Targeting ART1, a Novel Immune Checkpoint, for the Treatment of Lung Cancer
Abstract
We propose to study the role of a protein called ART1 in lung cancer. ART1 has not been previously described in lung tumors, but we have found several clues to suggest that it might play a role in lung cancer progression. We also have preliminary data that show that ART1 is strongly expressed in over half of human lung cancers. ART1 works by breaking down a metabolite called NAD+ to modify proteins on immune cells in the tumor microenvironment. This modification can either activate or inactivate those proteins. In particular, we think that ART1 and NAD+ may activate a protein on T cells called P2X7R that it is associated with a phenomenon called NAD-induced cell death, a process that kills T cells that may normally work to attack tumor cells. In this manner, ART1 overexpression on cancer cells would serve to blunt the body’s immune response against cancer, similar to “checkpoint inhibition,” which is the basis of many currently used immunotherapy drugs in lung cancer. If we block ART1 expression in lung cancer cells, we have shown that those cells are less able to spread and metastasize in mouse lung cancer models. We believe that we will see the same effect in human tumors. In our proposal, we plan to test a therapeutic antibody that blocks the actions of ART1. We anticipate that this antibody will decrease tumor growth and metastasis by blocking the ability of ART1 to kill T cells. Such treatment strategies have already shown great success in lung cancer by using antibody-based drugs that block checkpoint inhibitors such as PD1 or PD-L1. Furthermore, because cancer cells increase their expression of ART1 when under stress from treatment with radiation therapy or immunotherapy (both of which are commonly used to treat lung cancer), we believe that adding in a drug to block ART1 will work synergistically in that setting. Because ART1 is only active in local environments in which cells are dying and releasing NAD+, we do not think that blocking ART1 will have many negative consequences in normal tissues. In our application, we propose to (1) test anti-ART1 antibodies against lung cancer in mouse models with normal immune systems, (2) test combination therapy of anti-ART1 antibodies with immune therapy and radiation therapy, and (3) evaluate ART1 expression and its relationship to immune cells, particularly T cells expressing P2X7R, in a variety of human lung tumors and try to understand the role of ART1 expression in patients treated with radiation therapy or immunotherapy. Because we have already developed and optimized the binding and functional properties of anti-ART1 antibodies, we believe that we can rapidly produce them for use in patients within the next year through our Therapeutic Discovery Institute. We anticipate that an anti-ART1 therapeutic antibody will have a tremendous impact on lung cancer patients, offering another type of immunotherapy that helps to release the brakes on T cells and unleash the patient’s own immune system on his or her cancer. The project is highly relevant to Veterans, many of whose tumors should also strongly express ART1. We plan to evaluate tumor expression of ART1 as well as the immune microenvironment of tumors from patients undergoing surgery or biopsy at a Department of Veterans Affairs hospital. We will therefore assure that we understand the expected eligibility of Veterans for clinical trials targeting ART1 expression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910422
Entities
People
- Brendon Stiles
Organizations
- United States Army
- Weill Cornell Medicine