Tuesday, May 7, 2024
5/7/2024
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.
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