Adenovirus Coding for Interleukin-2 and Tumor Necrosis Factor Alpha Replaces Lymphodepleting Chemotherapy in Adoptive T Cell Therapy

Abstract

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.

Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1 inhibition

“…Oncolytic replication is also important, but perhaps chiefly because of its immunostimulatory consequences. Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (TILT-123) is an engineered oncolytic adenovirus with chimeric serotype 5/3 designed specifically to be coupled with T-cell-related therapies such as adoptive-cell transfer 18 (such as chimeric antigen receptor [CAR] T-cell therapy 19 ) or ICIs. 20 To go beyond the inherent immunostimulatory activity of the presence of adenovirus in tumors, TILT-123 was tailored to enhance the antitumor effect of CD8 T cells.…”

Oncolytic Adenovirus—A Nova for Gene-Targeted Oncolytic Viral Therapy in HCC

“…Recently, it had been demonstrated that oncolytic adenoviruses express interleukin-2 (IL-2), and the tumor necrosis factor alpha (TNF-a) can achieve an anti-tumor immunomodulatory effect similar to lymphodepletion. Importantly, using an oncolytic adenovirus is much safer than Lymphodepleting preconditioning with high-dose chemotherapy (106). According to Sun et al's study, rAd-IL-2 exhibits a significant induced anti-tumor immune response by recruiting CD4 + and CD8 + T cells, increasing the interferon-γ release, and stimulating cytotoxic T lymphocyte responses in the HCC tumor model (53).…”

Adenovirus and Immunotherapy: Advancing Cancer Treatment by Combination

“…A recent trial found regulated expression of recombinant IL-12, following intratumoral injection of Ad-RTS-hIL-12 in combination with oral veledimex, to be safe in 31 patients with recurrent glioblastoma [42]. In addition to IL-12, several other interleukins, including IL-2, IL-24 and IL-13, have been used to arm oncolytic adenovirus and have shown promising immune-activating properties in multiple preclinical cancer models [43][44][45].…”