Sonya Valley Ghidossi Vaccine Laboratory of the Roy E. Coats Research Laboratories of the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA.
Clin Cancer Res. 2009 Nov 15;15(22):7029-35. doi: 10.1158/1078-0432.CCR-09-1540. Epub 2009 Nov 10.
The availability of a variety of immune response modifiers creates an opportunity for improved efficacy of immunotherapy, but it also leads to uncertainty in how to combine agents and how to assess those combinations. We sought to assess the effect of the addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) to vaccination with a melanoma vaccine.
Ninety-seven patients with resected melanoma (stage II-IV) were enrolled, stratified by stage, and randomized to receive a cellular melanoma vaccine with or without GM-CSF. The primary endpoint was delayed-type hypersensitivity (DTH) response to melanoma cells. Antibody responses, peripheral leukocyte counts, and survival were also examined.
The GM-CSF arm showed enhanced antibody responses with an increase in IgM titer against the TA90 antigen and increased TA90 immune complexes. This arm also had diminished antimelanoma cell delayed-type hypersensitivity response. Peripheral blood leukocyte profiles showed increases in eosinophils and basophils with decreased monocytes in the GM-CSF arm. These immune changes were accompanied by an increase in early melanoma deaths and a trend toward worse survival with GM-CSF.
These data suggest that GM-CSF is not helpful as an immune adjuvant in this dose and schedule and raise concern that it may be harmful. Based on the discordant findings of an immune endpoint and clinical outcome, the use of such surrogate endpoints in selecting treatments for further evaluation must be done with a great deal of caution.
各种免疫反应调节剂的出现为提高免疫疗法的疗效提供了机会，但也导致了如何联合使用这些药物以及如何评估这些联合用药的不确定性。我们旨在评估粒细胞/巨噬细胞集落刺激因子（GM-CSF）联合黑色素瘤疫苗接种对疗效的影响。
招募了 97 名接受过黑色素瘤切除术（II-IV 期）的患者，按分期分层，并随机分配接受含有或不含有 GM-CSF 的细胞黑色素瘤疫苗。主要终点是对黑色素瘤细胞的迟发型超敏反应（DTH）。还检查了抗体反应、外周白细胞计数和生存情况。
GM-CSF 组显示出增强的抗体反应，TA90 抗原的 IgM 滴度增加，TA90 免疫复合物增加。该组对黑色素瘤细胞的迟发型超敏反应也减弱。外周血白细胞谱显示 GM-CSF 组的嗜酸性粒细胞和嗜碱性粒细胞增加，单核细胞减少。这些免疫变化伴随着早期黑色素瘤死亡增加和 GM-CSF 组生存趋势恶化。
这些数据表明，GM-CSF 作为这种剂量和方案的免疫佐剂没有帮助，并引起人们对其可能有害的担忧。基于免疫终点和临床结果的不一致发现，在选择进一步评估的治疗方法时，必须非常谨慎地使用这些替代终点。
