RT Journal Article
SR Electronic
T1 TG6050, an oncolytic vaccinia virus encoding interleukin-12 and anti-CTLA-4 antibody, favors tumor regression via profound immune remodeling of the tumor microenvironment
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e009302
DO 10.1136/jitc-2024-009302
VO 12
IS 7
A1 Azar, Fadi
A1 Deforges, Jules
A1 Demeusoit, Christelle
A1 Kleinpeter, Patricia
A1 Remy, Christelle
A1 Silvestre, Nathalie
A1 Foloppe, Johann
A1 Fend, Laetitia
A1 Spring-Giusti, Clémentine
A1 Quéméneur, Eric
A1 Marchand, Jean-Baptiste
YR 2024
UL http://jitc.bmj.com/content/12/7/e009302.abstract
AB Background TG6050 was designed as an improved oncolytic vector, combining the intrinsic properties of vaccinia virus to selectively replicate in tumors with the tumor-restricted expression of recombinant immune effectors to modify the tumor immune phenotype. These properties might be of particular interest for “cold” tumors, either poorly infiltrated or infiltrated with anergic T cells.Methods  TG6050, an oncolytic vaccinia virus encodes single-chain human interleukin-12 (hIL-12) and full-length anti-cytotoxic T-lymphocyte-associated antigen-4 (@CTLA-4) monoclonal antibody. The relevant properties of TG6050 (replication, cytopathy, transgenes expression and functionality) were extensively characterized in vitro. The biodistribution and pharmacokinetics of the viral vector, @CTLA-4 and IL-12, as well as antitumoral activities (alone or combined with immune checkpoint inhibitors) were investigated in several “hot” (highly infiltrated) and “cold” (poorly infiltrated) syngeneic murine tumor models. The mechanism of action was deciphered by monitoring both systemic and intratumoral immune responses, and by tumor transcriptome analysis. The safety of TG6050 after repeated intravenous administrations was evaluated in cynomolgus monkeys, with a focus on the level of circulating IL-12.Results Multiplication and propagation of TG6050 in tumor cells in vitro and in vivo were associated with local expression of functional IL-12 and @CTLA-4. This dual mechanism translated into a strong antitumoral activity in both “cold” and “hot” tumor models (B16F10, LLC1 or EMT6, CT26, respectively) that was further amplified when combined with anti-programmed cell death protein-1. Analysis of changes in the tumor microenvironment (TME) after treatment with TG6050 showed increases in interferon-gamma, of CD8+T cells, and of M1/M2 macrophages ratio, as well as a drastic decrease of regulatory T cells. These local modifications were observed alongside bolstering a systemic and specific antitumor adaptive immune response. In toxicology studies, TG6050 did not display any observable adverse effects in cynomolgus monkeys.Conclusions TG6050 effectively delivers functional IL-12 and @CTLA-4 into the tumor, resulting in strong antitumor activity. The shift towards an inflamed TME correlated with a boost in systemic antitumor T cells. The solid preclinical data and favorable benefit/risk ratio paved the way for the clinical evaluation of TG6050 in metastatic non-small cell lung cancer (NCT05788926 trial in progress).Data sets used in the current study are available on reasonable request. The assigned accession numbers for sequencing data reported in this paper are GEO: GSE259379 and GSE259380.