A conjugate of a tumor-targeting ligand and a T cell costimulatory antibody to treat brain tumors
A conjugate of a tumor-targeting ligand and a T cell costimulatory antibody to treat brain tumors
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DOI：
10.1021/bc049911e
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发表时间：
2004-09-01
影响因子：
4.7
通讯作者：
Roy, EJ
中科院分区：
文献类型：
--
作者：
Gawlick, U;Kranz, DM;Roy, EJ
T细胞免疫疗法是治疗脑肿瘤的潜在策略，因为它提供了高度的特异性，外渗到实体瘤中的能力，以及引发长期保护性免疫应答的潜力。已经开发了各种方法来克服对癌症的T细胞免疫耐受性，包括使用细胞因子和双特异性抗体。用促炎细胞因子IL-12刺激T细胞可以引发抗肿瘤免疫。可以使用针对T细胞表面上的活化分子和肿瘤抗原的双特异性抗体来增加T细胞活化。我们研究了全身性IL-12给药与抗CD 28抗体和叶酸受体配体的缀合物的组合的作用。高亲和力叶酸受体在SV 11小鼠的内源性脉络丛肿瘤上表达，所述SV 11小鼠是在SV 40启动子控制下的大T抗原转基因小鼠。SV 11小鼠具有免疫活性，但对脉络丛肿瘤表达的大T抗原具有免疫耐受性。MRI分析显示，IL-12和抗CD 28 Fab/叶酸的施用显著减缓了肿瘤生长。在治疗动物的脉络丛肿瘤中发现了活化的CD 8（+）T细胞。与单独的IL-12相比，用IL-12 +抗-CD 28 Fab/叶酸盐治疗动物延长存活。细胞因子治疗结合肿瘤靶向共刺激可能是一个有用的辅助治疗。
T cell immunotherapy is a potential strategy for the treatment of brain tumors because it offers a high degree of specificity, the ability to extravasate into solid tumors, and the potential for eliciting a long-term protective immune response. Various approaches have been developed to overcome T cell immune tolerance to cancer, including the use of cytokines and bispecific antibodies. T cell stimulation with the proinflammatory cytokine IL-12 can elicit antitumor immunity. T cell activation can be increased using bispecific antibodies against activating molecules on the surface of T cells and a tumor antigen. We studied the effects of systemic IL-12 administration in combination with a conjugate of an anti-CD28 antibody and a ligand for the folate receptor. The high affinity folate receptor is expressed on endogenously arising choroid plexus tumors of SV11 mice, which are transgenic for large T antigen under the control of the SV40 promoter. SV11 mice are immunocompetent, yet immunologically tolerant to large T antigen expressed by choroid plexus tumors. MRI analysis showed that the administration of IL-12 and anti-CD28 Fab/folate significantly slowed tumor growth. Proliferating CD8(+) T cells were found in choroid plexus tumors of treated animals. Treatment of animals with IL-12 + anti-CD28 Fab/folate prolonged survival compared to IL-12 alone. Cytokine treatment combined with tumor-targeted costimulation may be a useful adjunct treatment.