Oratz R, Dugan M, Roses D F, Harris M N, Speyer J L, Hochster H, Weissman J, Henn M, Bystryn J C
Kaplan Cancer Center, New York University School of Medicine, NY 10016.
Cancer Res. 1991 Jul 15;51(14):3643-7.
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.
黑色素瘤抗原疫苗是一种在概念上颇具吸引力的方法，用于预防或延缓手术切除的恶性黑色素瘤患者疾病复发。然而，目前疫苗的免疫原性相对较低。环磷酰胺在抗原暴露前低剂量给药时，是一种免疫调节剂，已显示出在动物和人类中可增强体液和细胞抗肿瘤反应。我们进行了一项前瞻性、随机临床试验，以研究环磷酰胺预处理是否能增强多价、同种异体黑色素瘤抗原疫苗对肿瘤负荷低的黑色素瘤患者的免疫原性。45例切除的II期黑色素瘤（区域转移）患者被随机分配接受黑色素瘤疫苗或黑色素瘤疫苗加环磷酰胺治疗。所有患者接受相同剂量和方案的疫苗免疫；随机分配接受环磷酰胺治疗的患者在每次疫苗免疫前3天静脉注射300mg/m²。在基线（治疗前）和第四次免疫后，通过对试验剂量疫苗的迟发型超敏反应（DTH）皮肤反应性评估细胞免疫反应。在相同时间点，通过十二烷基硫酸钠-聚丙烯酰胺凝胶电泳和患者血清间接免疫沉淀物的放射自显影分析测量体液免疫反应。24例患者被随机分配接受环磷酰胺预处理，21例仅接受疫苗治疗；每组分别有22例和18例患者可评估。两组之间在细胞（DTH）或体液（抗体）反应方面差异无统计学意义。分别接受环磷酰胺加疫苗和仅接受疫苗治疗的22例患者中的16例（73%）和18例患者中的15例（83%）诱导出DTH反应。环磷酰胺组治疗后DTH反应的平均增加量为9.5mm，而仅疫苗组为9.9mm。12例接受环磷酰胺预处理的患者中有8例（66%）和12例仅接受疫苗治疗的患者中有9例（75%）在治疗后产生了更高滴度的抗黑色素瘤抗体。两组在无病生存期或总生存期方面未观察到差异。总之，低剂量环磷酰胺预处理未能增强完全切除的早期黑色素瘤患者对多价、同种异体黑色素瘤疫苗的免疫原性。
