Saturday, June 19, 2021
6/19/2021
Project Summary Despite the clinical successes of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC), many patients experience resistance after an initial response or face the possibility of potentially life-threatening side effects. A subset of NSCLC patients could benefit from immunostimulatory molecules, such as immune checkpoint stimulators, to accentuate the therapeutic effects of ICIs. We focused on the 4-1BB pathway as a powerful immune checkpoint stimulatory that is critical to the generation of CD8+ T killer responses and long- term immune memory. Given that the natural ligand lacks function in soluble form, we generated a novel recombinant oligomeric form of an agonist, SA-4-1BBL, that has robust immunostimulatory function with demonstrated immunoprevention and immunotherapy efficacy in various tumor models. The objective of this proposal is to develop a novel, NSCLC-specific, viral delivery system that expresses SA-4-1BBL within the tumor for therapy. This proposal builds on our expertise in developing oncolytic adenoviral delivery vehicles and the development of SA-4-1BBL recombinant protein as a robust immunomodulator for cancer immunoprevention and therapy. To further improve the translational potential by reducing time and cost, we developed a novel prototype oncolytic viral system to deliver SA-4-1BBL (OAdSA-4-1BBL) to NSCLC tumors. The preliminary results show that OAdSA-4-1BBL efficiently stimulates splenocyte proliferation in vitro and also has the capability to express SA-4-1BBL plus initiate replication within lung tumor in vivo. This novel vector combines, in one single agent, oncolytic and immunogenic cell death with a costimulatory molecule (oncolytic immunotherapy). The assembled team includes the PI who is a cancer gene therapy expert aligned with two cancer immunology experts. The patented costimulatory molecule SA-4-1BBL of the coinvestigator/consultant is to be tested with the established vector of the PI. The ultimate goal is to move this tumor-targeted treatment into early clinical trials with the hope of preventing currently incurable distant recurrences of this recalcitrant disease. The hypothesis is that OAdSA-4-1BBL will significantly stimulate the immune system, thereby improving antitumor NSCLC response. We will test the hypothesis using the following aims: 1) evaluate OAdSA-4-1BBL-mediated killing effect and immune response in vitro and 2) assess therapeutic efficacy of OAd-SA-4-1BBL as an anti-tumor compound in vivo. The evaluation of oncolytic immunotherapy (OAdSA-4-1BBL) as a novel generation of immunotherapies could benefit patients whose treatment is currently resistant to established immune checkpoint inhibitors and could have broad implications in other cancer types.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
