A Randomized Trial of Adjuvant Chemotherapy and Immunotherapy in Cutaneous Melanoma

Veronesi, Umberto; Adamus, J; Aubert, Carole E.; Bajetta, Emilio; Beretta, G; Bonadonna, G.; Bufalino, Rosaria; Cascinelli, Natale; Cocconi, Giorgio; Durand, Jean Bernard; Marsillac, J. De; Ikonopisov, R. L.; Kiss, Béla; Lejeune, F.; MacKie, Rona M.; Madej, G; Mulder, Hillary; Mechl, Zdeněk; Milton, G. W.; Morabito, Alberto; Peter, Hans; Priario, Julio C; Paul, E.; Rümke, P; Sertoli, R.; Tomin, R

doi:10.1056/nejm198210073071503

Cited by 266 publications

(38 citation statements)

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“…32 Moreover, a number of randomized trials have indicated that BCG is not effective as a postsurgical adjuvant treatment of melanoma. 33 Similarly, the topical application of DNFB that we employed cannot be considered therapeutic. Neither DNFB nor the related compound, DNCB, has systemic antitumor effects; 34 furthermore, 4 of the 6 patients who exhibited partial or complete tumor regression in our study did not receive DNFB before sensitization.…”

Section: Discussionmentioning

confidence: 99%

Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

et al. 2001

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Key words: melanoma; vaccine; immunotherapy; autologous; cyclophosphamideStudies performed and published over the past 30 years have made it clear that immunizing a tumor-bearing patient to his or her own tumor cells is exceedingly difficult. An appealing explanation for this difficulty is that tumor antigens are weakly immunogenic and often induce tolerance, i.e., paralysis of the immune response, rather than effective immunity. 1 Fortunately, advances in basic immunology have disclosed a number of ways of breaking immunologic tolerance. One way is the judicious use of cytotoxic drugs. In 1967, Maguire and Ettore 2 made the surprising discovery that administration of cyclophosphamide to animals prior to an immunization caused the cell-mediated immune response to be augmented rather than suppressed. We have shown that this phenomenon applies to cancer-bearing humans as well. Thus, the administration of low-dose (300 mg/m 2 ) cyclophosphamide prior to an immunization with autologous tumor cells greatly increased the development of cell-mediated immunity to those cells. 3 A second approach to circumventing tolerance is the use of haptens-small molecules that are incapable of inducing an immune response unless they are coupled to a larger molecule. Coupling of a hapten to a protein, i.e., hapten modification, often results in the induction of an immune response to the protein that would otherwise not be possible. For example, Weigle, 4 in a series of now classic experiments, immunized mice with hapten-modified thyroglobulin. This resulted in the induction of an immune response not only to the hapten-modified thyroglobulin, but also to unmodified, i.e., native, thyroglobulin and produced autoimmune thyroiditis. A similar phenomenon was observed more recently by Neurath et al. 5 They found that application of the hapten dinitrophenyl to the colonic mucosa of mice resulted in the development of an autoimmune colitis, similar to human ulcerative colitis. Initially, these mice developed cellular immunity to the haptenmodified mucosa. However, as the chemically modified mucosa cells were shed, a potent immune response to the normal, unmodified mucosa developed, which led to the autoimmune pathology.The immunologic basis of these interesting phenomena is now clear: there are T lymphocytes generated by immunization with hapten-modified cells that are reactive to both modified and unmodified cells. For example, class I MHC-restricted T-cell clones generated from mice immunized with TNP-modified syngeneic lymphocytes respond to MHC-associated, TNP-modified "self" peptides. Furthermore, some TNP-reactive clones respond to certain MHC-binding, unmodified peptides as well. 6 These observations in animal models provide a strong rationale for a human cancer vaccine consisting of autologous tumor cells modified with a hapten, DNP, preceded by the administration of low-dose cyclophosphamide. We have observed that administration of DNP vaccine to patients with metastatic melanoma induces a unique reaction-the development of inflamma...

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Section: Discussionmentioning

confidence: 99%

Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

et al. 2001

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“…Two trials compared dacarbazine versus observation [349,350], one trial compared dacarbazine to placebo [351], and one trial investigated dacarbazine in combination with BCG versus observation [352]. Only one study examined methyl-CCNU [353].…”

Section: Level Of Evidence 1amentioning

confidence: 99%

Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”

Pflugfelder

Kochs

Blum

et al. 2013

J Deutsche Derma Gesell

180

148

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“…The early trials of adjuvant melanoma immunotherapy failed to show prolongation of patient survival (Fisher et al, 1981;Kaiser et al, 1981;Veronesi et al, 1982), but the role of the recombinant IFNs had yet to be tested. All subtypes of IFN have now been explored to prevent melanoma recurrence after disease resection.…”

Section: Does Adjuvant Interferon Offer Survival Benefit?mentioning

confidence: 99%