Enhancing anti-PD-1 blockade antitumor efficacy by oncolytic virotherapy-mediated tumor microenvironment immunomodulation

Immunotherapy with immune checkpoint inhibitors (ICIs) has been a significant breakthrough in lung cancer (LC) treatment, yet many patients do not fully benefit from ICIs. Abnormal antigen presentation, the immune- regulatory tumor microenvironment (TME), plus other factors contribute to primary or secondary resistance to ICIs. Therefore, there is an evident clinical unmet need to develop approaches to overcome LC resistance to ICIs. The long-term goal is to accelerate development of transductional targeting OAdSA-4-1BBL, an oncolytic adenovirus targeting preferentially transferrin receptor (TfR) in LC cells and that expresses a novel co-stimulatory molecule streptavidin-4-1BBL to treat non-small cell lung cancer (NSCLC) patients unresponsive to ICIs. The overall objective for this proposal is to evaluate the effectiveness of OAdSA-4-1BBL alone or combined with anti- PD1 blockade in an immunocompetent orthotopic lung cancer mouse model and develop a novel OAd expressing SA-human4-1BBL that preferentially infects and kill LC cells by targeting transferrin receptor (TfR). The central hypothesis is that OAdSA-4-1BBL-mediated immunomodulation of the TME promotes durable protective antitumor immunity to overcome resistance to ICIs in NSCLC, and that combined therapy OAdSA-4- 1BBL plus ICI will synergistically and permanently eradicate NSCLC tumors. The rationale for the proposed study is that rigorous scientific evidence supports an immunotherapeutic role for OAdSA-4-1BBL in an immunocompetent orthotopic LC host in settings of ICIs. Further, selectivity of TfR/OAdSA-h4-1BBL in patient- derived organoids (PDOs) likely provides a strong foundation for the development of clinical approaches testing TfR/OAdSA-h4-1BBL as a novel strategy to boost the effects of ICIs in NSCLC patients. Guided by strong preliminary data, the following specific aims are proposed: 1) Evaluate the immunotherapeutic efficacy of OAdSA-4-1BBL alone or in combination with anti-PD-1 blockade in an orthotopic LC mouse model and 2) Development and characterization of transductional targeting-(TfR) OAdSA-h4-1BBL in a PDOs. For Aim 1, syngeneic orthotopic lung tumor models expressing luciferase will be used to monitor antitumor efficacy of OAdSA-4-1BBL alone or in combination with anti-PD-1 blockade, OAdSA-4-1BBL-mediated immunogenic cell death will be evaluated, flow cytometry for immune cell phenotyping from tumors, lymph nodes, and spleen will be used to evaluate OAdSA-4-1BBL capacity to reprogram the TME. In Aim 2, an improved transductional targeting (TfR) OAd expressing SA-human-4-1BBL will be developed and tested in clinically relevant PDOs. The proposed research is novel because it combines a cancer selective tumoricidal agent with a novel, chimeric, and soluble co-stimulatory molecule SA-4-1BBL in one single agent that could overcome LC resistance to ICIs. The proposed research is significant because the results are expected to provide strong justification for continued development and future clinical trials using OAdSA-4-1BBL in combination with ICIs. Apart from advancing the field of oncolytic immunotherapy in NSCLC, this new generation of immunotherapies is expected to benefit patients with other cancer types that are also resistant to ICIs. Project Number: 1R21CA302730-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Jorge Gomez-Gutierrez | Institution: UNIVERSITY OF MISSOURI-COLUMBIA, COLUMBIA, MO | Award Amount: $409,158 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZCA1 SRB-K (M2)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11202926