Skip to main content
SpringerLink
Log in

Immunotoxin therapy of malignant melanoma

  • Immunoglobulins
  • Published:
Medical Oncology and Tumor Pharmacotherapy Aims and scope Submit manuscript

Abstract

Current standard therapies for metastatic malignant melanoma are poor, and surgical excision of disease remains the cornerstone of melanoma management. Unmodified monoclonal antibodies have been used therapeutically in this, and other, malignancies, but results have been disappointing. This has led to attempts to improve the efficacy of monoclonal antibodies by using them to target therapeutic modalities to tumors. These therapeutic modalities include chemotherapeutic, radiotherapeutic and cytotoxic agents. An example of the latter is ricin A-chain, which is so potent that it has been reported that one molecule of it entering the cytosol is sufficient to cause cell death. Preclinical studies support the potential of immunotoxins as effective therapy for malignancy. A phase I–II trial of immunotoxin therapy of malignant melanoma has been completed and a trial to determine clinical efficacy has been implemented.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Silverberg E: Cancer statistics.Cancer 34, 6 (1984).

    Google Scholar 

  2. Jensen O M, Bolander A M: Trends in malignant melanoma of the skin.World Health Statistics Quarterly 33, 2 (1980).

    CAS  Google Scholar 

  3. Silverberg E: Cancer in young adults (ages 15 to 34).Cancer 33, 32 (1982).

    Google Scholar 

  4. Moseley H S, Eilber F R, Morton D L: Melanoma, in Haskell C M (ed):Cancer Treatment, pp. 678–694. Philadelphia, W. B. Saunders (1980).

    Google Scholar 

  5. Luce J K: Chemotherapy of melanoma.Seminars in Oncology 2, 179 (1975).

    PubMed  CAS  Google Scholar 

  6. Seigler H F, Lucas V S, Pickett N J, Huang A T: DTIC, CCNU, bleomycin and vincristine (BOLD) in metastatic melanoma.Cancer 46, 2346 (1980).

    Article  PubMed  CAS  Google Scholar 

  7. Nathanson L, Kaufman S D, Carey R W: Vinblastine, infusion, bleomycin andcis-dichlorodiammine-platinum chemotherapy in metastatic melanoma.Cancer 48, 1290 (1981).

    Article  PubMed  CAS  Google Scholar 

  8. Hill G J, Moss S E, Golomb F M, Grage T B, Fletcher W S, Minton J P, Krementz E T: DTIC and combination therapy for melanoma: II DTIC (NSC 45388) Surgical Adjuvant Study Co (7) Protocol 7040.Cancer 47, 2556 (1981).

    Article  PubMed  Google Scholar 

  9. Balch C, Murray D, Presant G, Bartolucci A A: Ineffectiveness of adjuvant chemotherapy using DTIC and cyclophosphamide in patients with resectable metastatic melanoma.Surgery II, 454 (1984).

    Google Scholar 

  10. Pinsky C M, Hirshaut Y, Wanebo H J, Fortner J G, Mike V, Schottenfeld D, Oettgen H F: Randomized trial of bacillus Calmet-Guérin (percutaneous administration) as surgical adjuvant immunotherapy for patients with Stage II melanoma.Ann NY Acad Sci 277, 187 (1976).

    Article  PubMed  CAS  Google Scholar 

  11. Cunningham T J, Schoenfeld D, Nathanson L, Wolter J, Patterson W B, Cohen M H: A controlled study of adjuvant therapy in patients with stage I and II malignant melanoma, in Terry W D, Windhorst D (eds):Immunotherapy of Cancer: Present Status of Trials in Man, pp. 19–26. New York, Raven Press (1978).

    Google Scholar 

  12. Morton D L, Holmes E C, Eilber F R, Sparks F C, Ramming K P: Adjuvant immunotherapy of malignant melanoma: preliminary results of a randomized trial in patients with lymph node metastases, in Terry W D, Windhorst D (eds):Immunotherapy of Cancer: Present Status of Trials in Man, pp. 57–64. New York, Raven Press (1978).

    Google Scholar 

  13. Spitler L E, Sagebiel R: A randomized trial of levamisole versus placebo as adjuvant therapy in malignant melanoma.New Engl J Med 303, 1143 (1980).

    PubMed  CAS  Google Scholar 

  14. Bukowski R M, Deodhar S, Hewlett J S, Greenstreet R: Randomized controlled trial of transfer factor in stage II malignant melanoma.Cancer 51, 269 (1983).

    Article  PubMed  CAS  Google Scholar 

  15. Hilaris B S, Rabin M, Calabrese A S, Phillips R F, Herschkeuk U K: Value of radiation therapy for distant metastasis for malignant melanoma.Cancer 16, 765 (1963).

    Article  PubMed  CAS  Google Scholar 

  16. Gottlieb J A, Frei E, Luce J K: An evaluation of the management of patients with cerebral metastases from malignant melanoma.Cancer 29, 701 (1972).

    Article  PubMed  CAS  Google Scholar 

  17. Feun L G, Burgess M A, Hersh E M, Benjamin R S, Gehan E A, Murphy W K: The natural history of Stage IV-A melanoma.Proc Am Ass Cancer Res/Am Soc Clin Oncol (ASCO abstract)22, C372 (1981).

    Google Scholar 

  18. Nadler L M, Stashenko P, Hardy R, Kaplan W D, Button L M, Kufe D W, Antman K H, Schlossman S F: Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma associated antigen.Cancer Res 40, 3147 (1980).

    PubMed  CAS  Google Scholar 

  19. Miller R A, Oseroff A R, Stratte P T, Levy R: Monoclonal antibody therapeutic trials in seven patients with T-cell lymphoma.Blood 62, 988 (1983).

    PubMed  CAS  Google Scholar 

  20. Miller R A, Maloney D G, Warnke R, Levy R: Treatment of B cell lymphoma with monoclonal anti-idiotype antibody.New Engl J Med 306, 517 (1982).

    PubMed  CAS  Google Scholar 

  21. Ritz J, Pesando J M, Sallan S E, Clavell L A, Notis-McConarty J, Rosenthal P, Schlossman S F: Serotherapy of acute lymphoblastic leukemia with monoclonal antibody.Blood 58, 141 (1981).

    PubMed  CAS  Google Scholar 

  22. Dillman R O, Shawler D L, Sobol R E, Collins H A, Beauregard J C, Wormsley S B, Royston I: Murine monoclonal antibody therapy in two patients with chronic lymphocytic leukemia.Blood 59, 1036 (1982).

    PubMed  CAS  Google Scholar 

  23. Sears H F, Mattis J, Herlyn D, Hayry P, Atkinson B, Ernst C, Steplewski Z, Koprowski H: Phase I clinical trial of monoclonal antibody in treatment of gastro-intestinal tumours.Lancet i, 762 (1982).

    Article  Google Scholar 

  24. Lemkin S, Tokita K, Sherman G, Simko T, Schwartz L, Ciccirilli J, Drew S, Terasaki P: Phase I–II study of monoclonal antibodies in gastrointestinal cancer.ASCO Abstracts, C181 (1984).

  25. Remlinger K, Martin P J, Harper J A, Doney D C, Smith A, Deeg H J, Sullivan K, Storb R, Thomas E D: Murine monoclonal anti-T cell antibodies for treatment of steroid-resistant acute graft-versus-host disease.Hum Immun 9, 21 (1984).

    Article  PubMed  CAS  Google Scholar 

  26. Cosimi A B, Colvin R B, Burton R C, Rubin R H, Goldstein G, Kung P C, Hansen W P, Delmonico F L, Russell P S: Use of monoclonal antibodies to T-cell subsets for immunologic monitoring and treatment in recipients of renal allografts.New Engl J Med 305, 308 (1981).

    PubMed  CAS  Google Scholar 

  27. Oldham R, Woodhouse C, Schroff R, Abrams P, Fer M, Kimball E, Foon K, Morgan A C: Monoclonal antibody therapy of malignant melanoma:in vivo localization in cutaneous metastasis after intravenous administration.ASCO Abstracts, C251 (1984).

  28. Sobol R E, Dillman R O, Smith J D, Imai K, Ferrone S, Shawler D, Glassy M, Royston I: Phase I evaluation of murine monoclonal antimelanoma antibody in man: preliminary observations, in Mitchell M S, Oettgen H F (eds):Hybridomas in Cancer Diagnosis and Treatment, New York, Raven Press (1982).

    Google Scholar 

  29. Goodman G E, Baumier P, Hellstrom I, Hellstrom K E: Phase I trial of two murine monoclonal antibodies in human melanoma.ASCO Abstracts, C262 (1984).

  30. Larson S M, Carrasquillo J A, Krohn KA, Brown J P, McGuffin R W, Ferens J M, Graham M M, Hill L D, Beaumier P L, Hellström K E, Hellström I: Localization of131I-labeled p97-specific Fab fragments in human melanoma as a basis for radiotherapy.J Clin Invest 72, 2101 (1983).

    Article  PubMed  CAS  Google Scholar 

  31. Houghton A N, Mintzer D, Cordon-Cardo C, Welt S, Fliegel B, Vadhan S, Carswell E, Melamed M R, Oettgan H F, Old L J: Mouse monoclonal IgG3 antibody detecting GD3 ganglioside: a phase I trial in patients with malignant melanoma.Proc Natl Acad Sci, USA 82, 1242 (1985).

    Article  PubMed  CAS  Google Scholar 

  32. Ritz J, Schlossman S F: Utilization of monoclonal antibodies in the treatment of leukemia and lymphoma.Blood 59, 1 (1982).

    PubMed  CAS  Google Scholar 

  33. Rudiger H: Lectins, an introduction, in Bog-Hansen T C (ed):Lectins: Biology, Biochemistry, Clinical Biochemistry, Vol. 1. New York, Walter de Gruyter (1981).

    Google Scholar 

  34. Franz H, Ziska P: Affinitins: combining sites containing proteins, in Bog-Hansen TC (ed):Lectins: Biology, Biochemistry, Clinical Biochemistry, Vol. 1. New York, Walter de Gruyter (1981).

    Google Scholar 

  35. Olsnes S, Pihl A: Toxic lectins and related proteins, in Cohen P and Van Heynigen S (eds):Molecular Action of Toxins and Viruses. Amsterdam, Elsevier Biomedical Press (1982).

    Google Scholar 

  36. Fodstad O, Johannessen J V, Schjerven L, Pihl A: Toxicity of abrin and ricin in mice and dogs.J Toxic Envir Hlth 5, 1073 (1977).

    Article  Google Scholar 

  37. Vitetta E S, Krolick K A, Miyama-Inaba M, Cushley W, Uhr J W: Immunotoxins: a new approach to cancer therapy.Science 219, 644 (1983).

    Article  PubMed  CAS  Google Scholar 

  38. Lin J Y, Tserna K Y, Chan C C, Lin L T, Tung T C: Abrin and ricin: new antitumor substances.Nature 227, 292 (1970).

    Article  PubMed  CAS  Google Scholar 

  39. Tung T C, Hsu C T, Lin J W: Therepeutic effect of abrin and ricin on human cancers.J Formosan Med Ass 70, 41 (1971).

    Google Scholar 

  40. Fodstad O, Olsnes S, Pihl A: Inhibitory effect of abrin, ricin on the growth of transplantable murine tumors and of abrin on human cancers in nude mice.Cancer Res 37, 4559 (1977).

    PubMed  CAS  Google Scholar 

  41. Fodstad O, Kvalheim G, Godal A, Lotsberg J, Aamdal S, Host H, Pihl A: Phase I study of the plant protein ricin.Cancer Res 44, 862 (1984).

    PubMed  CAS  Google Scholar 

  42. Fodstad O, Pilh A: Synergistic effect of ricin in combination with daunorubicin,cis-dichlorodiammine-platinum(II) and vincristine in systemic L1210 leukemia.Cancer Res 42, 2152 (1982).

    PubMed  CAS  Google Scholar 

  43. Gilliland D G, Steplewski Z, Collier R J, Mitchell K F, Chang T H, Koprowski H: Antibody directed cytotoxic agents: use of monoclonal antibody to direct the action of toxin A chains to colorectal carcinoma cells.Proc Natl Acad Sci, USA 77, 4539 (1980).

    Article  PubMed  CAS  Google Scholar 

  44. Trowbridge I S, Domingo D L: Anti-transferrin receptor monoclonal antibody and toxin-antibody conjugates affect growth of human tumor cells.Nature (Lond) 294, 171 (1981).

    Article  CAS  Google Scholar 

  45. Seon B K: Specific killing of human T leukemia cell by immunotoxins prepared with ricin A chain and monoclonal antihuman T-cell leukemia antibodies.Cancer Res 44, 259 (1984).

    PubMed  CAS  Google Scholar 

  46. Krolick K A, Villemez C, Isakson P, Uhr J W, Vitetta E S: Selective killing of normal or neoplastic B cells by antibodies coupled to the A chain of ricin.Proc Natl Acad Sci, USA 77, 5419 (1980).

    Article  PubMed  CAS  Google Scholar 

  47. Krolick K A, Yuan D, Vitetta E S: Specific killing of a human breast carcinoma cell line by a monoclonal antibody to the A chain of ricin.J Immun Immunother 12, 39 (1981).

    Google Scholar 

  48. Blythman H E, Casellas P, Gros O, Gros P, Jansen F K, Paolucci F, Pau B, Vidal H: Immunotoxins: hybrid molecules of monoclonal antibodies and toxin subunit specifically kill tumor cells.Nature 290, 145 (1981).

    Article  PubMed  CAS  Google Scholar 

  49. Youle R J, Neville D M Jr: Kinetics of protein synthesis inactivation by ricin A anti-thy 1.1 monoclonal antibody hybrids.J Biol Chem 257, 1598 (1982).

    PubMed  CAS  Google Scholar 

  50. Raso V, Ritz J, Basola M, Schlossman S F: Monoclonal antibody-ricin A chain conjugate selectively cytotoxic for cells bearing the common acute lymphoblastic leukemia antigen.Cancer Res 42, 457 (1982).

    PubMed  CAS  Google Scholar 

  51. Ramakrishnan S, Houston L L: Prevention of growth of leukemia cells in mice by monoclonal antibodies directed against Thy 1.1 antigen disulfide linked to two ribosomal inhibitors: pokeweed antiviral protein or ricin A chain.Cancer Res 44, 1398 (1984).

    PubMed  CAS  Google Scholar 

  52. Seto M, Umemoto N, Saito M, Masuho Y, Hara T, Takahashi T: Monoclonal anti-MN46 antibody: ricin A chain conjugate:in vivo andin vitro antitumor activity.Cancer Res 42, 5209 (1982).

    PubMed  CAS  Google Scholar 

  53. Kishida K, Masuho Y, Saito M, Hara T, Fuji H: Ricin A chain conjugated with monoclona anti-L1210 antibody.In vitro andin vivo antitumor activity.Cancer Immun Immunother 16, 93 (1983).

    CAS  Google Scholar 

  54. Bernhard M I, Foon K A, Oeltmann T N, Key M E, Hwang K M, Clarke G C, Christensen W L, Hoyer L C, Hanna M G, Oldham R K: Guinea pig line 10 hepatocarcinoma model: characterization of monoclonal antibody andin vivo effect of unconjugated antibody and antibody conjugated to diphtheria toxin A chain.Cancer Res 43, 4420 (1983).

    PubMed  CAS  Google Scholar 

  55. Krolick K A, Uhr J W, Slavia S, Vitetta E S:In vivo therapy of a murine B cell tumor (BCL1) using antibody-ricin A chain immunotoxins.J Exp Med 155, 1797 (1982).

    Article  PubMed  CAS  Google Scholar 

  56. Spitler L E: Phase I clinical trials with immunotoxins, in Vogel C W (ed.):Immunoconjugates: Antibody Conjugates in Radioimaging and Therapy of Cancer. New York, Oxford University Press (in press).

  57. Spitler L S, del Rio M, Khentigan A, Wedel W I, Brophy N A, Miller L L, Harkonen W S, Rosendorf L L, Lee H M, Mischak R P, Kawahata R T, Stoudemire J B, Fradkin L B, Bautista E E, Scannon P J: Therapy of patients with malignant melanoma using a monoclonal antimelanoma antibody-ricin A chain immunotoxin.Cancer Res (in press).

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Children's Hospital, San Francisco and XOMA Corporation, 2910 Seventh Street, 94710, Berkeley, CA, U.S.A.

    Lynn E. Spitler

Authors
  1. Lynn E. Spitler
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spitler, L.E. Immunotoxin therapy of malignant melanoma. Med. Oncol. & Tumor Pharmacother. 3, 147–152 (1986). https://doi.org/10.1007/BF02934990

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02934990

Key words

Search

Navigation