Adenovirus Coding for Interleukin-2 and Tumor Necrosis Factor Alpha Replaces Lymphodepleting Chemotherapy in Adoptive T Cell Therapy.
Lymphodepleting preconditioning with high-dose chemotherapy is commonly used to increase the clinical efficacy of adoptive T cell therapy (ACT) strategies, however, with severe toxicity for patients. Conversely, oncolytic adenoviruses are safe and, when engineered to express interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-α), they can achieve antitumor immunomodulatory effects similar to lymphodepletion. Therefore, we compare the safety and efficacy of such adenoviruses with a cyclophosphamide- and fludarabine-containing lymphodepleting regimen in the setting of ACT. Human adenovirus (Ad5/3-E2F-D24-hTNF-α-IRES-hIL-2; TILT-123) replication was studied using a Syrian hamster pancreatic tumor model (HapT1) infused with tumor-infiltrating lymphocytes (TILs). Using the oncolytic virus instead of lymphodepletion resulted in superior efficacy and survival. Immune cells responsive to TNF-α IL-2 were studied using an immunocompetent mouse melanoma model (B16.OVA) infused with ovalbumin-specific T (OT-I) cells. Here, the adenovirus approach improved tumor control together with increased intratumoral Th1 cytokine levels and infiltration of CD8+ T cells and CD86+ dendritic cells. Similar to humans, lymphodepleting preconditioning caused severe cytopenias, systemic inflammation, and damage to vital organs. Toxicity was minimal in adenovirus- and OT-I-treated mice. These findings demonstrate that ACT can be effectively facilitated by cytokine-coding adenovirus without requiring lymphodepletion, a rationale being clinically investigated.
['Santos|João Manuel|JM|', 'Cervera-Carrascon|Víctor|V|', 'Havunen|Riikka|R|', 'Zafar|Sadia|S|', 'Siurala|Mikko|M|', 'Sorsa|Suvi|S|', 'Anttila|Marjukka|M|', 'Kanerva|Anna|A|', 'Hemminki|Akseli|A|']
D000256:Adenoviridae D000818:Animals D002460:Cell Line D004195:Disease Models, Animal D005822:Genetic Vectors D006801:Humans D016219:Immunotherapy, Adoptive D007376:Interleukin-2 D008297:Male D008545:Melanoma D008647:Mesocricetus D051379:Mice D013601:T-Lymphocytes D014409:Tumor Necrosis Factor-alpha
interleukin-2 tumor necrosis factor alpha chemotherapy lymphodepleting preconditioning adoptive T cell therapy TCR modified T cell therapy TIL therapy oncolytic adenovirus