 436 (1976)
Takita, H., Minowada, J., Han, T., Takada, M., Lane, W. W.: Adjuvant immunotherapy in bronchogenic carcinoma. Ann. N.Y. Acad. Sci. 277, 345 (1976)
Wybran, J., Levin, A. S., Spitler, L. E., Fudenberg, H. H.: Rosetteforming cells, immunological disease and transfer factor. New Engl. J. Med. 288, 710 (1973)
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Abbreviations used: ELI — Endolymphatic Instillation; AITC — Autologous Irradiated Tumor Cells; BCG — Bacillus Calmette-Guérin; DHR — Delayed Hypersensitivity Reaction; PPD — Purified Protein Derivative (tuberculin); PHA — Phytohemagglutinin; SI — Stimulation Index; E-RFC — E-Rosette Forming Cells; PBL — Peripheral Blood Lymphocytes.
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Stein, J.A., Adler, A., Goldfarb, A.J. et al. Direct endolymphatic instillation (ELI) of BCG-Tumor cell mixture. Cancer Immunol Immunother 5, 31–39 (1978). https://doi.org/10.1007/BF00199205
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DOI: https://doi.org/10.1007/BF00199205