Marshall J L, Hoyer R J, Toomey M A, Faraguna K, Chang P, Richmond E, Pedicano J E, Gehan E, Peck R A, Arlen P, Tsang K Y, Schlom J
Georgetown University Medical Center, Vincent T. Lombardi Cancer Center, Washington, DC 20007, USA.
J Clin Oncol. 2000 Dec 1;18(23):3964-73. doi: 10.1200/JCO.2000.18.23.3964.
This trial sought to determine, for the first time, the validity in human vaccinations of using two different recombinant vaccines in diversified prime-and-boost regimens to enhance T-cell responses to a tumor antigen.
Eighteen patients with advanced tumors expressing carcinoembryonic antigen (CEA) were randomized to receive either recombinant vaccinia (rV)-CEA followed by three avipox-CEA vaccinations, or avipox-CEA (three times) followed by one rV-CEA vaccination. Subsequent vaccinations in both cohorts were with avipox-CEA. Immunologic monitoring was performed using a CEA peptide and the enzyme-linked immunospot assay for interferon gamma production.
rV-CEA followed by avipox-CEA was superior to the reverse order in the generation of CEA-specific T-cell responses. Further increases in CEA-specific T-cell precursors were seen when local granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose interleukin (IL)-2 were given with subsequent vaccinations. The treatment was extremely well tolerated. Limited clinical activity was seen using vaccines alone in this patient population. Antibody production against CEA was also observed in some of the treated patients.
rV-CEA was more effective in its role as a primer of the immune system; avipox-CEA could be given up to eight times with continued increases in CEA T-cell precursors. Future trials should use rV-CEA first followed by avipox-CEA. Vaccines specific to CEA are able to generate CEA-specific T-cell responses in patients without significant toxicity. T-cell responses using vaccines alone may be inadequate to generate significant anticancer objective responses in patients with advanced disease. Cytokines such as GM-CSF and IL-2 may play a key role in generating such responses.
本试验首次试图确定，在人类疫苗接种中，使用两种不同的重组疫苗进行多样化的初免 - 加强免疫方案，以增强对肿瘤抗原的T细胞反应的有效性。
18例表达癌胚抗原（CEA）的晚期肿瘤患者被随机分为两组，一组先接受重组痘苗病毒（rV）-CEA疫苗接种，随后进行三次禽痘病毒 - CEA疫苗接种；另一组先进行三次禽痘病毒 - CEA疫苗接种，随后进行一次rV-CEA疫苗接种。两组后续均接种禽痘病毒 - CEA疫苗。使用CEA肽和酶联免疫斑点试验检测干扰素γ的产生，进行免疫监测。
rV-CEA疫苗接种后再接种禽痘病毒 - CEA疫苗，在产生CEA特异性T细胞反应方面优于相反顺序。当在后续接种疫苗时给予局部粒细胞 - 巨噬细胞集落刺激因子（GM-CSF）和低剂量白细胞介素（IL）-2时，CEA特异性T细胞前体进一步增加。该治疗耐受性极佳。在该患者群体中，单独使用疫苗时观察到有限的临床活性。在一些接受治疗的患者中也观察到了针对CEA的抗体产生。
rV-CEA作为免疫系统的启动剂更有效；禽痘病毒 - CEA可接种多达八次，CEA T细胞前体持续增加。未来的试验应先使用rV-CEA，然后接种禽痘病毒 - CEA。CEA特异性疫苗能够在患者中产生CEA特异性T细胞反应，且无明显毒性。对于晚期疾病患者，单独使用疫苗产生的T细胞反应可能不足以产生显著的抗癌客观反应。GM-CSF和IL-2等细胞因子可能在产生此类反应中起关键作用。
