The α-emitter astatine-211 targeted to CD38 can eradicate multiple myeloma in a disseminated disease model.

Autor:	O'Steen S; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA., Comstock ML; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA., Orozco JJ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.; Department of Medicine and., Hamlin DK; Department of Radiation Oncology, University of Washington, Seattle, WA; and., Wilbur DS; Department of Radiation Oncology, University of Washington, Seattle, WA; and., Jones JC; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA., Kenoyer A; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA., Nartea ME; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA., Lin Y; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA., Miller BW; Department of Radiation Oncology, School of Medicine, University of Colorado, Aurora, CO., Gooley TA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA., Tuazon SA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.; Department of Medicine and., Till BG; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.; Department of Medicine and., Gopal AK; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.; Department of Medicine and., Sandmaier BM; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.; Department of Medicine and., Press OW; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.; Department of Medicine and., Green DJ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.; Department of Medicine and.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2019 Oct 10; Vol. 134 (15), pp. 1247-1256.
DOI:	10.1182/blood.2019001250
Abstrakt:	Minimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD-negative to ≤10-5, which is concerning because MRD-negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant subclones. Virtually all MM clones are exquisitely sensitive to radiation, and the α-emitter astatine-211 (211At) deposits prodigious energy within 3 cell diameters, which is ideal for eliminating MRD if effectively targeted. CD38 is a proven MM target, and we conjugated 211At to an anti-CD38 monoclonal antibody to create an 211At-CD38 therapy. When examined in a bulky xenograft model of MM, single-dose 211At-CD38 at 15 to 45 µCi at least doubled median survival of mice relative to untreated controls (P < .003), but no mice achieved complete remission and all died within 75 days. In contrast, in a disseminated disease model designed to reflect low-burden MRD, 3 studies demonstrated that single-dose 211At-CD38 at 24 to 45 µCi produced sustained remission and long-term survival (>150 days) for 50% to 80% of mice, where all untreated mice died in 20 to 55 days (P < .0001). Treatment toxicities were transient and minimal. These data suggest that 211At-CD38 offers the potential to eliminate residual MM cell clones in low-disease-burden settings, including MRD. We are optimistic that, in a planned clinical trial, addition of 211At-CD38 to an autologous stem cell transplant (ASCT) conditioning regimen may improve ASCT outcomes for MM patients. (© 2019 by The American Society of Hematology.)
Databáze:	MEDLINE
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