Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade

Samson et al, in your journal, provided evidence of an oncolytic reovirus gaining access to brain tumors after intravenous administration to patients (1). Reovirus RNA was widely detected in tumor cells of differing histological types. The authors, therefore, concluded that intravenous route holds promise as an efficient means of delivering oncolytic viruses to brain tumors, enabling regular scheduled treatments to be administered, while avoiding the need for neurosurgical methods of access. While this is a great step forward to develop oncolytic reovirus therapy, we would like to remind the readers that intravenous infusion of another oncolytic virus, the Newcastle Disease Virus (NDV) has already been proven to be safe and effective therapy in glioblastoma multiforme (GBM) patients. Therefore, it is perhaps useful to bring the recent past of the NDV oncolytic therapy into sharper focus with particular attention to GBM.

The median survival for grade IV GBM after tumor-directed surgery and chemoradiotherapy is 14.6 months (1). In fact, according to the consensus of experts GBM is incurable. The often extended periods of relative indolence exhibited by low-grade gliomas (LGG; WHO grade II) differ sharply from the aggressive, rapidly fatal clinical course of primary glioblastoma (GBM; WHO grade IV) (2).

An outlier case of a recurrent GBM patient was first discussed in a letter published by JAMA in 1999 (3). Despite conventional therapy including surgery, radiation, and chemotherapy, the MRI of the patient showed continued tumor enlargement. His functional and neurologic status deteriorated with increasing right-sided weakness and aphasia. He became wheelchair bound, had a Karnofsky score of 40, and received phenytoin due to frequent seizures. Therefore, he was treated intravenously with an oncolytic NDV. During two years of continuous daily NDV therapy, the MRI scans have demonstrated progressive shrinkage of the tumor by approximately 95%. This was the only treatment the patient received every day for the next 8 years. The NDV therapy had no significant toxic effects, including its lack of neurotoxic effects. Currently, 22 years after the start of the NDV therapy, the patient is well and working. This case is verifiable, as the patient was treated at the Hadassah Medical University, his case was reiterated in the Journal of Clinical Oncology emphasizing the fact that NDV was able to eradicate GBM in this seemingly hopeless situation and therefore merits further evaluation in this and other cancers (J Clin Oncol 31, 2013 (suppl; abstr e13029)).

As of January 1st, 2018, we found no other paper in PubMed that reported on a 20-year history of a grade IV, recurrent glioblastoma patient. Long survivors with GBM may have had relatively localized tumors.

Clearly, complete remission of a high-grade recurrent glioblastoma patient is an “outlier” case, which challenges the dogma of oncologists insisting that recurrent glioblastoma is an incurable disease. However, rare cancer successes should instigate 'exceptional' research efforts (4). In many clinical trials that failed to help enough patients, there were exceptions, rare patients with advanced cancer whose tumors shrank or even disappeared for many months or years. Previous NCI director and Nobel laureate Harold Varmus stated that we can really learn from such “exceptional responders” since they may explain why a drug sometimes has dramatic beneficial effects in certain patients, which in turn could allow more people to benefit from it.

While complete remission of a high-grade recurrent glioblastoma is exceptional, safe and successful treatment of advanced cancer by oncolytic NDV therapy is not (5).

Infection of tumors with oncolytic viruses is not a new type of treatment (6). At least 53 viruses have been tested as anticancer agents, of which 38 exerted antineoplastic effects in either animals or humans. Notwithstanding, relevant experiences obtained in patients with NDV during the last 50 years seems to be forgotten.

For example, the consensus still is that one of the major resistance mechanisms in oncolytic viral therapy results from the ability of the host to rapidly shut down viral replication by neutralizing antibodies. Furthermore, genetic engineering of viruses is required to enhance their oncolytic potential. This implies that non-engineered anti-cancer viruses were, and are, not sufficiently effective.
Actually, one of the first non-engineered anti-cancer viral therapies, the NDV therapy, is still safer and more efficient than any of the engineered oncolytic viruses currently being produced. NDV has a long history as a broad-spectrum oncolytic agent that can destroy tumor cells and stimulate the immune system. NDV is a single-stranded RNA virus, whose natural host is poultry. NDV therapy can be delivered systemically, even in the presence of high levels of neutralizing antibodies (see Figure 1 in Csatary et al, Anticancer Res. 1999;19(1B):635-8.)). Therefore, the virus is capable of targeting tumors in organs that are otherwise difficult to reach.

The first open phase II/B, placebo-controlled, multicenter NDV (MTH-68/H) trial demonstrated that viral treatment of patients with advanced cancers resulted in objective responses in 55% (18 of 33 patients), including 2 cases of complete remission. One-year survival was observed in 22 of 33 patients in the virus-treated group, compared to 4 of 26 patients in the control group. There were no 2-year survivors in the control group but 7 patients in the virus-treated group survived more than 2 years (7).

Several NDV strains (NDV-MTH-68/H, NDV-PV701, NDV-Ulster, NDV-HUJ) have been the subject of systematic clinical studies in patients who had exhausted all conventional cancer treatments (8) (9) (10). NDV-infected patient-derived tumor cell vaccines were also used to achieve long-lasting T cell-mediated systemic anti-tumor immune memory (10).

RWM and TB have no conflict of interest.

References
1. A. Samson et al., Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci. Transl. Med. 10, (2018).
2. J. T. Huse et al., Where are we now? And where are we going? A report from the Accelerate Brain Cancer Cure (ABC2) low-grade glioma research workshop. Neuro Oncol. 16, 173-178 (2014).
3. L. K. Csatary, T. Bakacs, Use of Newcastle disease virus vaccine (MTH-68/H) in a patient with high-grade glioblastoma. JAMA 281, 1588-1589 (1999).
4. J. Kaiser, Biomedicine. Rare cancer successes spawn 'exceptional' research efforts. Science 340, 263 (2013).
5. K. N. Bonab SF, Virotherapy with Newcastle Disease Virus for Cancer Treatment and its Efficacy in Clinical Trials. MOJ Immunol 5, 1 (2017).
6. L. K. Csatary, E. Csatary, R. W. Moss, Re: Scientific interest in Newcastle disease virus is reviving. J Natl. Cancer Inst 92, 493-494 (2000).
7. L. K. Csatary et al., Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect. Prev 17, 619-627 (1993).
8. A. L. Pecora et al., Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J. Clin. Oncol. 20, 2251-2266 (2002).
9. A. I. Freeman et al., Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Mol. Ther. 13, 221-228 (2006).
10. V. Schirrmacher, P. Fournier, Newcastle disease virus: a promising vector for viral therapy, immune therapy, and gene therapy of cancer. Methods Mol. Biol 542, 565-605 (2009).