Development of TGF-beta antagonists for cancer therapy

尽管转化生长因子-β作为肿瘤抑制因子和肿瘤促进剂在肿瘤发生中的双重作用，我们实验室和其他人的临床前数据已经表明，拮抗转化生长因子-β的策略可能选择性地减少这种生长因子的不良促癌作用，同时避免对肿瘤抑制和正常体内平衡的预期作用。基于这些有希望的临床前研究结果，一种抗转化生长因子-β抗体正处于治疗晚期癌症的早期临床试验阶段。然而，考虑到转化生长因子-β的复杂生物学，成功开发用于癌症治疗的转化生长因子-β拮抗剂将取决于对这些药物如何发挥作用的清楚了解，以及如何选择将从这种治疗中受益的患者的相关问题。在2008财年，我们在理解抗转化生长因子-β抗体在抑制肿瘤进展和转移方面的作用机制方面取得了实质性进展。为此，我们使用转移性乳腺癌的4T1同基因小鼠移植模型，结合全局和候选基因表达分析、分子组织学、免疫表型和免疫耗竭方法，进行了深入的机制分析。我们发现，一种中和所有三种转化生长因子-β亚型的单抗(1D11，Genzyme Corp)通过许多小分子作用于多个细胞隔室的协同作用来抑制肿瘤的发生和转移。靶细胞包括肿瘤细胞本身、免疫监视系统的组件和微血管系统。抗体的总体疗效大部分归功于增强的抗肿瘤免疫监视，涉及免疫系统的先天和适应性手臂。除了已知的转化生长因子-β对细胞毒性T细胞功能的抑制作用外，我们还发现了一种新的机制，即肿瘤诱导的转化生长因子-β通过IL-17依赖的机制进一步颠覆免疫系统的CD8+臂，为肿瘤提供直接的营养支持。转化生长因子-β抗体逆转了这两种作用。我们认为，抗转化生长因子-β抗体在肿瘤部位或附近的多个细胞靶点上的局部分布作用机制可能是该药物出人意料的低毒性的关键。这些数据对临床生物标记物的开发以及理解这类转化生长因子-β拮抗剂选择性影响肿瘤而不是正常组织的生物学基础具有重要意义。

Despite the dual role for TGF-beta as both tumor suppressor and tumor promoter in carcinogenesis, preclinical data from our lab and others has previously suggested that strategies to antagonize TGF-beta may selectively reduce the undesirable tumor promoting effects of this growth factor, while sparing the desirable effects on tumor suppression and normal homeostasis. Based on these promising preclinical results, an anti-TGF-beta antibody is in early phase clinical trials for the treatment of advanced cancer. However, given the complex biology of TGF-beta, the successful development of TGF-beta antagonists for cancer therapy will depend on a clear understanding of how these agents work and the related question of how to select patients who will benefit from this type of treatment. In FY08, we have made substantial progress in understanding the mechanism of action of an anti-TGF-beta antibody in suppressing tumor progression and metastasis. To do this, we have performed in depth mechanistic analyses using the 4T1 syngeneic mouse transplantation model of metastatic breast cancer, in combination with global and candidate gene expression analysis, molecular histology, immunophenotyping and immunodepletion approaches. We have found that a monoclonal antibody (1D11, Genzyme Corp) that neutralizes all three TGF-beta isoforms suppresses tumorigenesis and metastasis through the synergism of many small molecular effects on multiple cellular compartments. Target cells include the tumor cell itself, components of the immune surveillance system, and the microvasculature. Most of the overall efficacy of the antibody is due to enhanced anti-tumor immune surveillance, involving both innate and adaptive arms of the immune system. In addition to the known suppressive effects of TGF-beta on cytotoxic T-cell function, we also identified a novel mechanism whereby tumor-induced TGF-beta further subverts the CD8+ arm of the immune system into providing direct trophic support for the tumor through an IL-17-dependent mechanism. TGF-beta antibodies reverse both these effects. We propose that the locally distributed mechanism of action of anti-TGF-beta antibodies on multiple cell targets at or near the tumor site may be critical for the unexpectedly low toxicity of the agent. These data have important implications for clinical biomarker development and for understanding the biological basis of the selectivity of this class of TGF-beta antagonist in affecting the tumor and not the normal tissues.