Use of autologous monocytes as carrier cells for the systemic delivery of oncolytic agents based on the herpes simplex virus type 1 as an innovative treatment of acute myeloid leukemia

Acute Myeloid Leukemia is a heterogeneous hematologic malignancy characterized by the rapid proliferation of abnormal myeloid blasts in the bone marrow and peripheral blood. Despite the advancements in the therapeutic strategies, AML continues to pose a major challenge in elderly patients and those with relapsed and refractory diseases. Standard treatments like intensive chemotherapy followed by allogenic hematopoietic stem cell transplantation often led to severe toxicity and high rates of relapses. Leukemic stem cells are naturally hard to kill with standard chemotherapy and the environment around the cancer cells can weaken the immune system making the treatment even more difficult. Because of these challenges there is urgent need for the development of new types of treatment. Oncolytic viruses represent a promising class of biological agents that selectively infect, replicate within and lyse cancer cells, inducing tumor cells death and the activation of robust anti tumor immune response. Among the oncolytic viruses, Herpes Simplex Virus Type 1(HSV-1) emerges as a prominent agent thanks to its wide genome containing 30 kbp non-essential for its replication ease of genetic modification, its wide tropism and well-established safety profile. Usually oncolytic HSV-1 stains(oHSV-1) are engineered to attenuate their neurovirulence and enhance tumor selectivity. Despite these advancements in oHSV-1 manipulation, the delivery of oncolytic virus is still an issue. It is because of its limited invasiveness and reproducibility, the systemic administration represents the best way to vehiculate the desired OV. However, this strategy presents some limits such as possibility of the virus to be neutralized by circulating antibodies and difficult to reach and infiltrate tumor microenvironment. To overcome the limitations, we propose autologous monocytes as carrier cells for the systemic delivery of therapeutic agents, due to their several advantages, including ease of recovery and their natural tropism towards tumor sites. This approach can facilitate targeted delivery of HSV-1 to disseminated AML cells which are sequestered in immune privileged or difficult to reach sites. Firstly, it was assessed the ability of an oHSV-1 to infect and kill two different AML cell lines (MV4-11 and OCI-AML3). Secondly, it was observed the monocyte’s property to transmit viral infection and promote AML cell lines death. Finally, it was confirmed monocyte’s tropism for acute myelid leukemia cells. Overall, these results are promising for a future use of monocytes as carrier cells for oHSV-1 agents for acute myeloid leukemia treatment.