Measles virus for cancer therapy

Abstract

Measles virus offers an ideal platform from which to build a new generation of safe, effective oncolytic viruses. Occasional so-called spontaneous tumor regressions have occurred during natural measles infections, but common tumors do not express SLAM, the wild-type MV receptor, and are therefore not susceptible to the virus. Serendipitously, attenuated vaccine strains of measles virus have adapted to use CD46, a regulator of complement activation that is expressed in higher abundance on human tumor cells than on their nontransformed counterparts. For this reason, attenuated measles viruses are potent and selective oncolytic agents showing impressive antitumor activity in mouse xenograft models. The viruses can be engineered to enhance their tumor specificity, increase their antitumor potency, and facilitate noninvasive in vivo monitoring of their spread. A major impediment to the successful deployment of oncolytic measles viruses as anticancer agents is the high prevalence of preexisting anti-measles immunity, which impedes bloodstream delivery and curtails intratumoral virus spread. It is hoped that these problems can be addressed by delivering the virus inside measles-infected cell carriers and/or by concomitant administration of immunosuppressive drugs. From a safety perspective, population immunity provides an excellent defense against measles spread from patient to carers and, in 50 years of human experience, reversion of attenuated measles to a wild-type pathogenic phenotype has not been observed. Clinical trials testing oncolytic measles viruses as an experimental cancer therapy are currently underway.

Figure 1

Attenutated measles virus preferentially targets CD46 which is overexpressed on cancer cells, including multiple myeloma cells. (A) Cytospin of a bone marrow aspirate showing myeloma cells. (B) Bone marrow aspirates obtained from myeloma patients were separated into plasma cells (myeloma) and non-plasma cells (all normal hemapoietic cells in the marrow). Cells were stained with an anti-CD46 antibody and the numbers of CD46 receptors/cell were determined using BD-QuantiBrite Beads.[44] Primary myeloma cells express 7-fold higher CD46 receptors than normal non-plasma cells in the bone marrow. (C) Primary myeloma cells expressing high levels of CD46 receptors (shown on the left) are more susceptible to the cytopathic effects of measles induced syncytial formation compared to normal bone marrow cells isolated from the same bone marrow aspirates [44].

Figure 2

Genetic engineering of attenuated measles virus for cancer therapy. (A) The virus can be engineered to express soluble marker proteins (eg. MV-CEA) which are secreted into the circulation, thus enabling noninvasive monitoring of the profiles of viral gene expression over time by sampling body fluids[81]. (B) The virus can be engineered to express the sodium iodide symporter (MV-NIS) which concentrates radioiodine in the infected cell, thus enabling noninvasive monitoring of the sites of MV infection by gamma camera, SPECT-CT or PET-CT imaging.[84] Virotherapy can also be enhanced by a timely dose of beta-emitting I-131 to result in synergistic killing of MV infected tumors. (C) Arming of the virus with genes (e.g. P-gene from wild-type measles) that enable the virus to combat the innate antiviral immunity [102]. (D) Targeting virus entry, the H glycoprotein of measles virus can accommodate addition of large polypeptides (eg. Single-chain antibodies) as C-terminal extensions on the H protein. Mutations in the H protein that ablate fusion via CD46 and SLAM have been identified and incorporated in the retargeted viruses. The displayed ligand redirects binding of the virus to the new receptor to mediate virus entry and syncytial formation via the targeted receptor.[66]

Figure 3

Considerations for future improvements of measles virotherapy. Ideally, intravascularly administered viruses will reach the tumor sites to result in infection of tumor cells, viral spread and elimination of the tumors. However, anti-measles antibodies can potentially inhibit delivery of the viruses and viral spread in the infected tumor can be inhibited by cell mediated immunity. To combat these barriers to successful therapy, virus infected cell carriers can be exploited to act as Trojan horses to deliver virus to the tumor sites and cell mediated immunity can be controlled by judicious use of immunosuppressive agents such as cyclophosphamide.