Abstract
CF33-hNIS-anti-PD-L1 is an oncolytic chimeric poxvirus encoding two transgenes: human sodium iodide symporter and a single-chain variable fragment against PD-L1. Comprehensive preclinical pharmacology studies encompassing primary and secondary pharmacodynamics and biodistribution and safety studies were performed to support the clinical development of CF33-hNIS-anti-PD-L1. Most of the studies were performed in triple-negative breast cancer (TNBC) models, as the phase I trial is planned for patients with TNBC. Biological functions of virus-encoded transgenes were confirmed, and the virus demonstrated anti-tumor efficacy against TNBC models in mice. In a good laboratory practice (GLP) toxicology study, the virus did not produce any observable adverse effects in mice, suggesting that the doses proposed for the clinical trial should be well tolerated in patients. Furthermore, no neurotoxic effects in mice were seen following intracranial injection of the virus. Also, the risk for horizontal transmission of CF33-hNIS-anti-PD-L1 was assessed in mice, and our results suggest that the virus is unlikely to transmit from infected patients to healthy individuals. Finally, the in-use stability and compatibility of CF33-hNIS-anti-PD-L1 tested under different conditions mimicking the clinical scenarios confirmed the suitability of the virus in clinical settings. The results of these preclinical studies support the use of CF33-hNIS-anti-PD-L1 in a first-in-human trial in patients with TNBC.
Highlights
Oncolytic viruses are designed to replicate in cancer cells and kill them while leaving normal cells unharmed
talimogene laherparepvec (T-Vec), which is approved for the treatment of metastatic melanoma, is an engineered herpes simplex virus 1 (HSV-1) that is armed with the cytokine granulocyte macrophage colony-stimulating factor (GM-CSF).[2]
Because CF33 is a chimeric poxvirus generated from multiple species and strains of poxviruses, it was important to perform a thorough investigation of the viral genome and its stability
Summary
Oncolytic viruses are designed to replicate in cancer cells and kill them while leaving normal cells unharmed. A wide variety of viruses, either modified or in their natural form, have been studied for their oncolytic potentials. Many oncolytic viruses have been studied in clinical trials for the treatment of different types of malignancies.[1] far, only one oncolytic virus, talimogene laherparepvec (T-Vec), has received U.S Food and Drug Administration (FDA) approval. T-Vec, which is approved for the treatment of metastatic melanoma, is an engineered herpes simplex virus 1 (HSV-1) that is armed with the cytokine granulocyte macrophage colony-stimulating factor (GM-CSF).[2] The approval of T-Vec has resulted in a surge of interest in the field of oncolytic virotherapy
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