Faculty Bibliography

Melanoma antigen vaccines are a conceptually attractive approach to prevent or delay disease recurrence in patients with surgically resected malignant melanoma. However, the immunogenicity of current vaccines is relatively low. Cyclophosphamide, when given in low doses prior to antigen exposure, is an immunomodulator which has been shown to enhance both humoral and cellular antitumor responses in animals and humans. We conducted a prospective, randomized, clinical trial to study whether pretreatment with cyclophosphamide augments the immunogenicity of a polyvalent, allogeneic, melanoma antigen vaccine in patients with melanoma and low tumor burden. Forty-five patients with resected stage II melanoma (regional metastases) were randomly allocated to treatment with melanoma vaccine or melanoma vaccine plus cyclophosphamide. All patients received the same dose and schedule of vaccine immunizations; those randomized to cyclophosphamide received 300 mg/m2 i.v. 3 days prior to each vaccine immunization. Cellular immune responses were evaluated by delayed-type hypersensitivity (DTH) skin reactivity to a test dose of vaccine at baseline (prior to treatment) and following the fourth immunization. Humoral immune responses were measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiographic analysis of indirect immunoprecipitates of patients' sera at the same time points. Twenty-four patients were randomized to cyclophosphamide pretreatment and 21 to vaccine alone; 22 and 18 patients were evaluable in each group, respectively. Differences were statistically nonsignificant with respect to either cellular (DTH) or humoral (antibody) responses between the two groups. DTH responses were induced in 16 of 22 (73%) and 15 of 18 (83%) patients treated with cyclophosphamide plus vaccine and vaccine alone, respectively. The mean posttreatment augmentation in DTH response in the cyclophosphamide group was 9.5 mm, compared with 9.9 mm in the vaccine-only group. Eight of 12 (66%) cyclophosphamide-pretreated patients and 9 of 12 (75%) vaccine-only patients produced increased titers of antimelanoma antibodies following treatment. No differences were observed between the groups in disease-free or overall survival. In summary, low-dose cyclophosphamide pretreatment failed to augment the immunogenicity of a polyvalent, allogeneic, melanoma vaccine in patients with completely resected early-stage melanoma

The clinical course of 312 consecutive patients after initial presentation with metastatic melanoma, 165 of whom presented with regional metastases at cutaneous or subcutaneous, or both, nodal sites and 147 with metastases at distant sites, was reviewed. The five year survival rate for regional metastases was 43.4 per cent compared with a five year survival rate for distant metastases of 4.9 per cent (p less than 0.0001). Favorable prognostic variables for survival from first regional metastases included primary melanoma sites on the extremities compared with the head, neck and trunk (p = 0.043) and a disease-free interval of more than one year from primary surgical treatment to regional metastases (p = 0.0058). Favorable prognostic variables for survival from the first distant metastasis included a disease-free interval of more than one year from primary surgical treatment to distant metastases (p = 0.0092), the type of resection of metastatic disease (p = 0.00027) and the addition of systemic immunotherapy (p = 0.0011). Forty-nine patients with totally resectable distant metastases had a five year survival rate from the treatment of the initial metastasis of 13.1 per cent, whereas 33 patients having palliative resections had a five year survival rate of 7.5 per cent. All 165 patients who did not have resection for distant metastases died within five years. The results of our experience support therapeutic efforts to ablate both regional and distant metastases of malignant melanoma when feasible

Prior studies with the XMMME-001-RTA immunoconjugate composed of an antimelanoma monoclonal antibody and ricin A chain demonstrated some antitumor activity. However, almost all patients studied developed human antimurine antibodies and antiricin antibodies. In an effort to abrogate these host anti-immunotoxin immune responses and thus enhance antitumor activity, we treated 20 patients with the immunoconjugate plus a single dose of intravenous cyclophosphamide. An overall response rate of 20% was observed-predominantly in pulmonary and soft tissue nodules. There was no diminution in antibody responses against either the murine antibody or the ricin moiety. Further studies to elucidate the role of cyclophosphamide in monoclonal antibody therapy are planned

We report a statistically significant increase in tumor-infiltrating lymphocytes in subcutaneous melanoma metastases removed from patients immunized with a melanoma vaccine. Dense cellular infiltrates were seen in 10 of 11 nodules from vaccine-immunized patients, compared with 9 of 22 nodules from non-immunized patients (p = 0.02). Furthermore, these dense lymphocytic collections more frequently infiltrated the body of tumor nodules from immunized patients, whereas in non-immunized patients, lymphocytes were more often present only in the dermal tissue at the periphery of the nodule. Thus, allogeneic melanoma vaccines may augment immune responses to a patient's own tumor