Oncolytic viral purging of leukemic hematopoietic stem and progenitor cells with Myxoma virus

Abstract

High-dose chemotherapy and radiation followed by autologous blood and marrow transplantation (ABMT) has been extensively used for the treatment of certain cancers that are refractory to standard therapeutic regimes. However, a major challenge with ABMT for patients with hematologic malignancies is disease relapse, mainly due to either contamination with cancerous hematopoietic stem and progenitor cells (HSPCs) within the autograft or the persistence of residual therapy-resistant disease niches within the patient. Oncolytic viruses represent a promising therapeutic approach to prevent cancer relapse by eliminating tumor-initiating cells that contaminate the autograft. Here we summarize an ex vivo "purging" strategy with oncolytic myxoma virus (MYXV) to remove cancerinitiating cells from patient autografts prior to transplantation. MYXV, a novel oncolytic poxvirus with potent anti-cancer properties in a variety of in vivo tumor models, can specifically eliminate cancerous stem and progenitor cells from samples obtained from acute myelogenous leukemia (AML) patients, while sparing normal CD34+ hematopoietic stem and progenitor cells capable of rescuing hematopoiesis following high dose conditioning. We propose that a broader subset of patients with intractable hematologic malignancies who have failed standard therapy could become eligible for ABMT when the treatment schema is coupled with ex vivo oncolytic therapy.

Ex vivo virotherapy with myxoma virus does not impair hematopoietic stem and progenitor cells

“…A major challenge in treating patients with hematological malignancies, such as multiple myeloma, is disease relapse even despite high dose chemotherapy and autologous stem cell transplant (ASCT) 1–3 . Relapse disease occurs due to persistence of minimal residual disease from two potential sources: (1) contaminating cancer cells in the ASCT graft, and (2) protective niches in the transplant recipient that resist conditioning chemotherapy 4–7 .…”

Acute myeloid leukemia targeting by myxoma virus in vivo depends on cell binding but not permissiveness to infection in vitro

“…[1] A multitude of oncolytic virus candidates have been identified including: adenovirus, Herpes simplex virus, reovirus, measles virus, Newcastle disease virus and the poxviruses vaccinia and myxoma virus (MYXV) [2]. Significant progress has been made in developing many of these viruses as antineoplastic agents and several are currently in clinical trials [3, 4], including a genetically modified adenovirus, H101, which was recently approved by China’s State Food and Drug Administration for the treatment of head and neck cancer.…”

Myxoma virus-mediated oncolysis of ascites-derived human ovarian cancer cells and spheroids is impacted by differential AKT activity

“…Collection and isolation of ovarian cancer initiat ing cells from patient ascites have been successful by a number of groups using cell surface markers, such as CD133 + [52], CD44 + / CD24 + /EpCAM + [49], CD44 + /CD117 + [48], and CD44 + /MyD88 + [50], or by verapamil sensitive side population cells [51]. This has in creased relevance with regard to targeted killing by MYXV, since the idea of oncolytic viral purging of pluripotent cancer stem cells using MYXV has been recently applied in the context of human myeloid leukemia [53]. We propose that MYXV application directly to malig nant ascites may function in the same way, and provide an effective way to target ovarian cancer stem cells, perhaps those residing within dormant EOC spheroids and secondary metastases.…”