Sequential administration of MVA-based vaccines and PD-1/PD-L1-blocking antibodies confers measurable benefits on tumor growth and survival: Preclinical studies with MVA-βGal and MVA-MUC1 (TG4010) in a murine tumor model

Abstract

TG4010, a Modified Vaccinia virus Ankara (MVA) expressing human mucin1 (MUC1) has demonstrated clinical benefit for patients suffering from advanced non-small cell lung cancer (NSCLC) in combination with chemotherapy. To support its development, preclinical experiments were performed with either TG4010 or β-galactosidase-encoding MVA vector (MVA-βgal) in mice presenting tumors in the lung. Tumor growth was obtained after intravenous injection of CT26 murine colon cancer cells, engineered to express either MUC1 or βgal. Mice showed increased survival rates after repeated intravenous injections of TG4010 or MVA-βgal, compared to an empty MVA control vector. Treatment with MVA vectors led to the accumulation of CD3dimCD8dim T cells, with two subpopulations characterized as KLRG1+CD127− short-lived effector cells (SLECs), and KLRG1−CD127− early effector cells (EECs) comprising cells releasing IFNγ, Granzyme B and CD107a upon antigen-specific peptide stimulation. EECs were characterized by an up-regulation of PD-1. Tumor growth in the diseased lung correlated with the appearance of PD1+ Treg cells that partially disappeared after TG4010 treatment. At late stage of tumor development in the lung, PD-L1 was detected on CD45− tumor cells, on CD4+ cells, including Treg cells, on CD3+CD8+ and CD3dimCD8dim T lymphocytes, on NK cells, on MDSCs and on alveolar macrophages. We demonstrated that targeting the PD-1/PD-L1 pathway with blocking monoclonal antibodies several days after TG4010 treatment, at late stage of tumor development, enhanced the therapeutic protection induced by the vaccine, supporting the ongoing clinical evaluation of TG4010 immunotherapy in combination with Nivolumab.

Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics

“…In the late stages of disease, PD-L1 was detected on cancer cells and immune cells, including CD4 + T cells (including T reg cells), CD3 + CD8 + and CD3 dim CD8 dim T cells, natural killer (NK) cells, myeloid-derived suppressor cells, and alveolar macrophages. When PD-1 blockade using specific antagonist antibodies was applied several days after TG4010 treatment, therapeutic benefits associated with viral therapy were enhanced [60]. In a third study, MVA-BN-HER2 poxvirus-based active immunotherapy administered alone or in combination with CTLA-4 checkpoint blockade was investigated in the treatment of CT26-HER-2 lung metastases in mice.…”

Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment

“…A special category of these antigens comprises neoantigens, which are present on MHC molecules (38,39) (Figure 1). Surprisingly, neoantigens are unique to the patient rather than to the tumor, and are often downregulated in tumors, suggesting that tumors evade immune destruction (40)(41)(42)(43)(44)(45). These properties make neoantigens suitable targets for personalizing cancer vaccines and ACT (46,47).…”

“…TG4010, an attenuated poxvirus engineered to express MUC-1 and IL-2 prolonged the survival of patients with advanced NSCLC when administered with first-line chemotherapy and is now being tested in phase III clinical trials (43). Interestingly, TG4010 showed synergistic effects when used in combination with anti-PD-1/PD-L1 ICB in murine models (44). Other OVs being evaluated in lung cancer clinical trials include viruses derived from adenovirus, picornavirus, reovirus, as well as coxsackie, herpes simplex, maraba, measles, and vaccinia virus (39,100,101).…”

Comprehensive analysis of the mechanism and treatment significance of Mucins in lung cancer

“…Therefore, TG4010 can be used in combination with other targeted immunomodulators to maximize response rates and clinical benefits. Sequential treatment with anti-PD-1/PD-L1 after treated with TG4010(NCT02823990) shows a better overall survival in mice model [56]. Moreover, there are two clinical trials (NCT02823990 and NCT03353675) in studying about combing TG4010 and Nivolumab in NSCLC patients (Table 2).…”