Cancer Vaccine Development Program, United States Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
Cancer. 2010 Jan 15;116(2):292-301. doi: 10.1002/cncr.24756.
HER-2/neu, overexpressed in breast cancer, is a source of immunogenic peptides that include GP2 and E75. Phase 2 testing of E75 as an adjuvant vaccine has suggested a clinical benefit. GP2, derived from the transmembrane portion of HER-2/neu, has differing binding characteristics and may be more immunogenic than E75. Results of the first phase 1 trial of GP2 peptide vaccine are presented.
Disease-free, lymph node-negative, human leukocyte antigen (HLA)-A2(+) breast cancer patients were enrolled. This dose escalation trial included 4 groups to determine safety and optimal GP2 peptide/granulocyte-macrophage colony-stimulating factor (GM-CSF) dose. Toxicities were monitored. Immunologic response was assessed ex vivo via the HLA-A2:immunoglobulin dimer assay to detect GP2-specific CD8(+) T cells (and E75-specific CD8(+) T cells to assess epitope spreading) and in vivo via delayed type hypersensitivity (DTH) reaction (medians/ranges).
Eighteen patients were enrolled. All toxicities were grade < or =2. Eight (88.9%) of 9 patients in the first 3 dose groups required GM-CSF dose reductions for local reactions > or =100 mm or grade > or =2 systemic toxicity. GM-CSF dose was reduced to 125 microg for the final dose group. All patients responded immunologically ex vivo (GP2-specific CD8(+) T cells from prevaccination to maximum, 0.4% [0.0%-2.0%] to 1.1% [0.4%-3.6%], P < .001) and in vivo (GP2 pre- to postvaccination DTH, 0 mm [0.0-19.5 mm] to 27.5 mm [0.0-114.5 mm, P < .001). E75-specific CD8(+) T cells also increased in response to GP2 from prevaccination to maximum (0.8% [0.0%-2.41%] to 1.6% [0.86%-3.72%], P < .001).
The GP2 peptide vaccine appears safe and well tolerated with minimal local/systemic toxicity. GP2 elicited HER-2/neu-specific immune responses, including epitope spreading, in high-risk, lymph node-negative breast cancer patients. These findings support further investigation of the GP2 vaccine for the prevention of breast cancer recurrence.
HER-2/neu 在乳腺癌中过表达，是免疫原性肽的来源，包括 GP2 和 E75。E75 作为佐剂疫苗的 2 期试验表明具有临床益处。GP2 来源于 HER-2/neu 的跨膜部分，具有不同的结合特性，可能比 E75 更具免疫原性。本文呈现了 GP2 肽疫苗的首次 1 期临床试验结果。
招募了无病、淋巴结阴性、人类白细胞抗原 (HLA)-A2(+)乳腺癌患者。该剂量递增试验包括 4 个组，以确定 GP2 肽/粒细胞-巨噬细胞集落刺激因子 (GM-CSF)的安全性和最佳剂量。监测毒性。通过 HLA-A2：免疫球蛋白二聚体测定体外评估免疫反应，以检测 GP2 特异性 CD8(+)T 细胞（和 E75 特异性 CD8(+)T 细胞以评估表位扩展）和体内通过迟发型超敏反应 (DTH)反应（中位数/范围）。
共纳入 18 例患者。所有毒性均为<或=2 级。前 3 个剂量组的 9 例患者中，有 8 例（88.9%）因局部反应>或=100mm 或>或=2 级全身毒性需要 GM-CSF 剂量减少。GM-CSF 剂量减少至最后一组的 125μg。所有患者均在体外（从接种前到最大的 GP2 特异性 CD8(+)T 细胞，0.4%[0.0%-2.0%]至 1.1%[0.4%-3.6%]，P<0.001）和体内（GP2 接种前至接种后的 DTH，0mm[0.0-19.5mm]至 27.5mm[0.0-114.5mm]，P<0.001）对 GP2 作出免疫反应。E75 特异性 CD8(+)T 细胞也随着 GP2 的增加而增加，从接种前到最大（0.8%[0.0%-2.41%]至 1.6%[0.86%-3.72%]，P<0.001）。
GP2 肽疫苗似乎安全且耐受良好，局部/全身毒性最小。GP2 在高危、淋巴结阴性乳腺癌患者中引起了 HER-2/neu 特异性免疫反应，包括表位扩展。这些发现支持进一步研究 GP2 疫苗预防乳腺癌复发。
