Therapeutische Tumorvakzination

Die Vorstellung, einen Impfstoff gegen Tumoren des Menschen zu entwickeln, ist so alt wie die Immunologie. Erste Versuche begannen vor 200 Jahren. Bis in die späten 30er Jahre des vorigen Jahrhunderts, als man weder Antibiotika noch Zytostatika hatte, setzte man ganz auf die körpereigenen Abwehrkräfte und suchte nach Wegen, diese zu verstärken. Frühzeitig wurde erkannt, dass Bakterien und ihre Produkte in der Lage waren, die Abwehrkräfte zu stimulieren. Gleichzeitig war man schon früh davon überzeugt, dass es auch beim Menschen eine spezifische Immunabwehr gegen Tumoren gibt, obwohl das erst in jüngster Zeit wirklich nachgewiesen wurde. Leider blieben die über viele Jahre immer wieder durchgeführten Studien zur Immunstimulation mit unspezifischen Agentien, inklusive der neuesten Entwicklungen wie Zytokine und LAK-Zellen, in ihren klinischen Ergebnissen sehr unbefriedigend.

Nach Versuchen, durch Vakzination mit autologen oder allogenen Tumorzellen eine spezifische Immunantwort aufzubauen, die teilweise von Erfolg gekrönt waren, hat sich mit zunehmendem methodischen Fortschritt und besserer Charakterisierung von Tumorantigenen die Möglichkeit einer Vakzinierung mit tumortypischen Antigenen entwickelt. Diese Form einer aktiven spezifischen Immuntherapie, kombiniert mit Maßnahmen zur Verstärkung der Immunreaktion und mit gentherapeutischen Ansätzen, könnte im Anschluss an tumordestruktive Maßnahmen zu einem deutlichen Fortschritt, das heißt besseren Heilungsraten menschlicher Tumoren führen.

Die Entwicklung von Tumorvakzinen basiert auf den Prämissen, dass es qualitative und quantitative Unterschiede zwischen Tumorzellen und Normalzellen gibt, dass das Immunsystem diese Unterschiede prinzipiell erkennen kann und dass man es lehren kann, eine Tumorabstoßung im Zuge einer Immunantwort zu vollziehen. Vakzinetherapie hat also das Ziel, eine spezifische Immunantwort gegen einen vorhandenen Tumor zu induzieren oder eine vorhandene, aber zu schwache spezifische Immunreaktion gegen einen Tumor durch Maßnahmen zur Steigerung der Immunantwort zu verstärken.

Dabei geht es vor allem um die vollständige Elimination restierender Tumorzellen nach operativer Entfernung der Haupttumormasse. Vakzinetherapie ist also Teil eines multimodalen Therapieansatzes, wobei tumordestruktive Maßnahmen, wie Operation, Radiotherapie und Chemotherapie, kombiniert werden mit spezifischer Immunisierung gegen einen autologen Tumor (Tumorvakzine) in Verbindung mit Maßnahmen, die die Immunantwort unspezifisch verstärken, wie antiimmunsuppressive Maßnahmen (Cyclophosphamid, Cimetidin, Indometacin) [[1]], Zytokine (Interleukin-2, Interferon alpha) [[45], [58]], Zytokininduktoren (BCG, C. parvum, Levamisol) [[33], [34]] sowie Makrophagen- und NK-Zell-stimulierende Maßnahmen (KLH, Mistellektin, Interleukin-1) und Hyperthermie [[26], [33], [38]].

Literatur

• 1 Ahlert Th.. Erfahrungsbericht „Aktive Spezifische Immuntherapie”. an der Universitäts Frauenklinik Heidelberg 1995
• 2 Ahlert  Th., Sauerbrei W., Bastert G.. et al. . Tumor-cell number and viability as quality and efficacy parameters of autologous virus-modified cancer vaccines in patients with breast or ovarian cancer.  J Clin Oncol. 1997;  15 1354-1366
• 3 Allison A. C., Byars N. E.. An adjuvant formulation that selectively elicits the formation of antibodies of protective isotypes and of cell-mediated immunity.  J Immunol Meth. 1986;  95 157-168
• 4 Alters S. E., Philip R., Philip J. R., Gadea J. R.. Immunotherapy of cancer. Generation of CEA specific CTL using CEA-peptide pulsed dendritic cells.  Adv Exp Med Biol. 1997;  417 519-524
• 5 Altman Lk.. Who goes first?. Random House, New York 1986: 287
• 6 Apostolopoulos V., McKenzie L. F., Pietersz G. A.. Breast cancer Immunotherapy: current status and future prospects.  Immunol Cell Biol (Australia). 1996;  74 457-464
• 7 Austin F. C., Boone C. W.. Virus augmentation of the antigenicity of tumor cell extracts.  Adv cancer Res. 1979;  30 301-345
• 8 Berd jr. D., Maguíre H. C., McCue P.. et al. . Treatment of metastatic melanoma with an autologous tumor-cell vaccine: clinical and immunologic results in 64 patients.   J Clin Oncol. 1990;  8 1858-1867
• 9 Bier H., Armonat G., Bier J.. et al. . Postoperative active-specific immunotherapy of lymph node micrometastasis in a guineapig tumor model.  Otorhinolaryngology. 1989;  51 197-205
• 10 Chen L., Ashe S., Brady W. A.. et al. . Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD 28 and CTLA-4.   Cell. 1992;  71
• 11 Chen T. T., Tao M. H., Levy R.. Idiotype-cytokine fusion proteins as cancer vaccines. Relative efficacy of IL-2, IL-4, and granulocyte macrophage colony-stimulating factor.  J Immunol. 1994;  153 4775-4787
• 12 Cooper P. D., McComb C., Steele E. J.. The adjuvanticity of Algammulin, a new vaccine adjuvant.  Vaccine. 1991;  9 408-415
• 13 Coussens L., Yang-Feng T. L., Chen A. L. E.. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene .  Sience. 1985;  230 1132-1139
• 14 Dillman T. O., Nayak S. K., Beutel L.. Establishing in vitro cultures of autologous tumor cells for use in active specific immunotherapy.  J Immunother. 1993;  14 65-69
• 14a Ding L., Lalani E. N., Reddish M.. et al. . Immunogenicity of synthetic peptides related to the core peptide sequence endoded by the human Muc-I mucin gene: Effect of immunization on the growth of murine mammary adenocarcinoma cells transfected with the human Muc-I gene.  Cancer Immunol Immunother. 1993;  36 9-17
• 15 Disis M. L., Calenoff E., McLaughlin G.. et al. . Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer.  Cancer Res. 1994;  54 16-20
• 16 Disis M. L., Gralow J. R., Bernhard H.. et al. . Peptide-based, but not whole protein, vaccines elicit immunity to HER-2/neu, an oncogenic self protein.  J Immunol. 1996;  156 3151-3158
• 17 Disis M. L., Cheever M. A., Gralow J. R.. et al. .A phase I study of a HER-2/neu peptide based vaccine with GM-CSF as an adjuvant in patients with advanced stage HER-2/neu expressing cancers. Protocol Nr. 1045.00 The Fred Hutchinson Cancer Research Center Seattle, USA
• 18 Domagk G.. Die Bedeutung körpereigener Abwehrkräfte für die Ansiedlung von Geschwulstzellen.  Z Krebsforsch. 1949;  56 247-251
• 19 Evemann J. F., Burnstein T.. Immune enhancement of the tumorigenicity of hamster brain tumor cells persistently infected with measles virus.  Int J Cancer. 1974;  16 861-869
• 20 Fazely F., Dezube B. J., Allen-Ryan J.. et al. . Pentoxifylline (Trental) decreases the replication of the human immunodeficiency virus type 1 in human peripheral blood mononuclear cells and in cultured T cells.  Blood. 1991;  77 1653-1656
• 21 Forni G., Giovarelli M., Cavallo F.. et al. . Cytokine-induced tumor immunogenicity from exogenous cytokines to gene therapy.  J Immunother. 1993;  14 253-257
• 22 Fragerberg J., Hjelm A. L., Ragenhammar P,. et al. . Tumorregression in monoclonal antibody-treated patients correlates with the presence of antiidiotype-reactive T lymphocytes.  Cancer Res. 1995;  55 1824-1827
• 23 Freedman R. S., Bowen J. M., Herson J. H.. et al. . Immunotherapy for vulvar carcinoma with virus-modified homologous extracts.  Obstet Gynekol. 1983;  62 707-714
• 24 Gabrilovich D. L., Nadaf S., Corak J.. et al. . Dendritic cells in antitumor immune responses. II. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice, are effective antigen carriers in the therapy of established tumors.  Cell Immunol. 1996;  170 111-119
• 25 Garrido F., Ruez-Caballo F., Cabrera T.. et al. . Implications for immunosurveillance of altered HLA class I phenotypes in human tumors.  Immunology to day. 1997;  18 89-95
• 26 Hajto T., Hostanska K., Gabius H. J.. Mudulatory potency of the b-galactoside-specific lectin from mistletoe extract (Iscador) on the host defense in vivo in rabbits and patients.  Cancer Res. 1989;  49 4803-4808
• 27 Hamburg V. T., Svet-Moldarsky G. J.. Artificial heterogenisation of tumors by means of herpes simplex and polyoma viruses.  Nature . 1964;  203 772-773
• 28 Hanna jr. M. G., Peters L. C., Hoover jr. H. C.. Immunotherapy by active specific immunisation.Basic principles and preclinical studies.  In: DeVita, V.T. jr., Hellman, S., Rosenberg, S.A. (eds.): Biologic Therapy of Cancer, J.B. Lippincott Company Philadelphia, New York, London, Hagerstown 1991: 651-669
• 29 Helling F., Shang A., Calves M.. et al. . GD₃ vaccines for melanoma: Superior immunogenicity of keyhole limpet hemocyanin conjugate vaccines.  Cancer Res. 1994;  54 197-202
• 30 Hellström K. E., Hellström I.. Evidence, that tumor antigens enhance tumor growth in vivo by interacting with a radiosensitive (suppressor ?) cell population.  Proc Natl Acad Sci USA. 1978;  75 436-440
• 31 Hellström I., Hellström K. E.. Tumor enhancing suppressor activator T-cells in spleens and thymuses of tumor immune mice.  Proc Natl Acad Sci USA. 1979;  76 5294-5298
• 32 Hellström K. E., Hellström I.. Principles of tumor immunity: Tumor antigens. In: DeVita, V.T. jr., Hellman, S., Rosenberg, S.A. (eds.): Biologic Therapy of Cancer J.B. Lippincott Company Philadelphia, New York, London, Hagerstown 1991: 35-52
• 33 Herr H. W.. Instillation therapy of bladder cancer. In: DeVita, V.T. jr., Hellman, S., Rosenberg, S.A. (eds.): Biologic Therapy of Cancer J.B. Lippincott Company Philadelphia, New York, London, Hagerstown 1991: 643-650
• 34 Hersh E. M., Tayler C. W.. Immunotherapy by active immunisation of the host using non specific stimulants and immunomodulators. In: DeVita, V.T. jr., Hellman, S., Rosenberg, S.A. (eds.): Biologic Therapy of Cancer J.B. Lippincott Company Philadelphia, New York, London, Hagerstown 1991: 613-626
• 35 Hoover H. C., Brandhorst J. S., Peters L. C.. et al. . Adjuvant active specific immunotherapy for human colorectal cancer: 6,5-year median follow-up of a phase III prospectively randomized trial.  J Clin Oncol. 1993;  11 390-399
• 36 Hsu F. J., Caspar C. B., Czerwinski D.. et al. . Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma, long-term results of a clinical trial.   Blood . 1997;  89 3129-3135
• 37 Itzkowitz S. H., Yuan M., Montgomery C. K.. et al. . Expression of Tn, sialosyl-Tn and T-antigens in human colon cancer.  Cancer Res. 1989;  49 191-204
• 38 Jäger E.. Development of vaccines for treatment of breast cancer. Proc. 6th Int. Conf. Adjuvant Therapy of Primary Breast Cancer. St. Gallen Febr/1998: Abstr. S 12
• 39 Kaerre K., Ljunggren H. G., Piontek. et al. . Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy.  Nature. 1986;  319 375-378
• 40 Kall M. A., Hellström I., Hellström K. E.. Different responses of lymphoid cells from tumor-bearing as compared to tumor-immunized mice when sensitized to tumor specific antigens in vitro (Microcytotoxicity assay, suppressor cells).  Proc Natl Acad Sci USA. 1975;  72 50-86
• 41 Kinney A. Y., Sahim A., Vernon S. W.. et al. . The prognostic significance of sialyl-Tn antigen in women treated with adjuvant chemotherapy for breast cancer. 9th Int Congr Breast Dis. Houston TX 1996
• 42 Klein E., Vanky F., Galili U.. et al. . Separation and characteristics of tumor infiltrating lymphocytes in man.  . In: Witz, I.P., Hanna, M.G. (eds.): Contemporary Topics in Immunobiology.  Plenum Press, New York. 1980;  79
• 43 Kobayashi H., Gotohda E., Hosokawa M.. et al. . Inhibition of metastasis in rats immunized with xenogenized autologous tumor cells after excision of the primary tumor.  J Natl Cancer Inst. 1975;  54 997-999
• 44 Koprowski H.. Basic aspects of immunotherapy of human tumors. In: Melchers, F. (ed.): Progress in Immunology VII. Springer Verlag Berlin 1989: 1087
• 45 Kurzrock R., Gutterman J. U., Talpaz M.. Interferons α β γ: Basic principles and preclinical studies.  In: DeVita, V.T. jr., Hellman, S., Rosenberg, S.A. (eds.): Biologic Therapy of Cancer J.B. Lippincott Company Philadelphia, New York, London, Hagerstown 1991: 241-274
• 46 Larson S. M., Cheung Nai-kong V., Leibel S. A.. Antibodies in cancer therapy. Radioisotope conjugates.  In: DeVita, V.T. jr., Hellman, S., Rosenberg, S.A. (eds.): Biologic Therapy of Cancer J.B. Lippincott Company Philadelphia, New York, London, Hagerstown 1991: 496-511
• 47 Lee J. H., Klein H. G.. Cellular gene therapy.  Hematol Oncol Clinics North Amer. 1995;  9 91-113
• 48 Lehner B., Schlag P., Liebrich W.. et al. . Postoperative active specific immunization in curatively resected colorectal cancer patients with a virus-modified autologous tumor cell vaccine.  Cancer Immunol Immunother. 1990;  32 173-178
• 49 Lindenmann J., Klein P. A.. Viral oncolysis: increased immunogenicity of host cell antigen associated with influenza virus.  J Exp Med. 1967;  26 93-108
• 50 Lindenmann J.. Viruses as immunological adjuvants in cancer.  Biochim Biophys Acta. 1974;  355 49-56
• 51 Linsley P. S., Brady W., Grosmaire L.. Binding of the B-cell activation antigen B7 to CD 28 costimulates T-cell proliferation and interleukin-2 mRNA accumulation.  J Exp Med. 1991;  173 721-730
• 52 Livingstone P. O., Oettgen H. F., Old L. J.. Specific active Immunotherapy in cancer treatment. In: Mihich E (ed); Immunolocial Approaches to Cancer Therapeutics John Whiley & Sons, New York 1982: 363
• 53 Livingstone P. O., Watanabe T., Shiku H.. et al. . Serological response of melanoma patients receiving melanoma cell vaccines.  I.Autologous cultured melanoma cells.  Int J Cancer. 1982;  30 413-418
• 54 Livingstone P. O., Adlusi S., Helling F.. et al. . Phase I trial of immunological adjuvant QS-21 with a GM2 ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma.  Vaccine. 1994;  12 1275-1280
• 55 Livingstone P. O.. Approaches to augmenting the immunogenicity of melanoma gangliosides: From whole melanoma cells to ganglioside-KLH conjugate vaccines.  Immunol Rev. 1995;  145 149-166
• 56 Livingstone P., Zhang S., Adlusi S.. et al. . Tumor cell reactivity mediated by IgM antibodies in sera from melanoma patients vaccinated with GM2 ganglioside covalently linked to KLH is increased by IgG antibodies.  Cancer Immunol Immunother. 1997;  43 324-330
• 57 Longenecker B. M., Reddisch M., Kogarty R.. et al. .Specificity of the IgG response in mice and human breast cancer patients following immunization against synthetic sialyl-Tn, an epitope with possible functional significance in metastasis. In: Cerian, R.L. (ed.): Antigen and Antibody Molecular Engineering in Breast Cancer Diagnosis and Treatment. Plenum Press New York 1994: 105
• 58 Lotze M. T., Rosenberg S. A.. Interleukin-2: Clinical applications. In: DeVita, V.T. jr., Hellman, S., Rosenberg, S.A. (eds.): Biologic Therapy of Cancer J.B. Lippincott Company Philadelphia, New York, London, Hagerstown 1991: 159-177
• 59 Lurquin C., Van Peel A., Mariamé B.. et al. . Structure of the gene coding for tum- transplantation antigen P91 A: The mutated exon encodes a peptide recognized with L^d by cytolytic T-cells.  Cell . 1989;  58 293-303
• 60 MacLean G. D., Bowen-Yacyshyn M. B., Samuel J.. et al. . Active immunization of human ovarian cancer patients against a common carcinoma (Thomson-Friedenreich) determinant using a synthetic carbohydrate antigen.  J Immunother . 1992;  11 292-305
• 61 MacLean G. D., Reddish M. A., Koganty R. R.. et al. . Immunization of breast cancer patients using a synthetic syalyl-Tn glycoconjugate plus Detox adjuvant.  Cancer Immunol Immunother. 1993;  36 215-222
• 62 MacLean G. D., Reddish M. A., Koganty R. R.. et al. . Antibodies against mucin-associated syalyl-Tn-epitopes correlate with survival of metastatic adenocarcinoma patients undergoing active specific immunotherapy with synthetic STn vaccine.  J Immunother. 1996;  19 59-67
• 63 MacLean G. D., Miles D. W., Rubens R. D.. et al. . Enhancing the effect of Theratope STn-KLH cancer vaccine in patients with metastatic breast cancer by pretreatment with low-dose intravenus cyclophosphamide.  J Immunother. 1996;  309-316
• 64 Maupas P., Goudeau A., Coursaget P.. et al. . Immunisation against hepatitis B in man.  Lancet . 1976;  1 1367-1370
• 65 Mellstedt H., Frödin J. E., Basucci G.. et al. . The therapeutic use of monoclonal antibodies in colorectal carcinoma.  Semin Oncol. 1991;  18 462-475
• 66 Miles D. W., Towlson K. E., Graham R.. et al. . A randomised phase II study of sialyl-Tn and Detox B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer.  Brit J Cancer. 1996;  74 1292-1296
• 67 Mitchison N. A.. Immunologic approach to cancer.  Transplant Proc. 1970;  11 92-103
• 68 Morcein W., Sundquist B., Höglund S.. et al. . Iscom a novel structure for antigenic presentation of membrane proteins from enveloped viruses.  Nature. 1984;  308 457-460
• 69 Nabel G. J., Fox B. A., Post L.. et al. . A molecular genetic intervention for AIDS - effects of a transdominant negative form of Rev.  Human Gene Ther. 5;  79-92
• 70 Nepom J. T., Hellström L., Hellström K. E.. Antigen-specific purification of blocking factors from sera of mice with chemicaly induced tumors.  Proc Natl Acad Sci USA. 1977;  74 4605 -4614
• 71 Oettgen H. F., Od L. J.. The history of cancer immunotherapy.  In: DeVita, V.T. jr., Hellman, S., Rosenberg, S.A. (eds.): Biologic Therapy of Cancer J.B. Lippincott Company Philadelphia, New York, London, Hagerstown 1991: 87-119
• 72 Plautz G. E., Yang Z. Y., Wu B. Y.. et al. . Immunotherapy of malignancy by in vivo gene transfer into tumors.  Proc Natl Acad Sci USA. 1993;  90 4645-4649
• 73 Price M. R.. Breast-cancer-associated antigens defined by monoclonal antibodies.  Subcell Biochem. 1988;  12 1-12
• 74 Reisfeld R. A.. Immunochemical characterization of human tumor antigen.  Semin Oncol. 1986;  13 153-164
• 75 Ribi E., Amano K., Cantrell J.. et al. . Preparation and antitumor activity of nontoxic lipid A.  Cancer Immunol Immunother. 1982;  12 91-96
• 76 Riethmüller G., Schneider-Gädicke E., Schlimok G.. et al. . Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes'C colorectal carcinoma.  Lancet. 1994;  343 1177-1183
• 77 Rosato F. E.. Active specific immunotherapy of human solid tumors.  Ann NY Acad Sci. 1976;  277 332-331
• 78 Rosenberg S. A., Packard B. S., Aebershold P. M.. et al. . Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report.  N Engl J Med. 1988;  319 1676
• 79 Schirrmacher V., Heicappell R.. Preventation of metastatic spread by postoperative immunotherapy with virally modified autologous cells. II Establishment of specific systemic anti-tumor immunity.  Clin Exp Metast. 1987;  5 147-156
• 80 Schirrmacher V., von Hoegen P.. Importance of tumor cell membrane integrity and viability for cytotoxyc T-lymphocyte activation by cancer vaccines.  Vaccines Res. 1993;  2 183-196
• 81 Schirrmacher V.. Active specific immunotherapy. A new modality of cancer treatment involving the patients own immune system.  Onkologie. 1993;  16 290-296
• 82 Schumacher K., Wolf M. F., Ludwig A.. et al. . Thomsen-Friedenreich antigens, tumor markers with prognostic value in breast cancer.  Nova Acta Leopoldina NF. 1997;  115-120
• 83 Seigler H. F., Buckley C. F., Sheppard L. B.. et al. . Adoptive transfer and specific active immunisation of patients with malignant melanoma.  Ann NY Acad Sci. 1976;  277 522-531
• 84 Shoham J., Hirsch R., Zakay-Rones Z.. et al. . Augmentation of tumor cell immunogenicity by viruses: an approach to specific immunotherapy of cancer.  Nat Immun Cell Growth Regul. 1990;  9 165-172
• 85 Sjögren H. O., Hellström K. E., Bansal S. C.. et al. . Suggestive evidence that the “locking antibodies” of tumor-bearing individuals may be antigen antibody complexes.  Proc Natl Acad Sci USA. 1971;  68 1372-1384
• 86 Springer G. F.. T and Tn, general carcinoma autoantigens.  Science. 1984;  224 1198-1206
• 87 Stoeck M., Marland-Noske C., Manasterski M.. et al. . In vitro expansion and analysis of T lymphocyte microcultures obtained from the vaccination sites of cancer patients undergoing active specific immunization with autologous Newcastle-disease-virus-modified tumor cells.  Cancer Immunol Immunother. 1993;  37 240-244
• 88 Szmuness W., Stevens C. E., Harley E. J.. et al. . Hepatitis B vaccine. Demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States.  N Engl J Med. 1980;  303 833-841
• 89 Tao M. H., Levy R.. Idiotype/granulocyte-macrophage colony-stimulating factor fusion protein as vaccine for B-cell lymphoma.  Nature. 1993;  362 755-758
• 90 Topalian S. L., Rosenberg S. A.. Adoptive cellular therapy: Basic principles. In: DeVita, V.T. jr., Hellman, S., Rosenberg, S.A. (eds.): Biologic Therapy of Cancer J.B. Lippincott Company Philadelphia, New York, London, Hagerstown 1991: 178-196
• 91 Townsend A., Gotsch F., Davey J.. Cytotoxic T cells recognize fragments of the influenza nucleoprotein.  Cell . 1985;  457-467
• 92 Townsend A., Bastian J., Brownlen G.. Cytotoxic T lymphocytes recognize influenza hemagglutinin that lacks a signal sequence.  Nature . 1986;  324 575-577
• 93 Townsend A., Rothbard J., Gotch F.. et al. . .The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides.  Cell. 44 959-968
• 94 Townsend S. E., Allison J. P.. Tumor rejection after direct costimulation of CD8 + T Cells by B7-transfected melanoma cells.  Science . 1993;  259 366-370
• 95 Vitetta E. S., Thorpe P. E.. Antibodies in cancer therapy: Immunotoxins. In: DeVita, V.T. jr., Hellman, S., Rosenberg, S.A. (eds.): Biologic Therapy of Cancer J.B. Lippincott Company Philadelphia, New York, London, Hagerstown 1991: 482-495
• 96 Wallack M. K.. Specific tumor immunity produced by the injection of vaccinia viral oncolysates.  J Surg Res. 1982;  33 11-16
• 97 Wallich R., Bulbuc N., Haemmerling G.. et al. . Abrogation of metastatic properties of tumor cells by de novo expression of H-2K antigens following H-2 gene transfection.  Nature. 1985;  315 301-305
• 98 Wolf M. F., Ludwig A., Fritz P.. et al. . Increased expression of Thomsen-Friedenreich antigens during tumor progression in breast cancer patients.  Tumor Biol. 1988;  9 190-194
• 99 Wolf S. F., Bliss J., van Cleave V.. et al. . Interleukin 12 (IL-12) as vaccine adjuvant promotes T helper (Th) cell type 1 (Th1) and suppresses Th cell type 2 (Th2) immune responses.  Cancer Biother. 1995;  10 81-86
• 100 Yeh M. Y., Hellström I., Hellström K. E.. Clonal variation in expression of a human melanoma antigen defined by a monoclonal antibody.  J Immunol. 1981;  1312-1318
• 101 Zatloukal K., Schmidt W., Cotten M.. et al. . Somatic gene therapy for cancer: the utility of transferinfection in generating tumor vaccines.  Gene. 1993;  135 199-207
• 102 Zhang S., Walberg L. A., Ogata S.. et al. . Immune sera and monoclonal antibodies define low configurations for the sialyl Tn tumor antigen.  Cancer Res. 1995;  55 3364-3368

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