Lindsey Kimberly R, Gritz Linda, Sherry Richard, Abati Andrea, Fetsch Patricia A, Goldfeder Lisa C, Gonzales Monica I, Zinnack Kimberly A, Rogers-Freezer Linda, Haworth Leah, Mavroukakis Sharon A, White Donald E, Steinberg Seth M, Restifo Nicholas P, Panicali Dennis L, Rosenberg Steven A, Topalian Suzanne L
Surgery Branch, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland, USA.
Clin Cancer Res. 2006 Apr 15;12(8):2526-37. doi: 10.1158/1078-0432.CCR-05-2061.
Two clinical trials were conducted to evaluate the clinical efficacy and immunologic impact of vaccination against the tyrosinase protein plus systemic interleukin 2 (IL-2) administration in patients with advanced metastatic melanoma.
Full-length tyrosinase was employed as an immunogen to induce diverse immunologic responses against a commonly expressed melanoma antigen. Heterologous prime/boost vaccination with recombinant vaccinia and fowlpox vectors encoding tyrosinase was first explored in a randomized three-arm phase II trial, in which vaccines were administered alone or concurrently with low-dose or high-dose IL-2. In a subsequent single cohort phase II trial, all patients received the same vaccines and high-dose IL-2 sequentially rather than concurrently.
Among a total of 64 patients treated on these trials, 8 objective partial responses (12.5%) were observed, all in patients receiving high-dose IL-2. Additional patients showed evidence of lesional regression (mixed tumor response) or overall regression that did not achieve partial response status (minor response). In vitro evidence of enhanced immunity against tyrosinase following protocol treatments was documented in 3 of 49 (6%) patients tested serologically, 3 of 23 (13%) patients tested for T-cell recognition of individual tyrosinase peptides, and 4 of 16 (25%) patients tested for T-cell recognition of full-length tyrosinase protein with real-time reverse transcription-PCR techniques.
Whereas prime/boost immunization with recombinant vaccinia and fowlpox viruses enhanced antityrosinase immunity in some patients with metastatic melanoma, it was ineffective alone in mediating clinical benefit, and in combination with IL-2 did not mediate clinical benefit significantly different from that expected from treatment with IL-2 alone.
开展两项临床试验，以评估针对酪氨酸酶蛋白接种疫苗并全身性给予白细胞介素2（IL-2）对晚期转移性黑色素瘤患者的临床疗效和免疫影响。
全长酪氨酸酶被用作免疫原，以诱导针对一种常见表达的黑色素瘤抗原的多种免疫反应。在一项随机三臂II期试验中，首先探索了用编码酪氨酸酶的重组痘苗病毒和禽痘病毒进行异源初免/加强免疫接种，在该试验中，疫苗单独给药或与低剂量或高剂量IL-2同时给药。在随后的单队列II期试验中，所有患者依次而非同时接受相同的疫苗和高剂量IL-2。
在这些试验中总共治疗的64例患者中，观察到8例客观部分缓解（12.5%），均在接受高剂量IL-2的患者中。其他患者显示有病灶消退（混合肿瘤反应）或总体消退的证据，但未达到部分缓解状态（微小反应）。在49例接受血清学检测的患者中有3例（6%）、23例接受个体酪氨酸酶肽T细胞识别检测的患者中有3例（13%）以及16例接受全长酪氨酸酶蛋白T细胞识别实时逆转录-PCR技术检测的患者中有4例（25%）记录到方案治疗后针对酪氨酸酶的免疫增强的体外证据。
虽然用重组痘苗病毒和禽痘病毒进行初免/加强免疫在一些转移性黑色素瘤患者中增强了抗酪氨酸酶免疫，但单独使用时在介导临床获益方面无效，并且与IL-2联合使用时介导的临床获益与单独使用IL-2治疗预期的获益没有显著差异。
