Researchers here demonstrate a way to greatly increase the number of cancer-targeted viruses that can be safely infused into a patient. By disabling the ability of the virus to self-replicate they prevent it from causing dangerous side-effects:
The researchers used a specific method and dose of UV light to transform regular replicating viruses into unique particles that could no longer replicate and spread, but could still enter cancer cells efficiently, kill them and stimulate a strong immune response against the cancer. These particles were able to kill multiple forms of leukemia in the laboratory, including samples taken from local patients who had failed all other therapies. Normal blood cells were not affected. This novel treatment was also successful in mouse models of leukemia. In fact, 80 per cent of the mice that received the therapy had markedly prolonged survival and 60 per cent were eventually cured, while all of the untreated mice died of their leukemia within 20 days.
Rhabdoviruses (RVs) are currently being pursued as anticancer therapeutics for various tumor types, notably leukemia. However, modest virion production and limited spread between noncontiguous circulating leukemic cells requires high-dose administration of RVs, which exceeds the maximum tolerable dose of the live virus. Furthermore, in severely immunosuppressed leukemic patients, the potential for uncontrolled live virus spread may compromise the safety of a live virus approach.
We hypothesized that the barriers to oncolytic virotherapy in liquid tumors may be overcome by administration of high-dose non-replicating RVs. We have developed a method to produce unique high-titer bioactive yet non-replicating rhabdovirus-derived particles (NRRPs). This is the first successful attempt to eradicate disseminated cancer using non-replicating virus-derived particles, and represents a paradigm shift in the field of oncolytic virus-based therapeutics. Through in silico and in vitro testing, we demonstrate that NRRPs, analogous to live virus, are tumor selective, given that they exploit defects in innate immune pathways common to most tumors. However, this platform is unencumbered by the principle safety concern associated with live virus replication, that is, the potential for uncontrolled viral spread in immunocompromised patients. Indeed, the superior safety margin afforded by the NRRP platform was exemplified by the observation that high-titer intracranial NRRP administration was well tolerated by murine recipients.
Here we establish that NRRPs exhibit both direct cytolytic and potent immunogenic properties in multiple acute leukemia models. A peculiar form of programmed cell death involves the induction of adaptive immune responses against the dying cell. This process, commonly referred to as immunogenic apoptosis, is essential to the efficacy of several current chemotherapeutics and is required for host defense against viral infection including live RVs. Our in vivo results indicate that a similar process is induced by NRRPs and is a driving factor for treatment efficacy.