Tumor stromal barrier and cancer stromal targeting therapy

Abstract

Antibody drug conjugates (ADCs) are effective for tumors with no or little stroma, such as malignant lymphoma or breast cancer. However, in refractory cancers (pancreatic cancer or scirrhous gastric cancer) forming hypovascular and stroma-rich tumors, the penetration of monoclonal antibodies (mAbs) into the cells is impeded (stromal barrier), which leads to failure of conventional cell-targeting ADCs. To overcome this, we developed cancer stromal targeting (CAST) therapy using anti-collagen IV or anti-fibrin mAbs. These stroma-targeting ADCs selectively extravasated from leaky tumor vessels and bound to collagen IV or fibrin on the tumor stroma, from which effective sustained release of the payload drug occurred. The released drug subsequently diffused through the tumor tissue, causing marked arrest of tumor growth associated with damage to tumor vessels and death of cancer cells. In terms of the pathological findings after treatment, empty sleeves collagen IV-positive and CD31-negative remnant ring structures) were observed in the destroyed vessels. This review highlights the tumor stromal barrier and the development of CAST therapy. Insights into the pharmacokinetics and efficacy of antibodies or ADCs may also be informative to understand the pathophysiological role of the tumor microcirculation involved in the stromal barrier.