T-independent response mediated by oncolytic tanapoxvirus recombinants expressing interleukin-2 and monocyte chemoattractant protein-1 suppresses human triple negative breast tumors

Abstract

Human triple negative breast cancer (TNBC) is an aggressive disease, associated with a high rate of recurrence and metastasis. Current therapeutics for TNBC are limited, highly toxic and show inconsistent efficacy due to a high degree of intra-tumoral and inter-tumoral heterogeneity. Oncolytic viruses (OVs) are an emerging treatment option for cancers. Several OVs are currently under investigation in preclinical and clinical settings. Here, we examine the oncolytic potential of two tanapoxvirus (TPV) recombinants expressing mouse monocyte chemoattractant protein (mMCP)-1 [also known as mCCL2] and mouse interleukin (mIL)-2, in human TNBC, in vitro and in vivo. Both wild-type (wt) TPV and TPV recombinants demonstrated efficient replicability in human TNBC cells and killed cancer cell efficiently in a dose-dependent manner in vitro. TPV/∆66R/mCCL2 and TPV/∆66R/mIL-2 expressing mCCL2 and mIL-2, respectively, suppressed the growth of MDA-MB-231 tumor xenografts in nude mice significantly, as compared to the mock-injected tumors. Histological analysis of tumors showed areas of viable tumor cells, necrotic foci and immune cell accumulation in virus-treated tumors. Moreover, TPV/∆66R/mIL-2-treated tumors showed a deep infiltration of mononuclear immune cells into the tumor capsule and focal cell death in tumors. In conclusion, TPV recombinants expressing mCCL2 and mIL-2 showed a significant therapeutic effect in MDA-MB-231 tumor xenografts, in nude mice through induction of potent antitumor immune responses. Considering the oncolytic potency of armed oncolytic TPV recombinants expressing mCCL2 and mIL-2 in an experimental nude mouse model, these viruses merit further investigation as alternative treatment options for human breast cancer.

(Im)maturity in Tumor Ecosystem

“…Agents act on maturation of anti-tumor immune cells can thus be designed for strengthening the power of the immune system against cancer. IL-2, for instance, promotes maturation of T cells ( 186 ), and it can be a key component of most of the immunotherapeutic approaches ( 187 ) due to its effects on promoting the effector function of cells like macrophages, NK cells, and CD8 + T cells ( 59 ). A point of value here is that even when maturation occurs in a cell like DCs, it may not be sufficient to induce a strong immunity ( 18 ), so agents designed to act on maturation of anti-tumor immune cells must also induce an effector functionality.…”

Triple-Negative Breast Cancer: Basic Biology and Immuno-Oncolytic Viruses

“…As of now, there are 157 studies across the world that are using OVs in the treatment of various cancers in human trials, with 10 having TNBC as the host disease [ 68 ]; however, there are many more virus platforms “in the pipelines” for BC/TNBC. Some of these viruses are as follows: adenovirus [ 69 , 70 ], vaccinia virus [ 71 , 72 ], tanapoxvirus [ 73 ], parapoxvirus [ 74 ], marabavirus [ 75 ], poliovirus [ 76 ], measles virus [ 77 ], herpes simplex virus [ 78 ], and Newcastle disease virus [ 79 ].…”

“…Since then, the field of oncolytic virology has rapidly expanded, with the advent of genome sequencing to specifically target and remove pathogenicity genes [ 114 ], add in genes with immunomodulatory characteristics [ 73 ], and even modify viral surface proteins to allow the specific replication of an OV into tumor cells with corresponding receptors [ 77 ]. Genetic manipulation allowed for the attenuation of pathogenicity without crippling oncolytic efficacy, potentially even enhancing it.…”

Oncolytic Viruses for Malignant Glioma: On the Verge of Success?

“…Several OVs have been designed to express immunostimulatory cytokines, such as IL-2 [123][124][125], IL-12 [126,127], IL15Rα-IL15 fusion protein [128], IL-4 [129], GM-CSF [130,131] and chemokines [132,133], which have shown promising results in pre-clinical studies in malignant glioma tumor models; however, this review focuses on OVs that are in clinical studies. At least two OVs, M032-and DNX-2440-expressing immunostimulatory proteins to potentiate anti-tumor immune responses are currently in clinical trials in malignant glioma patients.…”

“…Oncolytic virotherapy uses two main approaches to achieve the higher levels of pro-inflammatory factors in the TME: (1) engineering OVs to express immunostimulatory proteins and (2) the administration of immune stimulators and OVs in combination. Several OVs have been designed to express immunostimulatory cytokines, such as IL-2 [ 123 , 124 , 125 ], IL-12 [ 126 , 127 ], IL15Rα-IL15 fusion protein [ 128 ], IL-4 [ 129 ], GM-CSF [ 130 , 131 ] and chemokines [ 132 , 133 ], which have shown promising results in pre-clinical studies in malignant glioma tumor models; however, this review focuses on OVs that are in clinical studies. At least two OVs, M032- and DNX-2440-expressing immunostimulatory proteins to potentiate anti-tumor immune responses are currently in clinical trials in malignant glioma patients.…”