Oncolytic Adenovirus Armed with a Novel Agonist of the CD137 Immune Checkpoint Stimulator Suppresses Tumor Growth

• Published in: Vaccines (Basel) 2024-03, Vol.12 (3), p.340
• Main Authors: Ramos-Gonzalez, Martin R, Tarique, Mohammad, Batra, Lalit, Arguc, Feyza, Garza-Morales, Rodolfo, Shirwan, Haval, Yolcu, Esma S, Gomez-Gutierrez, Jorge G
• Format: Article
• Language: English
• Subjects: Adenosine triphosphate; adenovirus; Adenoviruses; Animal models; Apoptosis; ATP; Autophagy; cancer; CD137 antigen; CD8 antigen; Cell death; Cell membranes; Cell proliferation; Cell viability; Cytomegalovirus; Cytotoxicity; Dendritic cells; Drug delivery systems; Drugs; Evaluation; Genomes; Health aspects; Immune checkpoint inhibitors; Immunotherapy; Infections; lung; Lung cancer; Lymphocytes; Lymphocytes T; Materials; Membrane proteins; Metastases; Monoclonal antibodies; Oncolysis; oncolytic; Polyclonal antibodies; Proteins; SA-4-1BBL; Solid tumors; Stimulators; Tumor cell lines; Tumor suppression; Tumors; Vehicles; Viruses
• ISSN: 2076-393X; 2076-393X
• DOI: 10.3390/vaccines12030340

Natural 4-1BBL (CD137L) is a cell membrane-bound protein critical to the expansion, effector function, and survival of CD8 T cells. We reported the generation of an active soluble oligomeric construct, SA-4-1BBL, with demonstrated immunoprevention and immunotherapeutic efficacy in various mouse tumor models. Herein, we developed an oncolytic adenovirus (OAd) for the delivery and expression of SA-4-1BBL (OAdSA-4-1BBL) into solid tumors for immunotherapy. SA-4-1BBL protein expressed by this construct produced T-cell proliferation in vitro. OAdSA-4-1BBL decreased cell viability in two mouse lung cancer cell lines, TC-1 and CMT64, but not in the non-cancerous lung MM14.Lu cell line. OAdSA-4-1BBL induced programmed cell death types I and II (apoptosis and autophagy, respectively), and autophagy-mediated adenosine triphosphate (ATP) release was also detected. Intratumoral injection of OAdSA-4-1BBL efficiently expressed the SA-4-1BBL protein in the tumors, resulting in significant tumor suppression in a syngeneic subcutaneous TC-1 mouse lung cancer model. Tumor suppression was associated with a higher frequency of dendritic cells and an increased infiltration of cytotoxic CD8 T and NK cells into the tumors. Our data suggest that OAdSA-4-1BBL may present an efficacious alternative therapeutic strategy against lung cancer as a standalone construct or in combination with other immunotherapeutic modalities, such as immune checkpoint inhibitors.