Malignant tumors are a major public health problem worldwide and the second leading cause of death. Although most solid malignancies can be surgically removed, the greatest challenge remains their post-surgery metastasis to other organs, causing about 90% of cancer deaths. For decades, radiation therapy (RT) and chemotherapy (CT) have been used before and/or after surgery in order to prevent the recurrence and metastasis of the malignancies. However, only a small proportion (5-10%) of patients benefit from chemotherapy or radiation therapy. Therefore, there is a need to develop new therapies to treat and prevent metastasis in malignancies. Inhibitors of apoptosis proteins (IAP) are a family of E3 ubiquitin ligases that block apoptosis and are frequently over-expressed in human tumors to promote cancer cell survival. Many IAP antagonists (IAPa) have been developed to kill malignant tumors, including ovarian carcinoma, colon cancer, melanoma, lymphoma, lung cancer, breast cancer and leukemia but most patients did not benefit from them. Tumor necrosis factor-α (TNFα) was originally identified as a tumoricidal agent but, when administered to patients failed due to significant toxicities and lack of efficacy. Previous evidence points out that neither TNFα nor an IAPa alone at a low dose kills the cancer cells.
Scientists at the University of Rochester have developed a new method to target a variety of malignant tumors to deliver TNFα using adoptive cells. This method involves combining engineered macrophages extracted from a patient to over-express a chimeric antigen receptor and secrete TNFα and combining them with an IAPa to kill the cancer cells specifically and effectively. Impressively, combined treatment of an IAPa and TNFα completely eliminated all lung metastasis and half of bone metastasis from human MDA-MB-231 cells in mice in vivo.