Targeted Repolarization of Tumor-Associated Macrophages in Lung Cancer
Abstract
The goal of this study is to investigate whether a novel conjugate of a vitamin (folate) and a clinically used compound (everolimus) will have effect on the immune cells to eliminate cancer cells. This conjugate is designed to modulate the immune-suppressive macrophages in the tumor. In general, we expect the conjugate to be a safe compound. The new drug conjugation will allow everolimus to target a type of cells called macrophages more specifically, thereby minimizing the exposure of normal cells. The outcome of our research will benefit lung cancer, which is the most common cause of cancer-related deaths in men and women. An estimated 159,480 patients died from this disease in 2013. For military personnel and Veterans in the United States, lung cancer is the number one cause of cancer death, with approximately 20,000 Veterans diagnosed with lung cancer in the Department of Veterans Affairs Medical System. One explanation for the high frequency of lung cancer in Veterans is that up to 40% of military personnel and Veterans currently smoke, and 77% of all Veterans have smoked during their lifetime. In addition, a significant proportion of military personnel have been exposed to smoke and other aerosolized toxic compounds while deployed abroad, which is speculated to further increase the risk for lung cancer. With current standard treatments, the 5-year survival for lung cancer is still <15%. The strong networks of immunosuppression created by the tumor greatly reduce the efficacy of the treatments. Much evidence points to the role of tumor associated macrophages (TAMs) as partially responsible for tumor resilience and disease progression. Hence, the ability to decrease TAM function may be of major therapeutic significance if this can be done incrementally and without full-scale depletion of immune cells that are essential to maintenance of homeostasis. Folate receptor beta (FRbeta) has been identified as a potential target on TAMs. The effects of pharmacologic targeting of TAMs on immune responses are largely unknown. Based upon preliminary data, we hypothesize that TAM inhibitors such as mammalian targets of rapamycin (mTOR) inhibitors will be key to regulation of CD8 T cell functions. Accordingly, we will investigate: (1) Can a folate-mTOR inhibitor repolarize suppressive M2 TAMs to an anti-tumor M1 phenotype? In order to answer this question, we will harvest TAMs from humans undergoing lung cancer surgery and then determine if our drug can convert TAMs from a pro-tumor to an anti-tumor phenotype. (2) Can a folate-mTOR drug conjugate improve effector T cell immune responses in the tumor microenvironment by re-polarizing TAMs in vivo? We will study our drug therapy in two different mouse models, which each have specific advantages to studying lung cancer. (3) Can our folate-mTOR inhibitor conjugate have clinical efficacy in a naturally occurring lung tumor canine model. Since dogs develop lung cancer due to secondhand smoke exposure and they develop histologically similar tumors to humans, this animal model will serve as a strong preclinical test to our new drug conjugate. Together, the studies proposed will dissect the functions of TAMs and test whether these molecules provide key therapeutic targets for manipulation of the immune responses, especially in those circumstances when reduction of TAM suppression is desirable. Hence, our studies should have major consequences for development of new strategies for immunotherapy in patients with malignancies. This will have a tremendous impact to the field and may lead to additional ideas targeting TAMs to treat tumors. The novel folate-everolimus conjugate contains a vitamin and an approved drug that is clinically used for several indications, including cancers. Although it needs to be confirmed, we expect the conjugate to be a safe compound. If it is confirmed to be effective to limit tumors in the mouse and the naturally occurring large canine lu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510362
Entities
People
- Sunil Singhal
Organizations
- United States Army
- University of Pennsylvania