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Immunotherapy with monoclonal antibodies in metastatic melanoma

  • World Progress In Surgery
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Abstract

Therapy for metastatic melanoma has been disappointing to date. Treatment with chemotherapy only uncommonly results in complete responses and rarely results in long-term survivors. The identification of human melanoma cell surface antigens has led to the development of an array of mouse monoclonal antibodies (MAb) for use in the diagnosis and therapy of patients with metastatic melanoma. Strategies utilizing MAbs based on immunologic approaches have been developed. Naked MAbs directed against glycoprotein surface antigens or conjugated to toxins or radionuclides have shown little biologic or clinical activity. However, phase I studies of MAb directed against glycolipid antigens have yielded objective tumor shrinkage with occasional complete responses. Severe toxicity has been seen infrequently. Possible anti-tumor mechanisms include complement activation and antibody-dependent cellular cytotoxicity utilizing natural killer cells or monocytes as effector cells. Strategies to enhance the anti-tumor effects of MAb, including combinations with cytotoxic agents and cytokines, have been introduced with limited success thus far. The development of a human IgG anti-mouse antibody has been seen in nearly all treated patients. A new generation of MAb engineered to overcome the immunogenicity of mouse MAb and to enhance immune effector function will soon enter clinical trials.

Résumé

Le traitement du mélanome métastasé s'est avéré décevant jusqu'à ce jour. Le traitement par chimiothérapie permet dans de rares cas seulement une réponse complète et d'exceptionnels survivants à long terme. La mise en évidence d'antigène de surface au niveau des cellules de mélanomes humains a permis de développer d'un éventail d'anticorps monoclonaux de souris (Mab). Ces anticorps monoclonaux sont utilisés dans un but diagnostique ou thérapeutique dans le mélanome métastasé. Des stratégies utilisant les anticorps monoclonaux de souris et reposant sur des bases immunologiques ont été développées. Des anticorps Mab dirigés contre des antigènes glycoprotéiques de surface, seuls ou conjugués à des toxines ou même à des éléments radioactifs semblent avoir une faible activité biologique ou clinique. Des essais de phase I utilisant des anticorps Mab dirigés contre des antigènes glycolipidiques montrent une diminution objective de la taille tumorale avec quelques réponses complètes occasionnelles. Une toxicité sévère a été observé de façon rare. Les mécanismes possibles de l'action antitumorale associent l'activation du complément, la cytotoxicité cellulaire médiée par les anticorps, les cellules effectrices étant les cellules tueuses naturelles (natural Killer) et les monocytes. Les stratégies qui favorisent l'effet antitumoral des anticorps Mab, comprenant des combinaisons d'agents cytotoxiques et des cytokines, ont été essayées avec des succès limités jusque là. L'apparition d'une IgG humaine anticorps de souris a été recontrée chez presque tous les patients traités. Une nouvelle génération d'anticorps Mab préparés de manière à maîtriser l'immunogenicité de l'anticorps de souris et à favoriser l'action immunologique doivent prochainement être testés dans des essais cliniques.

Resumen

El tratamiento del melanoma metastásico ha sido poco halagador hasta la fecha; la quimioterapia resulta apenas en raras respuesta completas y pocos sobrevivientes a largo plazo. La identificación de los antígenos de superficie de la célula de melanoma ha llevado al desarrollo de una variedad de anticuerpos monoclonales de ratón (AcR) para uso en el diagnóstico, y se han desarrollado estrategias para el uso de AcsR en aproches inmunológicos. Los AcsR dirigidos contra los antígenos glicoproteicos de superficie o conjugados con toxinas o radionúclidos han demostrado mínima actividad biológica o clínica. Sin embargo, estudios de fase I de AcR dirigido contra antígenos glicolípidos han señalado disminución objetiva del tamaño del tumor con ocasionales respuestas completas. La toxicidad severa ha sido infrecuente. Posibles mecanismos antitumorales incluyen la activación del complemento y la citotoxicidad celular anticuerpo-dependiente utilizando células asesinas naturales o monocitos como las células efectoras. Se han introducido, con éxito limitado hasta ahora, estrategias para incrementar el efecto antitumoral del AcR, incluyendo la combinación de agentes citotóxicos y de citocinas. El desarrollo de una Ig anti-anticuerpo de ratón ha sido observado en casi todos los pacientes tratados. Una nueva generación de AcsR estructurados para sobrepasar la inmunogenicidad del AcR y para estimular la función efectora inmune habrá de ser ingresada pronto a los ensayos clínicos.

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  1. Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, 10021, New York, New York, USA

    Thomas A. Steffens M.D., Dean F. Bajorin M.D. & Alan N. Houghton M.D.

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  1. Thomas A. Steffens M.D.
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  2. Dean F. Bajorin M.D.
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Steffens, T.A., Bajorin, D.F. & Houghton, A.N. Immunotherapy with monoclonal antibodies in metastatic melanoma. World J. Surg. 16, 261–269 (1992). https://doi.org/10.1007/BF02071530

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