Phase I trial of systemic administration of Edmonston strain of measles virus genetically engineered to express the sodium iodide symporter in patients with recurrent or refractory multiple myeloma

Abstract

MV-NIS is an Edmonston-lineage oncolytic measles virus expressing the human sodium-iodide symporter--a means for monitoring by noninvasive imaging of radioiodine. Patients with relapsed, refractory myeloma who had explored all other treatment options were eligible for this Phase I trial. Cohort 1 was treated with intravenous MV-NIS, and Cohort 2 received cyclophosphamide two days prior to MV-NIS. Thirty-two patients were treated. Cohort 1 initially enrolled to 4 dose-levels without reaching MTD and subsequently to 2 higher dose-levels when improved virus manufacture technology made it possible. MTD was not reached in Cohort 1, and TCID50 1011 is the dose being used in a Phase II trial of single agent MV-NIS. Grade 3–4 AEs in both cohorts at all dose levels were: neutropenia (n=9); leukocyte count decreased (n=5); thrombocytopenia (n=2); and CD4 lymphocytes decreased, anemia and lymphopenia (each n=1). MV-N RNA sequences were amplified from gargle specimens, blood and urine. 123I scans were positive in 8 patients. One patient achieved a CR; transient drops in serum FLCs were seen in other patients. MV-NIS is capable of replicating before being cleared by the immune system. Oncolytic viruses offer a promising new modality for the targeted infection and destruction of disseminated myeloma.

Oncolytic measles virus therapy enhances tumor antigen-specific T-cell responses in patients with multiple myeloma

“…The complete disease remission seen in one of the patients enrolled in this study was reported earlier [14,17]. This patient had rapid tumor regression accompanied by documented tumor-selective replication of MV-NIS, evidenced by NIS imaging.…”

Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens

“…MV can infect 20 to 70% of memory cells, including B cells, T cells, and plasma cells in the lymphoid tissue and peripheral blood during the first 3 to 10 days after infection (7,10,24). Clinical trials of systemic administration of engineered MV for oncolytic therapy of multiple myeloma also demonstrated efficient entry of MV into the bone marrow and plasma cell infection (36). In wild-type MV infections, lymphocytes undergo rapid proliferation during immune activation (37), and lymphocyte counts (and other immunological markers) return to normal levels within weeks of infection.…”

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…After NIS expressed by OVs takes up the iodide isotope, OV localization can be monitored using single-photon emission computed tomography or positron emission tomography [26,167]. MV-NIS is an oncolytic MV expressing NIS, and it has entered clinical trials for the treatment of multiple myeloma [21].…”

“…Some OVs can cross the blood-brain barrier (BBB) to kill brain tumor cells, such as reovirus [7] and parvovirus H-1 (H-1PV) [8], and OVs can turn "cold" tumors into "hot" tumors, thereby increasing the cellular sensitivity to other immunotherapies [9,10]. To date, many OVs, including DNA viruses, such as adenovirus (AdV) [11,12], vaccinia virus (VACV) [13,14], herpesvirus [15,16], and parvovirus [17] and RNA viruses, such as reovirus [18,19], Newcastle disease virus (NDV) [20], and measles virus (MV) [21] (Table 1) have been evaluated for cancer treatment (Fig. 1).…”