Remission of disseminated cancer after systemic oncolytic virotherapy

Abstract

MV-NIS is an engineered measles virus that is selectively destructive to myeloma plasma cells and can be monitored by noninvasive radioiodine imaging of NIS gene expression. Two measles-seronegative patients with relapsing drug-refractory myeloma and multiple glucose-avid plasmacytomas were treated by intravenous infusion of 10(11) TCID50 (50% tissue culture infectious dose) infectious units of MV-NIS. Both patients responded to therapy with M protein reduction and resolution of bone marrow plasmacytosis. Further, one patient experienced durable complete remission at all disease sites. Tumor targeting was clearly documented by NIS-mediated radioiodine uptake in virus-infected plasmacytomas. Toxicities resolved within the first week after therapy. Oncolytic viruses offer a promising new modality for the targeted infection and destruction of disseminated cancer.

FIGURE 1

Clinical response to systemically administered MV-NIS. A, Serial free light chain (FLC) measurements in patients 1 and 2 as a surrogate of myeloma tumor burden, increasing at myeloma relapse and decreasing after successful therapy. Asterisks indicate the timing of relevant bone marrow (BM) and positron emission tomography—computed tomography (PET-CT) examinations. B, High-sensitivity 8-color plasma cell (PC) flow cytometry performed on pretherapy BM samples from both patients (left panels) shows CD38- and CD138-positive, CD19-negative monoclonal PCs (λ-restricted in patient 1, κ-restricted in patient 2) with hyperdiploid DNA content. In these same studies performed on BM samples obtained 6 weeks after therapy (right panels), the abnormal PCs are not present. C, Alternate coronal PET-CT sections at the level of the left frontal plasmacytoma in patient 1 before and 7 weeks after MV-NIS therapy. Far right panel shows higher magnification of the middle sections, focusing on the plasmacytoma. Note the pretherapy cerebral compression and altered skin contour that normalize after therapy. ASCT = autologous stem cell transplant; DAPI = 4′,6′-diamidino-2-phenylindole; MV = measles virus; UNL = upper normal limit.

FIGURE 2

Intratumoral propagation of systemically administered MV-NIS. A, Serial single-photon emission computed tomography (SPECT)—computed tomography (CT) images from patient 1 at baseline (d-1) and on days 8 (d8) and 15 (d15) after MV-NIS infusion at the level of the left frontal plasmacytoma. Two adjacent transaxial slices from 6 hours after isotope administration are shown for each time point. There is a small area of increased uptake in the plasmacytoma visible in the lower slice on the day 8 scan (circle). This area of increased uptake is more extensive, and visible in both slices (circles), on the day 15 scan. B, Serial SPECT-CT images from patient 2 at baseline and on days 8, 15, and 28 (d28) after MV-NIS infusion at the level of the inguinal region. Compared with the baseline images, there is greatly increased radioiodine uptake in a deep-seated intramuscular plasmacytoma in the right hemipelvis on day 8 after MV-NIS administration, which is diminishing by day 15 and is back to baseline by day 28 (arrows). On the same transaxial slices, there is moderately increased radioiodine uptake in the large left inguinal lymph node on day 8, which again is diminishing by day 15 and back to baseline by day 28 (arrowheads). C, Anteroposterior fluorodeoxyglucose positron emission tomography (PET)—CT image obtained before MV-NIS administration and the corresponding iodine 123 SPECT-CT images obtained 8 days and 28 days after virus administration. All areas of intense radioiodine uptake (aside from the bladder) in the day 8 SPECT-CT scan are seen to correspond to glucose-avid plasmacytomas in the PET-CT image (circles).